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Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials

Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus... Background: Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival. Methods: We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation). Results: Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months (HR = 0.07; P = 0.0003), 12 months (HR = 0.05, P < 0.0001), and 18 months (HR = 0.11; P = 0.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HR = 0.33; P = 0.0007) and a higher TOI improvement rate (58.1% versus 30.0%; P =0.025). Conclusions: Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint. Trial registration: ClinicalTrials.gov identifier, NCT00769704 (https://clinicaltrials.gov/ct2/show/NCT00769704) October 7, 2008 Keywords: Melanoma, Talimogene laherparepvec, Durable response rate, Patient-reported outcomes * Correspondence: howard.kaufman@rutgers.edu Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 2 of 9 Background (GM-CSF) to subcutaneous GM-CSF, to evaluate whether A growing body of clinical evidence indicates that tra- DRR is associated with measures of clinical benefit, such ditional response criteria may not be sufficient to com- as OS and QoL or treatment-free interval (TFI) after pletely characterize the full spectrum of activities of therapy. Talimogene laherparepvec is thought to mediate current anticancer immunotherapies and/or define the antitumor activity, at least in part, through activation of clinical benefit associated with their use. Although a num- systemic immune responses and initial results from previ- ber of immunotherapies have recently been approved ous clinical trials demonstrated delayed kinetics of re- based, in part, upon tumor responses evaluated by trad- sponse similar to observations from T-cell checkpoint itional response criteria (eg, Response Evaluation Criteria inhibitor trials [8, 15]. DRR, defined as a continuous in Solid Tumors [RECIST] [1, 2] or World Health response (complete response [CR]/partial response [PR]) Organization [WHO] criteria for response [3]), these beginning in the first 12 months of treatment and lasting criteria may not accurately capture the full benefits of 6 months or longer, was the primary endpoint in OPTiM. immunotherapy-based drugs or regimens. In particular, Although results from the OPTiM study have been these measures of response lack a durability dimension, reported previously [15], this analysis was undertaken to and thus therapeutic benefit may be overestimated. Con- further validate the DRR endpoint by determining if DR is versely, because responses may occur after an initial in- associated with other measures of clinical benefit. These crease in tumor burden or appearance of new tumor data have implications for incorporating DRR as a lesions characterized as progressive disease by WHO cri- regulatory endpoint in tumor immunotherapy clinical teria or RECIST [4–11], therapeutic benefit may be under- trial designs. estimated. Consequently, allowing for disease progression before response is critical for evaluation of immunother- apies because initial tumor growth may not always be Methods indicative of treatment failure [4, 11]. Study design Assuming response criteria that allow for progression Study design and patient population for OPTiM have prior to response are used, a conventional analysis is to been previously described [15]. Briefly, eligible patients evaluate duration of response for responders; however, with histologically confirmed, surgically unresectable, no prospective criteria are designated for interpreting stage IIIB/IIIC/IV melanoma that could undergo direct/ the clinical relevance of this information at the patient ultrasound-guided injection of dermal, subcutaneous, or level or for treatment effect in a controlled study. To lymph node melanoma metastases were included. Pa- this end, the endpoint of durable response rate (DRR) tients were randomized 2:1 to receive intralesional tali- has been proposed, which includes standard response mogene laherparepvec or subcutaneous GM-CSF. The criteria and a prospective durability dimension. Although primary endpoint was DRR, defined as the rate of ob- DRR has not been validated as a surrogate endpoint for jective response (CR/PR) by modified WHO criteria last- clinical benefit, anticancer agents have been approved ing ≥6 months continuously and beginning within the based on a demonstrated ability to achieve retrospect- first 12 months of initiating treatment where disease ively defined durable responses (DRs) [12–14]. With progression was allowed prior to onset of response. Key the allowance for progression prior to response, we hy- secondary endpoints included OS, best overall response, pothesized that DRR is an appropriate measure of the onset and duration of response, and time to treatment ability of immunotherapy anticancer agents to mediate failure. Exploratory objectives included evaluation of a clinically meaningful, sustained reduction in tumor patients’ QoL and analysis of the influence of achieving burden that may be associated with measures of clinical a response on OS. benefit such as prolonged overall survival (OS), im- proved quality of life (QoL), and freedom from successive anticancer therapies. This is especially im- Analysis population portant for immunotherapy-based regimens since the Data cutoff for DR and QoL analyses was December kinetics of response may be different when compared 2012, and data cutoff for OS and subsequent therapy to cytotoxic chemotherapy or targeted therapy that me- analyses was February 2013. Data cutoff for duration of diate antitumor activity directly in tumor cells. response per investigator was August 2014 (final anal- For this analysis, we used prospectively collected clinical ysis). A landmark approach was used to limit lead-time data from the OPTiM trial, a randomized phase 3 study bias because the minimum time required to achieve a that compared intralesional talimogene laherparepvec, a DR was 9 months (ie, 3 months to first tumor assess- genetically modified herpes simplex virus (HSV) type-1, ment plus minimum 6 months of response duration). designed to selectively replicate in tumors and produce Analyses excluded patients with a follow-up duration human granulocyte macrophage-colony stimulating factor less than the landmark time. Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 3 of 9 Assessments Melanoma treatments administered after discon- Assessment of durable response in OPTiM has been de- tinuation of talimogene laherparepvec/GM-CSF were scribed previously [15]. Briefly, visible/palpable lesions recorded during the survival follow-up. Subsequent were assessed by clinical evaluation performed on day 1 therapy was defined as any systemic anticancer therapy of each cycle; computed tomography assessments of re- for melanoma after discontinuation of study therapy sponse were performed at baseline and every 12 weeks and was categorized as chemotherapy/targeted agents thereafter. Patients who had a best response of CR/PR or immunotherapy. per modified WHO criteria based on investigator assess- ment or were on therapy ≥9 months were evaluated for Statistical analysis response by a blinded endpoint assessment committee The primary analysis was planned when no further pa- (EAC) [15]. Patients were considered in response if tients had the possibility of meeting the criteria for dur- there was ≥50% reduction in total tumor burden of all able response; the final OS analysis was planned for after measurable lesions compared with baseline or, if any all patients had reached 18 months from their first dose new tumors/lesions had appeared, compared with when of treatment. To mitigate potential for lead-time bias (ie, they were first documented. Disease progression was patients who live long enough to have a DR tend to have considered a >25% increase in total tumor burden or longer survival, irrespective of whether durable re- appearance of new lesions, and clinically relevant dis- sponse prolongs survival), OS for patients who had ease progression was defined as disease progression as- achieved a DR and were alive was compared with OS sociated with a decline in performance status and/or for patients who had not achieved a DR and were alive required alternative therapy. Treatment continued for in a landmark analysis at 9, 12, and 18 months after 24 weeks, irrespective of progression. After 24 weeks, randomization [20]. In this analysis, OS was calculated treatment continued until clinically relevant disease pro- from a landmark time to death; patients who died or gression, intolerability, withdrawal of consent, complete who were censored before the landmark time were ex- remission, lack of response by 12 months, or disappear- cluded from the analysis. Because disease stage and line ance of all injectable lesions (talimogene laherparepvec of therapy were found to be associated with DR and OS only) [15]. After 12 months, patients with stable/respond- in multivariate analyses and because the talimogene ing disease could continue treatment for 6 additional laherparepvec treatment effect on DRR and OS was months. pronounced in patients with stage IIIB/IIIC/IVM1a Quality of life was assessed using a validated melanoma and treatment-naive patients in exploratory Functional Assessment of Cancer Therapy–Biologic subgroup analyses of OPTiM, Cox model hazard ratio Response Modifier (FACT-BRM) questionnaire, which estimates and log-rank tests in landmark analysis were comprises four domains (Physical, Social/Family, Emo- stratified by these factors, accounting for observed tional, and Functional well-being) and two treatment- baseline imbalances (ie, disease stages IIIB/IIIC/IVM1a specific subscales (Additional Concerns: Physical and versus IVM1b/IVM1c, first-line versus second-line or Mental) [16]. The Trial Outcome Index (TOI) is a 27- later therapy). item sum of the scores of the Physical and Functional To further evaluate any potential association between well-being domains and the two treatment-specific achievement of DR and OS, the time when DR was subscales of FACT-BRM that has been shown to be a achieved was also evaluated in a Cox proportional helpful single scale instrument for assessment of QoL in hazards model as a time-dependent covariate for all clinical trials [17, 18]. Changes in QoL were evaluated randomized patients. Treatment-free interval (defined as using the TOI as well as the FACT-BRM Total, FACT- time from the last dose of study therapy to first dose of BRM subdomains, and treatment-specific subscales. The subsequent therapy or censoring in the absence thereof questionnaire was completed before study procedures at end of follow-up) was estimated using the Kaplan- were conducted on day 1 of each treatment cycle (5 Meier method. As with OS, the association between TFI weeks for the first cycle and 4 weeks for subsequent and achieving a DR was evaluated in a landmark analysis treatment cycles) until the end of treatment and at the using a Cox proportional hazards model and log-rank end-of-treatment visit (30 days after last treatment). In test. The TOI analysis set included patients with a base- this analysis, a clinically meaningful improvement in line score (defined as the maximum possible score—5- QoL was defined as a ≥5-point increase from baseline point absolute increase criterion for improvement), ≥1 lasting ≥28 days for the TOI and FACT-BRM Total and post-baseline non-missing score, and tumor assessments a ≥2-point increase for all other domains and Additional for ≥9 months of follow-up. Associations between Concerns [19]. A minimum clinically important differ- FACT-BRM improvement and achievement of DR were ence for TOI of 5 to 7 points has been established for evaluated using an odds ratio stratified by disease stage group changes. and line of therapy in a landmark analysis at 9 months Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 4 of 9 after randomization. Odds ratios for those who achieved Table 1 Baseline Demographics and Clinical Characteristics for Patients Treated with Talimogene Laherparepvec and GM-CSF a DR versus those who did not and P values for TOI improvement were obtained by fitting an exact logistic Characteristics All Patients Patients with Durable (N = 436) Response (N = 51) regression model using DR status as a predictor and Median age (range), years 63 (22–94) 70 (36–91) TOI improvement as response. Statistical significance was evaluated at a nominal two-sided 0.05 significance Sex, n (%) level without multiplicity assessment. Men 250 (57) 31 (61) Women 186 (43) 20 (39) Results Disease substage, n (%) Patients IIIB 34 (8) 10 (20) In total, 436 patients were included in the intent-to-treat IIIC 97 (22) 19 (37) population (295 in the talimogene laherparepvec arm and 141 in the GM-CSF arm). Baseline demographic/clinical IVM1a 118 (27) 13 (26) characteristics for the study population are summarized in IVM1b 90 (21) 3 (6) Table 1 and have been reported previously by arm [15]. At IVM1c 96 (22) 6 (12) the primary analysis, 86 patients in the intent-to-treat Missing 1 (<1) 0 (0) population achieved an OR per EAC and, of these, the OR LDH, n (%) duration did not qualify for a DR for 35 patients but it did ≤ ULN 390 (89) 47 (92) for 51 (talimogene laherparepvec, n = 48; GM-CSF, n =3), 23 of whom had progression before response (all in > ULN 20 (5) 0 (0) the talimogene laherparepvec arm). Among the 86 pa- Line of therapy, n (%) tients with an OR, a similar proportion of DR versus First-line 203 (47) 33 (65) non-DR patients had early stage disease (82% versus Second or greater 233 (53) 18 (35) 74%) and received first-line therapy (65% versus 63%). ECOG performance status, n (%) At the final analysis, 59 patients achieved a DR per 0 306 (70) 41 (80) investigator (talimogene laherparepvec, n = 57; GM-CSF, n = 2; Additional file 1: Figure S1), indicating that re- 1 114 (26) 10 (20) sponses continued to evolve over time. Missing 16 (4) 0 (0) HSV serostatus, n (%) Association between durable response and overall survival Positive 142 (33) 34 (67) Achieving a DR was associated with a statistically signifi- Negative 253 (58) 13 (26) cant improvement in OS in a landmark analysis at 9 Unknown/missing 41 (9) 4 (8) months (HR = 0.07; 95% CI, 0.01–0.48; P = 0.0003; Fig. 1a), at 12 months (HR = 0.05, 95% CI, 0.01–0.33; P < 0.0001; BRAF status, n (%) Fig. 1b), and at 18 months (HR = 0.11; 95% CI, 0.03–0.44; Mutation 69 (16) 5 (10) P = 0.0002; Fig. 1c). Because comparisons of OS and DR Wild-type 68 (16) 6 (12) maybe confounded(eg,bylead-timebias),weemployed Unknown/missing 299 (68) 40 (78) analytical techniques to mitigate against such potential Treatment assignment, n (%) biases. The association between DR and OS remained after Talimogene laherparepvec 295 (68) 48 (94) adjusting for potentially confounding imbalances in disease stage and line of therapy (both were shown to be predictive GM-CSF 141 (32) 3 (6) for treatment effect of talimogene laherparepvec in post DRR durable response rate, ECOG Eastern Cooperative Oncology Group, GM-CSF granulocyte macrophage-colony stimulating factor, HSV herpes hoc exploratory analyses [15]) between those who achieved simplex virus, LDH lactate dehydrogenase, ULN upper limit of normal a DR and those who did not (9 months, HR = 0.07; 95% CI, a Intent-to-treat population Includes one patient with unknown disease stage 0.01–0.54; 12 months, HR = 0.05; 95% CI, 0.01–0.035; 18 4 patients in the talimogene laherparepvec arm were not treated with months, HR = 0.11, [95% CI, 0.03–0.47]; Table 2). Consist- talimogene laherparepvec ent results were obtained when achievement of DR was 11 patients in the GM-CSF arm were not treated with GM-CSF evaluated in a Cox proportional hazards model as a time-dependent covariate among all randomized patients assessments at ≥9 months of follow-up and were in- (HR = 0.08; 95% CI, 0.03–0.26). cluded in the TFI analysis; of these, 50 patients achieved a DR per the EAC (talimogene laherparepvec, Durable response and treatment-free interval n = 47; GM-CSF, n = 3) and 79 patients did not Of the 436 patients included in the intent-to-treat (talimogene laherparepvec, n =65; GM-CSF, n =14). Of population, 129 received study therapy and had tumor the 50 patients with a DR, 11 (22%) were treated with Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 5 of 9 Fig. 1 Kaplan-Meier plots of overall survival in patients who achieved a durable response versus patients who did not achieve a durable response prior to landmark times of 9 months (a), 12 months (b), and 18 months from randomization (c), and treatment-free survival in patients who achieved a durable response versus patients who did not achieve a durable response (d). For landmark analyses, OS was calculated from the landmark time (9, 12, or 18 months after randomization) to death. TFI analysis was limited to treated patients Median months (95% CI) Durable responders (n=22) NE (NE–NE) with tumor assessments ≥9 months. Unadjusted hazard ratios (HR) and Non-durable responders (n=313) 20.2 (16.4–27.9) log-rank P values are shown. DR durable response, NE not evaluable, Hazard ratio: 0.07 (95% CI, 0.01–0.54) OS overall survival, TFI treatment-free interval P value: 0.0003 0 5 10 15 20 25 30 35 Time from landmark time, months Patients at risk: DR: 22 22 21 17 11 5 1 0 Non-DR: 313 252 205 137 84 41 12 0 subsequent systemic anti-melanoma therapy after the end of their assigned treatment with GM-CSF/talimogene laherparepvec (talimogene laherparepvec, n =9; GM-CSF, n = 2). Of 79 patients without a DR, 38 (48%) were treated with subsequent systemic anti-melanoma therapy (talimogene laherparepvec, n = 28; GM-CSF, n =10). Kaplan-Meier plots of freedom from subsequent sys- temic anti-melanoma therapy in patients who achieved a Median months (95% CI) Durable responders (n=36) NE (NE–NE) DR versus patients who did not achieve a DR with Non-durable responders (n=268) 19.9 (14.8–NE) Hazard ratio: 0.05 (95% CI, 0.01–0.35) tumor assessments at ≥9 months, including hazard ra- P value: <0.0001 tio (HR) and log-rank P value, are shown in Fig. 1. DR 05 10 15 20 25 30 35 was associated with a significantly longer median TFI Time from landmark time, months Patients at risk: DR: 36 36 31 23 9 4 1 0 (HR = 0.33; 95% CI, 0.17–0.65; P = 0.0007; Fig. 1d). Non-DR: 268 206 149 95 51 25 3 0 Achieving a DR was also associated with a 27.5% (95% CI, 10.6–44.4) reduced risk of initiating subse- quent systemic therapy at 36 months (DR, 76.5% [95% CI, 61.4–86.2]; no DR, 49.0% [95% CI, 36.9–60.0]). Quality of life Median months (95% CI) Of the 129 patients with tumor assessments at ≥9 Durable responders (n=50) NE (NE–NE) 20 Non-durable responders (n=186) NE (NE–NE) months of follow-up, 117 had QoL data and 103 had Hazard ratio: 0.11 (95% CI, 0.03–0.47) data for the TOI analysis. Overall, achieving a DR was P value: 0.0002 associated with improved scores in the TOI, the FACT- 0 5 10 15 20 25 30 Time from landmark time, months BRM Total, and all FACT-BRM domains and treatment- Patients at risk: DR: 50 40 29 13 2 1 0 Non-DR: 186 125 73 35 15 1 0 specific subscales, except for social well-being (Fig. 2a). Achievement of a DR was associated with a higher TOI improvement rate. Among patients who achieved a DR, 58.1% (25/43) had a clinically meaningful TOI improve- ment, compared with 30.0% (18/60) of patients who did not achieve a DR (P = 0.025; Fig. 2b). In a landmark anal- ysis limited to patients with ≥9 months of follow-up for Events Median months tumor response assessment, the odds ratio for TOI im- n/N (%) (95% CI) Durable responders (n=50) 11/50 (22) NE (NE–NE) provement was 2.8 (95% CI, 1.1–7.0; Table 3). A sensitivity 20 Non-durable responders (n=79) 38/79 (48) 22.2 (5.0–NE) analysis evaluated whether the association was retained Hazard ratio=0.33 (95% CI, 0.17–0.65) P value=0.0007 when TOI improvement required a larger absolute in- 0 4 8 12162024 283236 40444852 5660 crease from baseline and/or longer improvement duration. Months from last dose Patients at risk: Although nominal 0.05 significance was not achieved in DR: 50 43 41 40 39 37 36 35 31 23 16 10 31 00 Non-DR: 79 50 43 34 32 26 21 17 11 8 5 4 2 1 0 0 all cases, it was achieved for a magnitude up to 9 points or a duration up to 4 cycles. In addition, with one exception, odds ratios were greater than 1 for all magnitude and duration combinations (Additional file 1: Table S1). Probability of being treatment-free, % Overall survival, % Overall survival, % Overall survival, % Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 6 of 9 Table 2 Incidence of DR at Each Landmark Time Assessment in OPTiM Patients Treated with Talimogene Laherparepvec and GM-CSF Landmark Time, Months Patients Alive, n DR Achieved, n HR for OS in Patients with DR Adjusted HR for OS in Patients with DR Versus Those Without, HR (95% CI) Versus Those Without HR (95% CI) 9 335 22 0.07 (0.01–0.48) 0.07 (0.01–0.54) 12 304 36 0.05 (0.01–0.33) 0.05 (0.01–0.35) 18 236 50 0.11 (0.03–0.44) 0.11 (0.03–0.47) DR durable response, GM-CSF granulocyte macrophage-colony stimulating factor, HR hazard ratio, ITT intent-to-treat, OS overall survival Analysis was performed in ITT population of OPTiM Adjusted for disease stage (stage IIIB, IIIC, IVM1a versus stage IVM1b, IVM1c) and line of therapy (first-line versus second-line) Discussion Furthermore, patients with a DR have an approximately Data from this analysis of outcomes in the phase 3 two-thirds reduction in the risk of requiring a new therapy OPTiM study indicate that achievement of a DR in and were approximately 3 times more likely to have a clin- patients with unresectable regionally and distantly ically meaningful improvement in QoL. The association advanced melanoma was associated with several inde- with improvement in QoL is particularly notable in the pendent clinical benefits, providing further support for melanoma setting where skin lesions may be regarded as DR as a useful endpoint in patients with melanoma. disfiguring by patients. Taken together, this evidence indi- Achievement of a DR was associated with improved OS in cates that DR is an efficacy endpoint that is associated landmark analyses at 9, 12, and 18 months, lower risk of with other favorable clinical outcomes. subsequent systemic therapy use at 36 months, and im- Since the proposed mechanism of action of talimogene proved QoL at ≥9 months of follow-up. The risk of death laherparepvec includes release of tumor-associated anti- was decreased by approximately 90% for patients with a gens and cell- and damage-associated molecular pattern DR. Similar results were obtained in analyses adjusted for molecules, and local expression of GM-CSF, talimogene imbalances in baseline demographic/clinical characteris- laherparepvec is likely able to recruit and expand tumor tics and in a Cox proportional hazards model that evalu- associated antigen-reactive T cells [21]. This process may ated achievement of DR as a time-dependent covariate. take time, and lesions may continue to grow before Fig. 2 Association of durable response with (a) FACT-BRM domain and subscale improvement and (b) TOI Improvement. Analysis was limited to patients b c with tumor assessments ≥9 months evaluable for improvement. Odds ratio stratified by disease stage and lines of therapy. Only patients followed up for ≥9 months included. DR durable response, FACT-BRM Functional Assessment of Cancer Therapy Biologic Response Modifier, HR hazard ratio, TOI Trial Outcome Index Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 7 of 9 Table 3 TOI Association with Achieving a DR (per Endpoint Other attempts to define alternative clinical trial end- Assessment Committee) points for immunotherapy agents include modifications of Improvement Improvement TOI Improvement Rate, RECIST (such as immune-related response criteria; irRC Magnitude, Points Duration, Cycles Odds Ratio (95% CI) [4]), which are being used to evaluate tumor responses in 5 1 2.8 (1.1–7.0) clinical trials across a variety of tumor types [24]. A benefit 3 2.6 (1.0–6.9) to the use of irRC is that progressive disease prior to treat- ment response is permitted, consistent with the criteria 6 1 3.0 (1.2–7.8) for DR in the OPTiM study. However, like the WHO cri- 3 2.9 (1.1–8.1) teria and RECIST, irRC does not define a meaningful dur- 4 3.1 (1.1–9.1) ation for tumor response. Furthermore, endpoints such as 7 1 3.1 (1.2–8.4) objective response or progression-free survival based on 2 2.8 (1.1–7.6) irRC have not yet been validated as correlates of OS. 3 3.0 (1.0–9.4) Unlike survival endpoints, response indicates a direct biological effect of a therapy on the tumor. Patients can 8 1 3.1 (1.1–8.5) survive for prolonged periods without treatment, but tu- 2 2.8 (1.0–7.8) mors rarely recede or disappear without intervention. DR durable response, TOI Trial Outcome Index To be considered a DR, however, the response must be Intent-to-treat landmark analysis patients with ≥9months’ follow-up evaluable for TOI improvement were included; only odds ratio of TOI improvement rates maintained for a period of at least 6 months. This dur- with corresponding P values <0.05 are shown. Full results are available in ation component may make achieving a DR a more Additional file 1:Material Odds ratio (DR/non-DR) stratified by disease stage (IIIB/IIIC/IVM1a versus descriptive endpoint than others such as objective IVM1b/IVM1c) and line of therapy (first-line versus second-line or later therapy) response, which requires only response confirmation at least 4 weeks after the initial assessment of response. Six months was initially selected as a reasonable duration regression. Furthermore, this process may cause a local because most non-immunotherapy treatments rarely in- inflammatory-like response in lesions, resulting in a period duce responses beyond 6 months in melanoma [25]. The of “pseudo-progression” before response [15, 22]; thus, al- expanded use of DRR for other cancers allows for the ternative measures of clinical response may be needed. selection of the most appropriate duration based on the These observations of progression before response are natural history of the disease and known impact of consistent with the immune-mediated antitumor activity established therapeutic regimens. Thus, by altering the associated with the talimogene laherparepvec mechanism duration of response, DRR can be used in a more flex- of action, and have been reported with other immunother- ible manner for other cancers that may exhibit different apy agents such as ipilimumab [23]. With the allowance natural history and/or have other standard treatments for progression before response, our results demonstrate available that extend survival for variable times. The in- the utility of DR as an appropriate endpoint for oncolytic clusion of the initiation at any time within 12 months of virus clinical trials and for trials involving combination starting treatment allows capturing pseudoprogression, regimens of immunotherapeutic agents. An element of which has been reported in some immunotherapy trials, DR that may be a key to its clinical value is that it incorpo- and permits continued treatment beyond clinically rates a time component: responses must be maintained asymptomatic progression, as has been reported for irRC for ≥6 months continuously and begun within the first 12 proposed for tumor immunotherapy studies [4]. It is also months of initiating treatment. In contrast, the WHO cri- possible that a rate of durable stable disease might repre- teria and RECIST do not make allowance for progression sent an informative endpoint; however, further evalu- before response or define a meaningful minimum dur- ation would be required to validate such an endpoint. ation of response. In a randomized clinical trial of ipilimu- This study had certain limitations. First, these analyses mab in melanoma, a significant improvement in OS was were exploratory and should therefore be interpreted with seen; however, treatment had no impact on progression- caution. Second, although we identified associations be- free survival (PFS) [10]. These results highlight the inher- tween DR and clinical outcomes, causative relationships ent problems in using PFS using conventional response could not be evaluated. For example, although our analysis criteria as a primary endpoint in immunotherapy clinical indicated an association between DR and OS, it is possible trials, and the need for identification of alternative end- that factors other than achievement of DR (eg, imbalances points to accurately assess immunotherapy drugs in early in disease stage and line of therapy, or subsequent ther- phase clinical development where OS may not be a feas- apy) might have influenced the observed outcome. Al- ible endpoint. Our data support the use of DRR as a flex- though endeavors were made to mitigate the potential for ible and appropriate surrogate of OS and other measures confounding by such factors, it is difficult to determine of clinical benefit. how successful they might have been. Additionally, the Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 8 of 9 selection of 6 months as the minimum duration for Authors’ contributions HLK, RHIA, FAC, IP, and MR made substantial contributions to the analysis achievement of a durable response was based on re- and interpretation of the data and contributed to the drafting and revising sponses to cytotoxic chemotherapy agents; this time point of the manuscript. MW, ZZ, and MS made substantial contributions to the was, to an extent, arbitrary. In the OPTiM study, some acquisition of data, analysis and interpretation of data, and contributed to the drafting and revising of the manuscript. All authors read and approved patients had DRs that lasted substantially longer than 6 the final manuscript. months. It is unknown whether the associations found in this analysis would have been observed had the distribu- Ethics approval and consent to participate This was a retrospective exploratory evaluation of outcomes in the OPTiM tion of DR duration been closer to the 6-month minimum. study and, as such, ethical approval was not required to conduct this Finally, it is possible that the associations seen were driven analysis. Clinical outcomes in the primary analysis of the OPTiM have been by the preferential occurrence of complete response reported elsewhere [15]. As previously described, all patients provided their written informed consent to participate in the clinical study and study among patients with DR (of any duration). procedures were conducted in accordance with the ethical principles founded in the Declaration of Helsinki, as well as the demands of the national drug and data protection laws and any other applicable regulatory Conclusions requirements. Approval was obtained from the appropriate regulatory Results from this analysis indicate that the achievement of authorities of each participating country before sites were initiated. The study protocol was approved by an institutional review board (IRB)/independent a DR in patients with unresectable regionally and distantly ethics committee (IEC) at each participating institution, and all patients advanced melanoma was associated with improved clinical provided written informed consent before initiating any study procedures. benefit and QoL. Although causal relationships cannot be Consent for publication determined via these analyses, these findings support the Not applicable. utility of DR as a meaningful trial endpoint when assessing efficacy of immunotherapies for solid tumors. Further con- Competing interests HLK has been a consultant/advisor for BioVex and Amgen; has served as a sideration of durable response rate as a clinical endpoint in consultant for EMD Serono, Merck, Prometheus, and Sanofi; receives cancer immunotherapy trials is also warranted and may research funding from Amgen Inc., Bristol-Myers Squibb, EMD Serono, Merck, allow for improved selection of promising agents for later Prometheus, and Viralytics; has received compensation from Compass Therapeutics; and serves on a speaker’s bureau for Merck and returns all phase clinical development. honoraria to Rutgers University. RHIA has received honoraria from Amgen. FAC has received research funding from Amgen, Bristol-Myers Squibb, Novartis, and Morphotek; and has been a consultant to Amgen. IP has been a steering Additional file committee member and advisory board member for Amgen. MR has received honoraria from, been an advisory board member, and been a paid consultant Additional file 1: Table S1. TOI Improvement Rate Association with to Merck, Provectus, GSK, and Amgen; and has received honoraria from Merck, Achievement of a DR (per EAC). Figure S1. Talimogene laherparepvec Provectus, GSK, and Amgen. MW, ZZ, and MS are employees of and stock Duration of Response (per Investigator). As of the final analysis 93 of 295 holders in Amgen Inc. patients (31.5%) randomized to talimogene laherparepvec had an overall response per investigator assessment (complete response, n = 50; partial Publisher’sNote response, n = 43) and 57 patients (19.3%) had a durable response. Springer Nature remains neutral with regard to jurisdictional claims in (ZIP 1510 kb) published maps and institutional affiliations. Author details Abbreviations Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New CR: Complete response; DR: Durable response; DRR: Durable response rate; Brunswick, NJ 08901, USA. Huntsman Cancer Institute, University of Utah, EAC: Endpoint assessment committee; FACT-BRM: Functional Assessment of 1950 Circle of Hope Drive, Salt Lake City, UT 84112, USA. The University of Cancer Therapy-Biologic Response Modifier; GM-CSF: Granulocyte North Carolina Chapel Hill, 170 Manning Drive, Box 7305, Chapel Hill, NC macrophage-colony stimulating factor; HR: Hazard ratio; HSV: Herpes simplex 27599, USA. Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA virus; irRC: Immune-related response criteria; OS: Overall survival; 91320, USA. Department of Medicine, Roswell Park Cancer Institute, Elm and PFS: Progression-free survival; PR: Partial response; QoL: Quality of life; Carlton Streets, Buffalo, NY 14263, USA. MD Anderson Cancer Center, 1515 RECIST: Response Evaluation Criteria in Solid Tumors; TFI: Treatment-free Holcombe Blvd, Houston, TX 77030, USA. interval; TOI: Trial outcome index; WHO: World Health Organization Received: 4 May 2017 Accepted: 14 August 2017 Acknowledgments The authors thank Jennifer Gansert, MD, PhD (Amgen Inc.), for contribution to data interpretation, and Meghan Johnson, PhD (Complete Healthcare References Communications, LLC, West Chester, PA), for medical writing assistance in the 1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey preparation of this manuscript; their work was funded by Amgen Inc. We also J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, thank the patients and families who participated in the clinical trial. Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47. 2. 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Analysis of survival by tumor response � Inclusion in PubMed and all major indexing services and other comparisons of time-to-event by outcome variables. J Clin Oncol. � Maximum visibility for your research 2008;26:3913–5. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal for ImmunoTherapy of Cancer Springer Journals

Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials

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Springer Journals
Copyright
Copyright © 2017 by The Author(s).
Subject
Medicine & Public Health; Oncology; Immunology
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2051-1426
DOI
10.1186/s40425-017-0276-8
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28923101
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Abstract

Background: Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival. Methods: We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation). Results: Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months (HR = 0.07; P = 0.0003), 12 months (HR = 0.05, P < 0.0001), and 18 months (HR = 0.11; P = 0.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HR = 0.33; P = 0.0007) and a higher TOI improvement rate (58.1% versus 30.0%; P =0.025). Conclusions: Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint. Trial registration: ClinicalTrials.gov identifier, NCT00769704 (https://clinicaltrials.gov/ct2/show/NCT00769704) October 7, 2008 Keywords: Melanoma, Talimogene laherparepvec, Durable response rate, Patient-reported outcomes * Correspondence: howard.kaufman@rutgers.edu Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 2 of 9 Background (GM-CSF) to subcutaneous GM-CSF, to evaluate whether A growing body of clinical evidence indicates that tra- DRR is associated with measures of clinical benefit, such ditional response criteria may not be sufficient to com- as OS and QoL or treatment-free interval (TFI) after pletely characterize the full spectrum of activities of therapy. Talimogene laherparepvec is thought to mediate current anticancer immunotherapies and/or define the antitumor activity, at least in part, through activation of clinical benefit associated with their use. Although a num- systemic immune responses and initial results from previ- ber of immunotherapies have recently been approved ous clinical trials demonstrated delayed kinetics of re- based, in part, upon tumor responses evaluated by trad- sponse similar to observations from T-cell checkpoint itional response criteria (eg, Response Evaluation Criteria inhibitor trials [8, 15]. DRR, defined as a continuous in Solid Tumors [RECIST] [1, 2] or World Health response (complete response [CR]/partial response [PR]) Organization [WHO] criteria for response [3]), these beginning in the first 12 months of treatment and lasting criteria may not accurately capture the full benefits of 6 months or longer, was the primary endpoint in OPTiM. immunotherapy-based drugs or regimens. In particular, Although results from the OPTiM study have been these measures of response lack a durability dimension, reported previously [15], this analysis was undertaken to and thus therapeutic benefit may be overestimated. Con- further validate the DRR endpoint by determining if DR is versely, because responses may occur after an initial in- associated with other measures of clinical benefit. These crease in tumor burden or appearance of new tumor data have implications for incorporating DRR as a lesions characterized as progressive disease by WHO cri- regulatory endpoint in tumor immunotherapy clinical teria or RECIST [4–11], therapeutic benefit may be under- trial designs. estimated. Consequently, allowing for disease progression before response is critical for evaluation of immunother- apies because initial tumor growth may not always be Methods indicative of treatment failure [4, 11]. Study design Assuming response criteria that allow for progression Study design and patient population for OPTiM have prior to response are used, a conventional analysis is to been previously described [15]. Briefly, eligible patients evaluate duration of response for responders; however, with histologically confirmed, surgically unresectable, no prospective criteria are designated for interpreting stage IIIB/IIIC/IV melanoma that could undergo direct/ the clinical relevance of this information at the patient ultrasound-guided injection of dermal, subcutaneous, or level or for treatment effect in a controlled study. To lymph node melanoma metastases were included. Pa- this end, the endpoint of durable response rate (DRR) tients were randomized 2:1 to receive intralesional tali- has been proposed, which includes standard response mogene laherparepvec or subcutaneous GM-CSF. The criteria and a prospective durability dimension. Although primary endpoint was DRR, defined as the rate of ob- DRR has not been validated as a surrogate endpoint for jective response (CR/PR) by modified WHO criteria last- clinical benefit, anticancer agents have been approved ing ≥6 months continuously and beginning within the based on a demonstrated ability to achieve retrospect- first 12 months of initiating treatment where disease ively defined durable responses (DRs) [12–14]. With progression was allowed prior to onset of response. Key the allowance for progression prior to response, we hy- secondary endpoints included OS, best overall response, pothesized that DRR is an appropriate measure of the onset and duration of response, and time to treatment ability of immunotherapy anticancer agents to mediate failure. Exploratory objectives included evaluation of a clinically meaningful, sustained reduction in tumor patients’ QoL and analysis of the influence of achieving burden that may be associated with measures of clinical a response on OS. benefit such as prolonged overall survival (OS), im- proved quality of life (QoL), and freedom from successive anticancer therapies. This is especially im- Analysis population portant for immunotherapy-based regimens since the Data cutoff for DR and QoL analyses was December kinetics of response may be different when compared 2012, and data cutoff for OS and subsequent therapy to cytotoxic chemotherapy or targeted therapy that me- analyses was February 2013. Data cutoff for duration of diate antitumor activity directly in tumor cells. response per investigator was August 2014 (final anal- For this analysis, we used prospectively collected clinical ysis). A landmark approach was used to limit lead-time data from the OPTiM trial, a randomized phase 3 study bias because the minimum time required to achieve a that compared intralesional talimogene laherparepvec, a DR was 9 months (ie, 3 months to first tumor assess- genetically modified herpes simplex virus (HSV) type-1, ment plus minimum 6 months of response duration). designed to selectively replicate in tumors and produce Analyses excluded patients with a follow-up duration human granulocyte macrophage-colony stimulating factor less than the landmark time. Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 3 of 9 Assessments Melanoma treatments administered after discon- Assessment of durable response in OPTiM has been de- tinuation of talimogene laherparepvec/GM-CSF were scribed previously [15]. Briefly, visible/palpable lesions recorded during the survival follow-up. Subsequent were assessed by clinical evaluation performed on day 1 therapy was defined as any systemic anticancer therapy of each cycle; computed tomography assessments of re- for melanoma after discontinuation of study therapy sponse were performed at baseline and every 12 weeks and was categorized as chemotherapy/targeted agents thereafter. Patients who had a best response of CR/PR or immunotherapy. per modified WHO criteria based on investigator assess- ment or were on therapy ≥9 months were evaluated for Statistical analysis response by a blinded endpoint assessment committee The primary analysis was planned when no further pa- (EAC) [15]. Patients were considered in response if tients had the possibility of meeting the criteria for dur- there was ≥50% reduction in total tumor burden of all able response; the final OS analysis was planned for after measurable lesions compared with baseline or, if any all patients had reached 18 months from their first dose new tumors/lesions had appeared, compared with when of treatment. To mitigate potential for lead-time bias (ie, they were first documented. Disease progression was patients who live long enough to have a DR tend to have considered a >25% increase in total tumor burden or longer survival, irrespective of whether durable re- appearance of new lesions, and clinically relevant dis- sponse prolongs survival), OS for patients who had ease progression was defined as disease progression as- achieved a DR and were alive was compared with OS sociated with a decline in performance status and/or for patients who had not achieved a DR and were alive required alternative therapy. Treatment continued for in a landmark analysis at 9, 12, and 18 months after 24 weeks, irrespective of progression. After 24 weeks, randomization [20]. In this analysis, OS was calculated treatment continued until clinically relevant disease pro- from a landmark time to death; patients who died or gression, intolerability, withdrawal of consent, complete who were censored before the landmark time were ex- remission, lack of response by 12 months, or disappear- cluded from the analysis. Because disease stage and line ance of all injectable lesions (talimogene laherparepvec of therapy were found to be associated with DR and OS only) [15]. After 12 months, patients with stable/respond- in multivariate analyses and because the talimogene ing disease could continue treatment for 6 additional laherparepvec treatment effect on DRR and OS was months. pronounced in patients with stage IIIB/IIIC/IVM1a Quality of life was assessed using a validated melanoma and treatment-naive patients in exploratory Functional Assessment of Cancer Therapy–Biologic subgroup analyses of OPTiM, Cox model hazard ratio Response Modifier (FACT-BRM) questionnaire, which estimates and log-rank tests in landmark analysis were comprises four domains (Physical, Social/Family, Emo- stratified by these factors, accounting for observed tional, and Functional well-being) and two treatment- baseline imbalances (ie, disease stages IIIB/IIIC/IVM1a specific subscales (Additional Concerns: Physical and versus IVM1b/IVM1c, first-line versus second-line or Mental) [16]. The Trial Outcome Index (TOI) is a 27- later therapy). item sum of the scores of the Physical and Functional To further evaluate any potential association between well-being domains and the two treatment-specific achievement of DR and OS, the time when DR was subscales of FACT-BRM that has been shown to be a achieved was also evaluated in a Cox proportional helpful single scale instrument for assessment of QoL in hazards model as a time-dependent covariate for all clinical trials [17, 18]. Changes in QoL were evaluated randomized patients. Treatment-free interval (defined as using the TOI as well as the FACT-BRM Total, FACT- time from the last dose of study therapy to first dose of BRM subdomains, and treatment-specific subscales. The subsequent therapy or censoring in the absence thereof questionnaire was completed before study procedures at end of follow-up) was estimated using the Kaplan- were conducted on day 1 of each treatment cycle (5 Meier method. As with OS, the association between TFI weeks for the first cycle and 4 weeks for subsequent and achieving a DR was evaluated in a landmark analysis treatment cycles) until the end of treatment and at the using a Cox proportional hazards model and log-rank end-of-treatment visit (30 days after last treatment). In test. The TOI analysis set included patients with a base- this analysis, a clinically meaningful improvement in line score (defined as the maximum possible score—5- QoL was defined as a ≥5-point increase from baseline point absolute increase criterion for improvement), ≥1 lasting ≥28 days for the TOI and FACT-BRM Total and post-baseline non-missing score, and tumor assessments a ≥2-point increase for all other domains and Additional for ≥9 months of follow-up. Associations between Concerns [19]. A minimum clinically important differ- FACT-BRM improvement and achievement of DR were ence for TOI of 5 to 7 points has been established for evaluated using an odds ratio stratified by disease stage group changes. and line of therapy in a landmark analysis at 9 months Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 4 of 9 after randomization. Odds ratios for those who achieved Table 1 Baseline Demographics and Clinical Characteristics for Patients Treated with Talimogene Laherparepvec and GM-CSF a DR versus those who did not and P values for TOI improvement were obtained by fitting an exact logistic Characteristics All Patients Patients with Durable (N = 436) Response (N = 51) regression model using DR status as a predictor and Median age (range), years 63 (22–94) 70 (36–91) TOI improvement as response. Statistical significance was evaluated at a nominal two-sided 0.05 significance Sex, n (%) level without multiplicity assessment. Men 250 (57) 31 (61) Women 186 (43) 20 (39) Results Disease substage, n (%) Patients IIIB 34 (8) 10 (20) In total, 436 patients were included in the intent-to-treat IIIC 97 (22) 19 (37) population (295 in the talimogene laherparepvec arm and 141 in the GM-CSF arm). Baseline demographic/clinical IVM1a 118 (27) 13 (26) characteristics for the study population are summarized in IVM1b 90 (21) 3 (6) Table 1 and have been reported previously by arm [15]. At IVM1c 96 (22) 6 (12) the primary analysis, 86 patients in the intent-to-treat Missing 1 (<1) 0 (0) population achieved an OR per EAC and, of these, the OR LDH, n (%) duration did not qualify for a DR for 35 patients but it did ≤ ULN 390 (89) 47 (92) for 51 (talimogene laherparepvec, n = 48; GM-CSF, n =3), 23 of whom had progression before response (all in > ULN 20 (5) 0 (0) the talimogene laherparepvec arm). Among the 86 pa- Line of therapy, n (%) tients with an OR, a similar proportion of DR versus First-line 203 (47) 33 (65) non-DR patients had early stage disease (82% versus Second or greater 233 (53) 18 (35) 74%) and received first-line therapy (65% versus 63%). ECOG performance status, n (%) At the final analysis, 59 patients achieved a DR per 0 306 (70) 41 (80) investigator (talimogene laherparepvec, n = 57; GM-CSF, n = 2; Additional file 1: Figure S1), indicating that re- 1 114 (26) 10 (20) sponses continued to evolve over time. Missing 16 (4) 0 (0) HSV serostatus, n (%) Association between durable response and overall survival Positive 142 (33) 34 (67) Achieving a DR was associated with a statistically signifi- Negative 253 (58) 13 (26) cant improvement in OS in a landmark analysis at 9 Unknown/missing 41 (9) 4 (8) months (HR = 0.07; 95% CI, 0.01–0.48; P = 0.0003; Fig. 1a), at 12 months (HR = 0.05, 95% CI, 0.01–0.33; P < 0.0001; BRAF status, n (%) Fig. 1b), and at 18 months (HR = 0.11; 95% CI, 0.03–0.44; Mutation 69 (16) 5 (10) P = 0.0002; Fig. 1c). Because comparisons of OS and DR Wild-type 68 (16) 6 (12) maybe confounded(eg,bylead-timebias),weemployed Unknown/missing 299 (68) 40 (78) analytical techniques to mitigate against such potential Treatment assignment, n (%) biases. The association between DR and OS remained after Talimogene laherparepvec 295 (68) 48 (94) adjusting for potentially confounding imbalances in disease stage and line of therapy (both were shown to be predictive GM-CSF 141 (32) 3 (6) for treatment effect of talimogene laherparepvec in post DRR durable response rate, ECOG Eastern Cooperative Oncology Group, GM-CSF granulocyte macrophage-colony stimulating factor, HSV herpes hoc exploratory analyses [15]) between those who achieved simplex virus, LDH lactate dehydrogenase, ULN upper limit of normal a DR and those who did not (9 months, HR = 0.07; 95% CI, a Intent-to-treat population Includes one patient with unknown disease stage 0.01–0.54; 12 months, HR = 0.05; 95% CI, 0.01–0.035; 18 4 patients in the talimogene laherparepvec arm were not treated with months, HR = 0.11, [95% CI, 0.03–0.47]; Table 2). Consist- talimogene laherparepvec ent results were obtained when achievement of DR was 11 patients in the GM-CSF arm were not treated with GM-CSF evaluated in a Cox proportional hazards model as a time-dependent covariate among all randomized patients assessments at ≥9 months of follow-up and were in- (HR = 0.08; 95% CI, 0.03–0.26). cluded in the TFI analysis; of these, 50 patients achieved a DR per the EAC (talimogene laherparepvec, Durable response and treatment-free interval n = 47; GM-CSF, n = 3) and 79 patients did not Of the 436 patients included in the intent-to-treat (talimogene laherparepvec, n =65; GM-CSF, n =14). Of population, 129 received study therapy and had tumor the 50 patients with a DR, 11 (22%) were treated with Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 5 of 9 Fig. 1 Kaplan-Meier plots of overall survival in patients who achieved a durable response versus patients who did not achieve a durable response prior to landmark times of 9 months (a), 12 months (b), and 18 months from randomization (c), and treatment-free survival in patients who achieved a durable response versus patients who did not achieve a durable response (d). For landmark analyses, OS was calculated from the landmark time (9, 12, or 18 months after randomization) to death. TFI analysis was limited to treated patients Median months (95% CI) Durable responders (n=22) NE (NE–NE) with tumor assessments ≥9 months. Unadjusted hazard ratios (HR) and Non-durable responders (n=313) 20.2 (16.4–27.9) log-rank P values are shown. DR durable response, NE not evaluable, Hazard ratio: 0.07 (95% CI, 0.01–0.54) OS overall survival, TFI treatment-free interval P value: 0.0003 0 5 10 15 20 25 30 35 Time from landmark time, months Patients at risk: DR: 22 22 21 17 11 5 1 0 Non-DR: 313 252 205 137 84 41 12 0 subsequent systemic anti-melanoma therapy after the end of their assigned treatment with GM-CSF/talimogene laherparepvec (talimogene laherparepvec, n =9; GM-CSF, n = 2). Of 79 patients without a DR, 38 (48%) were treated with subsequent systemic anti-melanoma therapy (talimogene laherparepvec, n = 28; GM-CSF, n =10). Kaplan-Meier plots of freedom from subsequent sys- temic anti-melanoma therapy in patients who achieved a Median months (95% CI) Durable responders (n=36) NE (NE–NE) DR versus patients who did not achieve a DR with Non-durable responders (n=268) 19.9 (14.8–NE) Hazard ratio: 0.05 (95% CI, 0.01–0.35) tumor assessments at ≥9 months, including hazard ra- P value: <0.0001 tio (HR) and log-rank P value, are shown in Fig. 1. DR 05 10 15 20 25 30 35 was associated with a significantly longer median TFI Time from landmark time, months Patients at risk: DR: 36 36 31 23 9 4 1 0 (HR = 0.33; 95% CI, 0.17–0.65; P = 0.0007; Fig. 1d). Non-DR: 268 206 149 95 51 25 3 0 Achieving a DR was also associated with a 27.5% (95% CI, 10.6–44.4) reduced risk of initiating subse- quent systemic therapy at 36 months (DR, 76.5% [95% CI, 61.4–86.2]; no DR, 49.0% [95% CI, 36.9–60.0]). Quality of life Median months (95% CI) Of the 129 patients with tumor assessments at ≥9 Durable responders (n=50) NE (NE–NE) 20 Non-durable responders (n=186) NE (NE–NE) months of follow-up, 117 had QoL data and 103 had Hazard ratio: 0.11 (95% CI, 0.03–0.47) data for the TOI analysis. Overall, achieving a DR was P value: 0.0002 associated with improved scores in the TOI, the FACT- 0 5 10 15 20 25 30 Time from landmark time, months BRM Total, and all FACT-BRM domains and treatment- Patients at risk: DR: 50 40 29 13 2 1 0 Non-DR: 186 125 73 35 15 1 0 specific subscales, except for social well-being (Fig. 2a). Achievement of a DR was associated with a higher TOI improvement rate. Among patients who achieved a DR, 58.1% (25/43) had a clinically meaningful TOI improve- ment, compared with 30.0% (18/60) of patients who did not achieve a DR (P = 0.025; Fig. 2b). In a landmark anal- ysis limited to patients with ≥9 months of follow-up for Events Median months tumor response assessment, the odds ratio for TOI im- n/N (%) (95% CI) Durable responders (n=50) 11/50 (22) NE (NE–NE) provement was 2.8 (95% CI, 1.1–7.0; Table 3). A sensitivity 20 Non-durable responders (n=79) 38/79 (48) 22.2 (5.0–NE) analysis evaluated whether the association was retained Hazard ratio=0.33 (95% CI, 0.17–0.65) P value=0.0007 when TOI improvement required a larger absolute in- 0 4 8 12162024 283236 40444852 5660 crease from baseline and/or longer improvement duration. Months from last dose Patients at risk: Although nominal 0.05 significance was not achieved in DR: 50 43 41 40 39 37 36 35 31 23 16 10 31 00 Non-DR: 79 50 43 34 32 26 21 17 11 8 5 4 2 1 0 0 all cases, it was achieved for a magnitude up to 9 points or a duration up to 4 cycles. In addition, with one exception, odds ratios were greater than 1 for all magnitude and duration combinations (Additional file 1: Table S1). Probability of being treatment-free, % Overall survival, % Overall survival, % Overall survival, % Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 6 of 9 Table 2 Incidence of DR at Each Landmark Time Assessment in OPTiM Patients Treated with Talimogene Laherparepvec and GM-CSF Landmark Time, Months Patients Alive, n DR Achieved, n HR for OS in Patients with DR Adjusted HR for OS in Patients with DR Versus Those Without, HR (95% CI) Versus Those Without HR (95% CI) 9 335 22 0.07 (0.01–0.48) 0.07 (0.01–0.54) 12 304 36 0.05 (0.01–0.33) 0.05 (0.01–0.35) 18 236 50 0.11 (0.03–0.44) 0.11 (0.03–0.47) DR durable response, GM-CSF granulocyte macrophage-colony stimulating factor, HR hazard ratio, ITT intent-to-treat, OS overall survival Analysis was performed in ITT population of OPTiM Adjusted for disease stage (stage IIIB, IIIC, IVM1a versus stage IVM1b, IVM1c) and line of therapy (first-line versus second-line) Discussion Furthermore, patients with a DR have an approximately Data from this analysis of outcomes in the phase 3 two-thirds reduction in the risk of requiring a new therapy OPTiM study indicate that achievement of a DR in and were approximately 3 times more likely to have a clin- patients with unresectable regionally and distantly ically meaningful improvement in QoL. The association advanced melanoma was associated with several inde- with improvement in QoL is particularly notable in the pendent clinical benefits, providing further support for melanoma setting where skin lesions may be regarded as DR as a useful endpoint in patients with melanoma. disfiguring by patients. Taken together, this evidence indi- Achievement of a DR was associated with improved OS in cates that DR is an efficacy endpoint that is associated landmark analyses at 9, 12, and 18 months, lower risk of with other favorable clinical outcomes. subsequent systemic therapy use at 36 months, and im- Since the proposed mechanism of action of talimogene proved QoL at ≥9 months of follow-up. The risk of death laherparepvec includes release of tumor-associated anti- was decreased by approximately 90% for patients with a gens and cell- and damage-associated molecular pattern DR. Similar results were obtained in analyses adjusted for molecules, and local expression of GM-CSF, talimogene imbalances in baseline demographic/clinical characteris- laherparepvec is likely able to recruit and expand tumor tics and in a Cox proportional hazards model that evalu- associated antigen-reactive T cells [21]. This process may ated achievement of DR as a time-dependent covariate. take time, and lesions may continue to grow before Fig. 2 Association of durable response with (a) FACT-BRM domain and subscale improvement and (b) TOI Improvement. Analysis was limited to patients b c with tumor assessments ≥9 months evaluable for improvement. Odds ratio stratified by disease stage and lines of therapy. Only patients followed up for ≥9 months included. DR durable response, FACT-BRM Functional Assessment of Cancer Therapy Biologic Response Modifier, HR hazard ratio, TOI Trial Outcome Index Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 7 of 9 Table 3 TOI Association with Achieving a DR (per Endpoint Other attempts to define alternative clinical trial end- Assessment Committee) points for immunotherapy agents include modifications of Improvement Improvement TOI Improvement Rate, RECIST (such as immune-related response criteria; irRC Magnitude, Points Duration, Cycles Odds Ratio (95% CI) [4]), which are being used to evaluate tumor responses in 5 1 2.8 (1.1–7.0) clinical trials across a variety of tumor types [24]. A benefit 3 2.6 (1.0–6.9) to the use of irRC is that progressive disease prior to treat- ment response is permitted, consistent with the criteria 6 1 3.0 (1.2–7.8) for DR in the OPTiM study. However, like the WHO cri- 3 2.9 (1.1–8.1) teria and RECIST, irRC does not define a meaningful dur- 4 3.1 (1.1–9.1) ation for tumor response. Furthermore, endpoints such as 7 1 3.1 (1.2–8.4) objective response or progression-free survival based on 2 2.8 (1.1–7.6) irRC have not yet been validated as correlates of OS. 3 3.0 (1.0–9.4) Unlike survival endpoints, response indicates a direct biological effect of a therapy on the tumor. Patients can 8 1 3.1 (1.1–8.5) survive for prolonged periods without treatment, but tu- 2 2.8 (1.0–7.8) mors rarely recede or disappear without intervention. DR durable response, TOI Trial Outcome Index To be considered a DR, however, the response must be Intent-to-treat landmark analysis patients with ≥9months’ follow-up evaluable for TOI improvement were included; only odds ratio of TOI improvement rates maintained for a period of at least 6 months. This dur- with corresponding P values <0.05 are shown. Full results are available in ation component may make achieving a DR a more Additional file 1:Material Odds ratio (DR/non-DR) stratified by disease stage (IIIB/IIIC/IVM1a versus descriptive endpoint than others such as objective IVM1b/IVM1c) and line of therapy (first-line versus second-line or later therapy) response, which requires only response confirmation at least 4 weeks after the initial assessment of response. Six months was initially selected as a reasonable duration regression. Furthermore, this process may cause a local because most non-immunotherapy treatments rarely in- inflammatory-like response in lesions, resulting in a period duce responses beyond 6 months in melanoma [25]. The of “pseudo-progression” before response [15, 22]; thus, al- expanded use of DRR for other cancers allows for the ternative measures of clinical response may be needed. selection of the most appropriate duration based on the These observations of progression before response are natural history of the disease and known impact of consistent with the immune-mediated antitumor activity established therapeutic regimens. Thus, by altering the associated with the talimogene laherparepvec mechanism duration of response, DRR can be used in a more flex- of action, and have been reported with other immunother- ible manner for other cancers that may exhibit different apy agents such as ipilimumab [23]. With the allowance natural history and/or have other standard treatments for progression before response, our results demonstrate available that extend survival for variable times. The in- the utility of DR as an appropriate endpoint for oncolytic clusion of the initiation at any time within 12 months of virus clinical trials and for trials involving combination starting treatment allows capturing pseudoprogression, regimens of immunotherapeutic agents. An element of which has been reported in some immunotherapy trials, DR that may be a key to its clinical value is that it incorpo- and permits continued treatment beyond clinically rates a time component: responses must be maintained asymptomatic progression, as has been reported for irRC for ≥6 months continuously and begun within the first 12 proposed for tumor immunotherapy studies [4]. It is also months of initiating treatment. In contrast, the WHO cri- possible that a rate of durable stable disease might repre- teria and RECIST do not make allowance for progression sent an informative endpoint; however, further evalu- before response or define a meaningful minimum dur- ation would be required to validate such an endpoint. ation of response. In a randomized clinical trial of ipilimu- This study had certain limitations. First, these analyses mab in melanoma, a significant improvement in OS was were exploratory and should therefore be interpreted with seen; however, treatment had no impact on progression- caution. Second, although we identified associations be- free survival (PFS) [10]. These results highlight the inher- tween DR and clinical outcomes, causative relationships ent problems in using PFS using conventional response could not be evaluated. For example, although our analysis criteria as a primary endpoint in immunotherapy clinical indicated an association between DR and OS, it is possible trials, and the need for identification of alternative end- that factors other than achievement of DR (eg, imbalances points to accurately assess immunotherapy drugs in early in disease stage and line of therapy, or subsequent ther- phase clinical development where OS may not be a feas- apy) might have influenced the observed outcome. Al- ible endpoint. Our data support the use of DRR as a flex- though endeavors were made to mitigate the potential for ible and appropriate surrogate of OS and other measures confounding by such factors, it is difficult to determine of clinical benefit. how successful they might have been. Additionally, the Kaufman et al. Journal for ImmunoTherapy of Cancer (2017) 5:72 Page 8 of 9 selection of 6 months as the minimum duration for Authors’ contributions HLK, RHIA, FAC, IP, and MR made substantial contributions to the analysis achievement of a durable response was based on re- and interpretation of the data and contributed to the drafting and revising sponses to cytotoxic chemotherapy agents; this time point of the manuscript. MW, ZZ, and MS made substantial contributions to the was, to an extent, arbitrary. In the OPTiM study, some acquisition of data, analysis and interpretation of data, and contributed to the drafting and revising of the manuscript. All authors read and approved patients had DRs that lasted substantially longer than 6 the final manuscript. months. It is unknown whether the associations found in this analysis would have been observed had the distribu- Ethics approval and consent to participate This was a retrospective exploratory evaluation of outcomes in the OPTiM tion of DR duration been closer to the 6-month minimum. study and, as such, ethical approval was not required to conduct this Finally, it is possible that the associations seen were driven analysis. Clinical outcomes in the primary analysis of the OPTiM have been by the preferential occurrence of complete response reported elsewhere [15]. As previously described, all patients provided their written informed consent to participate in the clinical study and study among patients with DR (of any duration). procedures were conducted in accordance with the ethical principles founded in the Declaration of Helsinki, as well as the demands of the national drug and data protection laws and any other applicable regulatory Conclusions requirements. Approval was obtained from the appropriate regulatory Results from this analysis indicate that the achievement of authorities of each participating country before sites were initiated. The study protocol was approved by an institutional review board (IRB)/independent a DR in patients with unresectable regionally and distantly ethics committee (IEC) at each participating institution, and all patients advanced melanoma was associated with improved clinical provided written informed consent before initiating any study procedures. benefit and QoL. Although causal relationships cannot be Consent for publication determined via these analyses, these findings support the Not applicable. utility of DR as a meaningful trial endpoint when assessing efficacy of immunotherapies for solid tumors. Further con- Competing interests HLK has been a consultant/advisor for BioVex and Amgen; has served as a sideration of durable response rate as a clinical endpoint in consultant for EMD Serono, Merck, Prometheus, and Sanofi; receives cancer immunotherapy trials is also warranted and may research funding from Amgen Inc., Bristol-Myers Squibb, EMD Serono, Merck, allow for improved selection of promising agents for later Prometheus, and Viralytics; has received compensation from Compass Therapeutics; and serves on a speaker’s bureau for Merck and returns all phase clinical development. honoraria to Rutgers University. RHIA has received honoraria from Amgen. FAC has received research funding from Amgen, Bristol-Myers Squibb, Novartis, and Morphotek; and has been a consultant to Amgen. IP has been a steering Additional file committee member and advisory board member for Amgen. MR has received honoraria from, been an advisory board member, and been a paid consultant Additional file 1: Table S1. TOI Improvement Rate Association with to Merck, Provectus, GSK, and Amgen; and has received honoraria from Merck, Achievement of a DR (per EAC). Figure S1. Talimogene laherparepvec Provectus, GSK, and Amgen. MW, ZZ, and MS are employees of and stock Duration of Response (per Investigator). As of the final analysis 93 of 295 holders in Amgen Inc. patients (31.5%) randomized to talimogene laherparepvec had an overall response per investigator assessment (complete response, n = 50; partial Publisher’sNote response, n = 43) and 57 patients (19.3%) had a durable response. Springer Nature remains neutral with regard to jurisdictional claims in (ZIP 1510 kb) published maps and institutional affiliations. Author details Abbreviations Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New CR: Complete response; DR: Durable response; DRR: Durable response rate; Brunswick, NJ 08901, USA. Huntsman Cancer Institute, University of Utah, EAC: Endpoint assessment committee; FACT-BRM: Functional Assessment of 1950 Circle of Hope Drive, Salt Lake City, UT 84112, USA. The University of Cancer Therapy-Biologic Response Modifier; GM-CSF: Granulocyte North Carolina Chapel Hill, 170 Manning Drive, Box 7305, Chapel Hill, NC macrophage-colony stimulating factor; HR: Hazard ratio; HSV: Herpes simplex 27599, USA. Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA virus; irRC: Immune-related response criteria; OS: Overall survival; 91320, USA. Department of Medicine, Roswell Park Cancer Institute, Elm and PFS: Progression-free survival; PR: Partial response; QoL: Quality of life; Carlton Streets, Buffalo, NY 14263, USA. MD Anderson Cancer Center, 1515 RECIST: Response Evaluation Criteria in Solid Tumors; TFI: Treatment-free Holcombe Blvd, Houston, TX 77030, USA. interval; TOI: Trial outcome index; WHO: World Health Organization Received: 4 May 2017 Accepted: 14 August 2017 Acknowledgments The authors thank Jennifer Gansert, MD, PhD (Amgen Inc.), for contribution to data interpretation, and Meghan Johnson, PhD (Complete Healthcare References Communications, LLC, West Chester, PA), for medical writing assistance in the 1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey preparation of this manuscript; their work was funded by Amgen Inc. We also J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, thank the patients and families who participated in the clinical trial. Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47. 2. 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