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An Exceptional Responder to Nivolumab in Metastatic Non-Small-Cell Lung Cancer: A Case Report and Literature Review of Long-Term Survivors

An Exceptional Responder to Nivolumab in Metastatic Non-Small-Cell Lung Cancer: A Case Report and... Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 1816472, 7 pages https://doi.org/10.1155/2019/1816472 Case Report An Exceptional Responder to Nivolumab in Metastatic Non-Small-Cell Lung Cancer: A Case Report and Literature Review of Long-Term Survivors 1 1 1 1 1,2 Babak Baseri , Bachar Samra, Eric Tam , Edwin Chiu , and Andrea Leaf Department of Hematology/Oncology, State University of New York Downstate Medical Center, Brooklyn, New York, USA Department of Hematology/Oncology, Veterans Affairs New York Harbor Healthcare System, Brooklyn Campus, New York, USA Correspondence should be addressed to Babak Baseri; bbaseri.82@gmail.com Received 9 September 2019; Accepted 4 November 2019; Published 5 December 2019 Academic Editor: Constantine Gennatas Copyright © 2019 Babak Baseri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Exceptional responders to immune checkpoint inhibitors in metastatic non-small-cell lung cancer (NSCLC) are rare. Furthermore, the optimal duration of immunotherapy in patients who achieve complete remission and the benefit of rechallenge after recurrence remain unknown. Studying the clinical course of exceptional responders can help identify potential predictors of response to immunotherapy and further fine-tune our management algorithms in the absence of standard of care in challenging scenarios. Case Presentation. We highlight the case of a 73-year-old Vietnam War Veteran with active tobacco dependence who achieved complete response with nivolumab for metastatic NSCLC after four prior lines of chemotherapy. Nivolumab was discontinued after 10 cycles due to immune-mediated hepatitis that resolved with steroids. He remained in complete remission for 14 months while off therapy. Then, his tumor recurred twice locally in the mediastinum and he again achieved complete and durable responses after each recurrence with radiotherapy. Due to recurrence in both lungs one year later, he was rechallenged with nivolumab and achieved partial response after two months of therapy. He continues to do well five and a half years since his initial diagnosis of de novo metastatic NSCLC. Conclusion. Optimal management of exceptional responders to immune checkpoint inhibitors in metastatic NSCLC is largely unknown. Our case report adds to the limited data supporting the use of localized therapy for oligometastatic recurrences and rechallenge with immunotherapy for widespread disease in achieving disease control and long-term survival. 1. Introduction had an exceptional response to a short treatment course with nivolumab. The use of immune checkpoint inhibitors (ICI) in many malignancies including non-small-cell lung cancer (NSCLC) 2. Case Presentation has revolutionized the field of oncology and has magnified the critical role of the immune system in fighting cancer A 73-year-old Vietnam War Veteran with active tobacco [1, 2]. However, only a select group of patients derive clin- dependence (1:5 − 2 packs per day > 50 years), prostate can- ically meaningful benefit from immunotherapy, ranging cer in remission (status post definitive radiation in 2008), from improved quality of life to durable clinical responses, and alcoholic fatty liver disease was diagnosed in November including rare complete remissions that may last many 2013 with metastatic poorly differentiated lung adenocarci- months even beyond immunotherapy discontinuation [3, 4]. noma of the left upper lobe (LUL) with biopsy-proven pleu- The superior efficacy of immunotherapy in such exceptional ral and pericardial metastases after he presented with responders has sparked an intense research interest in can- pneumonia and lung nodules. Molecular studies were nega- cer immunobiology [1, 5]. Here, we describe the clinical tive for EGFR mutation and ALK rearrangement, and non- course of a patient with heavily pretreated NSCLC who diagnostic for ROS-1. 2 Case Reports in Oncological Medicine He was started on chemotherapy in January 2014 and 3. Discussion received five cycles of carboplatin, pemetrexed, and bevaci- zumab, followed by three cycles of maintenance pemetrexed Our case report highlights the oncologic management of a and bevacizumab (see Figure 1 for therapy sequence). Due to heavily pretreated patient with NSCLC who continues to be progression of disease (PD) with new liver lesions, he was alive and well four years since his initial nivolumab treat- switched to second-line docetaxel and he completed six ment. The major benefit in the field of immunooncology in cycles. Although interim positron emission tomography/- solid tumors, including lung cancer, has been the achieve- computed tomography (PET/CT) showed stable disease, ment of durable responses in a subset of patients receiving the patient developed a paraneoplastic syndrome of inappro- checkpoint inhibitors, with subsequent translation to longer priate antidiuretic hormone secretion (SIADH) during the survivals (Table 1). Most recently, the 5-year follow-up of sixth cycle, concerning for PD. Therapy was subsequently nivolumab for pretreated advanced solid tumors (up to 5 switched to erlotinib as third-line therapy. In the interim, prior lines of therapy) showed a 5-year overall survival the patient reported left shoulder pain that was attributed (OS) rate of 16% across both squamous and nonsquamous to a left apical lung tumor involving the pleura and was NSCLC [6], compared with a historical 4% rate with tradi- treated palliatively with RT (3000 cGy). Notably, hyponatre- tional cytotoxic therapy [7]. Similarly, the 5-year OS rate mia resolved within one week of initiating RT, suggesting an for pembrolizumab was recently reported as 15.6% (previ- abscopal effect given the high burden of disease outside of ously treated) and 23.2% (frontline) in the Keynote 001 trial the radiation field. After three months of receiving erlotinib, [8]. Furthermore, complete responses (CR) with ICIs are PET/CT showed PD but the patient continued to have a uncommon and have been reported in 1-6% of NSCLC good performance status. He was started on fourth-line ther- (Table 1). A large meta-analysis of nine randomized clinical apy with vinorelbine and received a total of four cycles until trials evaluating 4803 NSCLC patients treated with ICI he had recrudescence of SIADH. Imaging showed enlarging reported the incidence of CR as 1.5% compared to 0.7% hepatic metastasis and left apical and hilar lung lesions, but in chemotherapy groups [3], and found the use of ICIs no evidence of intracranial lesions. Thus, the decision was as first line (relative risk (RR) 2.39, P =0:032) or second made to switch therapy to nivolumab (240 mg IV every line (RR 4.99, P =0:038), and the use of nivolumab (RR two weeks) as fifth line. The patient received 10 cycles from 4.83, P =0:042) and atezolizumab (RR 3.26, P =0:01), but August 2015 to January 2016 and his SIADH resolved after 2 not pembrolizumab and ipilimumab, to be significantly asso- months. Following four months of therapy, nivolumab was ciated with higher CR rates. However, no correlation was held due to grade II transaminitis, for which he was started found between OS and CR (r =0:19, P =0:75). Limited data on prednisone 100 mg daily and had a prolonged steroid suggest that CRs may be more common in PDL-1-positive taper (for six months). PET/CT following discontinuation tumors and may be associated with the development of irAEs of therapy showed no evidence of disease (NED). Nivolumab (Table 1) [9]. was not restarted as he was in complete remission, and it was Predicting which patients will respond to checkpoint deemed that the risks of nivolumab rechallenge outweighed inhibitors is an evolving area of research. The current predic- its benefits. Repeat PET/CT scans (Figure 2) continued to tive markers of response to immunotherapy in NSCLC show sustained complete remission, which lasted 14 months remain imperfect and can be divided into two main groups. after discontinuation of nivolumab, until March 2017 when The first group includes host and tumor/microenvironment his tumor recurred in a 1.1 cm subcarinal node (biopsy factors that already exist prior to the initiation of immuno- proven, PDL-1 positive 80%; 22C3 pharmDX kit). Molecular therapy. These factors include male gender [10], PDL-1 studies showed RET rearrangement (10q11) in 84% of the expression [11, 12], smoking status [13, 14], tumor mutation cells (Leica BioSystems) and were negative for MET amplifi- burden [15], microsatellite instability [16], presence or cation and BRAF and HER2 mutations. Given local recur- absence of CD8+ tumor-infiltrating lymphocytes (TILs) rence with very low disease burden, decision was made to [11, 17], KRAS mutation or EGFR wild type [18], previous treat the subcarinal node with RT (3000 cGy, 10 daily frac- radiotherapy [19] or bevacizumab use [20], and baseline tions of 300 cGy), with a resultant complete response. Nine neutrophil-to-lymphocyte (NLR) ratio [21] and platelet-to- months later, PET/CT showed a new hypermetabolic focus lymphocyte ratio [22]. The second group of predictors (SUV 8.7) in the right paratracheal lymph node (LN, belongs to “evolving or developing” determinants that arise 1.2 cm from 0.6 cm previously) and a new hypermetabolic concurrently with immunotherapy treatment, which may focus (SUV 3.7) in the right middle paratracheal LN be subject to exploitation by external factors. These predic- (0.7 cm). Given limited disease, RT was administered to the tive markers include but are not limited to change in gut paratracheal LNs (3000 cGy), and complete response was microbiome [23], change in NLR [24] and lymphocyte-to- again achieved until 12 months later, when his disease monocyte ratio [25], and immune-related adverse events recurred in the lungs with new and growing bilateral subcen- (irAEs) [26, 27]. Based on current data, no new biomarkers timeter nodules. He was rechallenged with nivolumab and have been identified in long-term survivors specifically. In has achieved a partial response after two months of therapy. the aforementioned nivolumab phase I CA209-003 trial [6], He has no evidence of immune-mediated adverse events the majority of the long-term survivors were current smokers after 10 cycles. Of note, his SIADH has not recurred since (14 out of 16 patients). In subgroup analysis, the 5-year OS the initial nivolumab therapy, and he continues to be asymp- rate was higher in patients with PDL‐1 expression > 50% tomatic with excellent performance status. (43% vs. 20% in PDL‐1< 1, and 23% in PDL‐1 ≥ 1%). Most Case Reports in Oncological Medicine 3 Erlotinib Carbo/Pem+Bev followed by Pem+Bev Docetaxel RT 3000 cGy to LUL tumor Vinorelbine Nivolumab Time 0 4 12 16 23 26 (month) SIADH SIADH resolved resolved 2.1 cm Metastatic PD SD PD PD LUL NSCLC liver mets SIADH SIADH nodule diagnosed RT 3000 cGy to LN RT 3000 cGy to LNs Off therapy Nivolumab 31 45 51 56 59 68 70 72 CR for 14 months CR CR PR Now Immune- Recurrence #1 Recurrence #2 Recurrence #3 mediated (post nivolumab) 1.2 cm, 0.7 cm Subcentimeter hepatitis 1.1 cm subcarinal LN paratracheal LNs lung nodules PDL-1 80% Figure 1: Treatment timeline. The numbers below the axis represent the number of months since the initial presentation. Abbreviations: NSCLC—non-small-cell lung cancer; Carbo—carboplatin; Pem—pemetrexed; Bev—bevacizumab; LUL—left upper lobe of the lung; PD—progression of disease; SD—stable disease; CR—complete response; PR—partial response; LN—lymph node; PDL-1—programmed death ligand-1; SIADH—syndrome of inappropriate antidiuretic hormone secretion. (a) (b) (c) (d) Figure 2: PET/CT images showing increased metabolic activity in the mediastinum (a) and in the liver (b) prior to initiating nivolumab. Resolution of FDG-avid lesions in the mediastinum (c) and in the liver (d) 10 months after discontinuation of nivolumab. 4 Case Reports in Oncological Medicine Table 1: Long-term outcomes of patients treated with immune checkpoint inhibitors in metastatic NSCLC. Characteristics Outcomes and exceptional responders Clinical trials (5 yr data) Phase 1 (CA 209-003) Median OS 9.9 m 5-year OS 16% (43% for PDL‐1 ≥ 50%) Nivolumab 129 patients For 5-year survivors: 2nd line; Ref. [6] Median follow-up: 58 m 14/16 current or former smokers, 10/16 had received prior RT, 12/16 no further tx after stopping Nivo and without PD PDL‐1 ≥ 1% in 7, ≥50% in 5, <1% in 3 pts Phase Ib (Keynote 001) Treatment naïve: Median DOR 16.8 m; CR 3% (3 patients) Median OS 22.3 m 101 tx naïve Pembrolizumab 5-year OS 23.2% (29.6% for PDL‐1 ≥ 50%) 449 previously treated 1st line or later; Ref. [8] Previously treated: Median follow-up: 60.6 m Median DOR 38.9 m; CR 1.1% (5 patients) Median OS 10.5 m (15.5 m for PDL‐1 ≥ 50%) 5-year OS 15.6% (25% for PDL‐1 ≥ 50%) Clinical trials (3 yr data) Phase III (CheckMate 017, 057) Median DOR 23.8 m Nivolumab vs. Doc 854 patients CR 6% for those alive at 3 years 2nd line; Ref. [35] Median follow-up: 40.3 m 3-year OS: 17% (vs. 8% Doc), 8% (vs. 2%) for patients with liver metastases Phase III (Keynote 010) PDL‐1 ≥ 50%: Median OS 16.9 m (vs. 8.2 m Doc) Pembrolizumab vs. Doc 1033 patients 3-year OS: 35% (vs. 13% Doc) 2nd line or later; Ref. [49] Median follow-up: 42.6 m PDL‐1 ≥ 1‐49%: Median OS 11.8 m (vs. 8.4 m Doc) 3-year OS: 23% (vs. 11% Doc) Phase II (POPLAR) Median DOR: 22.3 m (vs. 7.2 m docetaxel) 3-year OS: Atezolizumab vs. Doc 287 patients ITT 16.6% (vs. 10% docetaxel) 2nd line; Ref. [50] Minimum 3-year follow-up IHC TC3 or IC3 37.5% (vs. 14.9%) IHC TC 2/3 or IC 2/3 21.2% (vs. 9.9%) Case reports 67 male; squamous cell ca Nivolumab-induced pneumonitis after 3 doses; Nivolumab PDL‐1 TPS > 50% following discontinuation of the drug, the patient continued to 3rd line; Ref. [28] TMB 87-91 Mut/Mb have complete remission for 14 months 80 male; squamous cell ca Nivolumab Radiation-induced pneumonitis RT (3 months prior to Nivo) 2nd line; Ref. [29] CR after 6 cycles, ongoing after 2 years of continuous nivolumab PDL‐1 positive > 5% 47 male; adenocarcinoma PR after 6 cycles; CR after 13 cycles (10 weeks after RT) Nivolumab Current smoker Nivo discontinued after cycle 17 due to pancreatitis; 2nd line; Ref. [31] SBRT to LNs while on Nivo still in CR almost 2 years since discontinuation Abbreviations: OS—overall survival; m—months; tx—treatment; DOR—duration of response; CR—complete response; PD—progressive disease; ITT—intention to treat; Nivo—nivolumab; doc—docetaxel; LN—lymph node; ca—carcinoma; NSCLC—non-small-cell lung cancer; RT—radiotherapy; SBRT—stereotactic body radiation therapy; IHC—immunohistochemistry; TC—tumor cells; IC—tumor-infiltrating immune cells; Mut/Mb—mutations per megabase; PDL-1—programmed death ligand-1. interestingly, 75% of the long-term survivors received nivolu- months). Majority of this cohort (75%) had partial response mab for no more than two years, required no further cancer as their best response, and none had a CR. therapy afterwards, and remained without disease progres- Case reports of exceptional responders to ICI in NSCLC sion as of their last follow-up visit (median follow-up of 58 are rare and possibly underreported (Table 1) [28–33]. Our Case Reports in Oncological Medicine 5 duration (87 patients) nivolumab in advanced NSCLC case is unique in several aspects. First, it is a real-world sce- nario of an exceptional responder to immunotherapy outside (CheckMate 153, n = 220) showed significant improvement of a clinical trial. Second, our patient has been diagnosed with in progression-free survival (hazard ratio (HR) 0.42, 95% confidence interval (CI): 0.25, 0.71) and a trend towards metastatic lung cancer more than 5.5 years and continues to do well with very limited disease burden following eight lines better OS (HR 0.63, 95% CI: 0.33, 1.20) favoring the contin- of therapy, including RT. Third, he exhibited many of the uous nivolumab arm [39]. However, it should be noted that predictive markers mentioned above, including high PDL-1 the continuous arm had a higher percentage of PDL‐1 expression (80%), smoking history, prior RT and bevacizu- expression > 50% (28% vs. 23%) and higher rates of CR (10% vs. 2%) at baseline (1-year randomization mark) com- mab use, and development of immune-mediated hepatitis requiring nivolumab to be held. Although he continues to pared to the 1-year fixed duration arm. Notably, two smoke daily, it currently remains unclear if active smoking patients who achieved CR in the 1-year treatment arm has any role in potentiating response to ICI. Interestingly, recurred 6 and 13 months after stopping treatment. Retreat- unlike what is reported in the literature on poor responses ment with nivolumab after disease progression while off therapy resulted in response in the majority of patients, to ICI in liver metastasis [34], our patient had a CR to nivo- lumab and his disease never recurred in his liver despite hav- although the duration of response to the rechallenge was ing a relatively large liver metastasis (Figure 2), possibly due short for those with early progression (<6 months) [39]. to the activation of the immune system that resulted in hep- Immune-related adverse events are major causes of ICI atitis. Notably, in phase III CheckMate 017 and 057 trials, interruption or discontinuation, complicating the subse- quent management of patients, particularly those who have nivolumab resulted in improved OS compared with doce- taxel in patients with liver metastases, and their immune- achieved durable clinical benefit. irAEs have been generally mediated hepatic adverse events were higher than the overall associated with better ICI efficacy as well as increased over- pooled population (10% vs. 6%) [35]. Fourth, the clinical all survival [26, 27, 40]. Although the optimal oncologic course following nivolumab discontinuation is interesting management of patients who discontinue therapy due to irAEs is unknown, current data [6, 28], including our case as he achieved CR lasting 14 months after a short course of nivolumab. Notably, the prolonged course of steroid taper report, suggest that patients who achieve a CR are more for his hepatitis did not affect his duration of response nor likely to have prolonged duration of response off therapy. Whether resuming immunotherapy (if prior irAE grade ≤ 2) did it affect his second response to nivolumab upon rechal- lenge. Ongoing responses following discontinuation of or adding chemotherapy in the absence of measurable metastatic disease further extends duration of response or immunotherapy is a well-known phenomenon and has been documented in clinical trials, including the nivolumab trial even achieves the ultimate goal of cure is currently above [6, 36]. Fifth, he was noted to have a RET rearrange- unknown. Limited data at this time suggest that it may be reasonable to rechallenge patients with immunotherapy ment on repeat biopsy. In contrast to our case, a recent case series by Offin et al. [37] showed that majority of RET- upon recurrence [6, 33, 41–44], or treat oligometastatic recurrences with surgery or radiation therapy, with lower rearranged lung cancers have low PDL-1 expression and low TMB, and exhibit poor responses to ICIs. However, only threshold to initiate systemic therapy following multiple one patient in that series had PDL‐1 expression > 50%, and recurrences or in those with higher burden of disease [6]. Furthermore, increased use of liquid biopsies (such as cir- hence no conclusions as to how to sequence targeted thera- pies in such patients can be drawn. In an ongoing global reg- culating tumor DNA) [45, 46], tumor markers (such as CEA, CA125) [47, 48], and blood parameters (such as istry (IMMUNOTARGET), it was noted that ICI efficacy in oncogenic-driven lung cancers is inconsistent and depends NLR) [46] as biomarkers of response or relapse in ICI- on smoking history, PDL-1 expression, and the type of treated patients will further identify early responders, discern CRs from occult disease, and guide therapy in patients with mutation (less benefit in RET/EGFR/ALK patients) [38]. In our case, we did not use a RET inhibitor as the patient’s can- early progression. cer recurrences were mostly localized, and it was thought that radiotherapy would provide the best local control with potential for greater disease-free and treatment-free inter- 4. Conclusion vals. Upon his last relapse, immunotherapy rechallenge was also more appealing given the patient’s initial complete Exceptional responders to immune checkpoint inhibitors are durable response and high PDL-1 expression. As expected, uncommon in metastatic NSCLC. Additionally, the optimal his local disease recurrences were successfully treated with duration of immunotherapy in patients who achieve complete radiation therapy, with responses lasting 9 and 12 months remission remains unknown. Our case report adds to the after each RT. Finally, rechallenge with nivolumab follow- limited data in the management of exceptional responders ing his third tumor recurrence resulted in rapid partial following discontinuation of immunotherapy. Treatment response after four cycles. In the future, we plan to use a of oligometastatic recurrences with localized therapy and RET inhibitor as the next line of therapy once he progresses rechallenge with immunotherapy may increase disease con- on nivolumab. trol and extend overall survival. Further understanding of Optimal duration of immunotherapy in responders tumor microenvironment and tumor/immune system inter- remains unclear and is an area of active investigation. A actions may help identify better predictors of response and randomized trial of continuous (76 patients) vs. 1-year fixed further improve patients’ outcomes. 6 Case Reports in Oncological Medicine [14] H. Borghaei, L. Paz-Ares, L. Horn et al., “Nivolumab versus Conflicts of Interest docetaxel in advanced nonsquamous non-small-cell lung can- The authors declare that they have no conflicts of interest. cer,” The New England Journal of Medicine, vol. 373, no. 17, pp. 1627–1639, 2015. [15] N. A. Rizvi, M. D. Hellmann, A. 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An Exceptional Responder to Nivolumab in Metastatic Non-Small-Cell Lung Cancer: A Case Report and Literature Review of Long-Term Survivors

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Copyright © 2019 Babak Baseri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 1816472, 7 pages https://doi.org/10.1155/2019/1816472 Case Report An Exceptional Responder to Nivolumab in Metastatic Non-Small-Cell Lung Cancer: A Case Report and Literature Review of Long-Term Survivors 1 1 1 1 1,2 Babak Baseri , Bachar Samra, Eric Tam , Edwin Chiu , and Andrea Leaf Department of Hematology/Oncology, State University of New York Downstate Medical Center, Brooklyn, New York, USA Department of Hematology/Oncology, Veterans Affairs New York Harbor Healthcare System, Brooklyn Campus, New York, USA Correspondence should be addressed to Babak Baseri; bbaseri.82@gmail.com Received 9 September 2019; Accepted 4 November 2019; Published 5 December 2019 Academic Editor: Constantine Gennatas Copyright © 2019 Babak Baseri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Exceptional responders to immune checkpoint inhibitors in metastatic non-small-cell lung cancer (NSCLC) are rare. Furthermore, the optimal duration of immunotherapy in patients who achieve complete remission and the benefit of rechallenge after recurrence remain unknown. Studying the clinical course of exceptional responders can help identify potential predictors of response to immunotherapy and further fine-tune our management algorithms in the absence of standard of care in challenging scenarios. Case Presentation. We highlight the case of a 73-year-old Vietnam War Veteran with active tobacco dependence who achieved complete response with nivolumab for metastatic NSCLC after four prior lines of chemotherapy. Nivolumab was discontinued after 10 cycles due to immune-mediated hepatitis that resolved with steroids. He remained in complete remission for 14 months while off therapy. Then, his tumor recurred twice locally in the mediastinum and he again achieved complete and durable responses after each recurrence with radiotherapy. Due to recurrence in both lungs one year later, he was rechallenged with nivolumab and achieved partial response after two months of therapy. He continues to do well five and a half years since his initial diagnosis of de novo metastatic NSCLC. Conclusion. Optimal management of exceptional responders to immune checkpoint inhibitors in metastatic NSCLC is largely unknown. Our case report adds to the limited data supporting the use of localized therapy for oligometastatic recurrences and rechallenge with immunotherapy for widespread disease in achieving disease control and long-term survival. 1. Introduction had an exceptional response to a short treatment course with nivolumab. The use of immune checkpoint inhibitors (ICI) in many malignancies including non-small-cell lung cancer (NSCLC) 2. Case Presentation has revolutionized the field of oncology and has magnified the critical role of the immune system in fighting cancer A 73-year-old Vietnam War Veteran with active tobacco [1, 2]. However, only a select group of patients derive clin- dependence (1:5 − 2 packs per day > 50 years), prostate can- ically meaningful benefit from immunotherapy, ranging cer in remission (status post definitive radiation in 2008), from improved quality of life to durable clinical responses, and alcoholic fatty liver disease was diagnosed in November including rare complete remissions that may last many 2013 with metastatic poorly differentiated lung adenocarci- months even beyond immunotherapy discontinuation [3, 4]. noma of the left upper lobe (LUL) with biopsy-proven pleu- The superior efficacy of immunotherapy in such exceptional ral and pericardial metastases after he presented with responders has sparked an intense research interest in can- pneumonia and lung nodules. Molecular studies were nega- cer immunobiology [1, 5]. Here, we describe the clinical tive for EGFR mutation and ALK rearrangement, and non- course of a patient with heavily pretreated NSCLC who diagnostic for ROS-1. 2 Case Reports in Oncological Medicine He was started on chemotherapy in January 2014 and 3. Discussion received five cycles of carboplatin, pemetrexed, and bevaci- zumab, followed by three cycles of maintenance pemetrexed Our case report highlights the oncologic management of a and bevacizumab (see Figure 1 for therapy sequence). Due to heavily pretreated patient with NSCLC who continues to be progression of disease (PD) with new liver lesions, he was alive and well four years since his initial nivolumab treat- switched to second-line docetaxel and he completed six ment. The major benefit in the field of immunooncology in cycles. Although interim positron emission tomography/- solid tumors, including lung cancer, has been the achieve- computed tomography (PET/CT) showed stable disease, ment of durable responses in a subset of patients receiving the patient developed a paraneoplastic syndrome of inappro- checkpoint inhibitors, with subsequent translation to longer priate antidiuretic hormone secretion (SIADH) during the survivals (Table 1). Most recently, the 5-year follow-up of sixth cycle, concerning for PD. Therapy was subsequently nivolumab for pretreated advanced solid tumors (up to 5 switched to erlotinib as third-line therapy. In the interim, prior lines of therapy) showed a 5-year overall survival the patient reported left shoulder pain that was attributed (OS) rate of 16% across both squamous and nonsquamous to a left apical lung tumor involving the pleura and was NSCLC [6], compared with a historical 4% rate with tradi- treated palliatively with RT (3000 cGy). Notably, hyponatre- tional cytotoxic therapy [7]. Similarly, the 5-year OS rate mia resolved within one week of initiating RT, suggesting an for pembrolizumab was recently reported as 15.6% (previ- abscopal effect given the high burden of disease outside of ously treated) and 23.2% (frontline) in the Keynote 001 trial the radiation field. After three months of receiving erlotinib, [8]. Furthermore, complete responses (CR) with ICIs are PET/CT showed PD but the patient continued to have a uncommon and have been reported in 1-6% of NSCLC good performance status. He was started on fourth-line ther- (Table 1). A large meta-analysis of nine randomized clinical apy with vinorelbine and received a total of four cycles until trials evaluating 4803 NSCLC patients treated with ICI he had recrudescence of SIADH. Imaging showed enlarging reported the incidence of CR as 1.5% compared to 0.7% hepatic metastasis and left apical and hilar lung lesions, but in chemotherapy groups [3], and found the use of ICIs no evidence of intracranial lesions. Thus, the decision was as first line (relative risk (RR) 2.39, P =0:032) or second made to switch therapy to nivolumab (240 mg IV every line (RR 4.99, P =0:038), and the use of nivolumab (RR two weeks) as fifth line. The patient received 10 cycles from 4.83, P =0:042) and atezolizumab (RR 3.26, P =0:01), but August 2015 to January 2016 and his SIADH resolved after 2 not pembrolizumab and ipilimumab, to be significantly asso- months. Following four months of therapy, nivolumab was ciated with higher CR rates. However, no correlation was held due to grade II transaminitis, for which he was started found between OS and CR (r =0:19, P =0:75). Limited data on prednisone 100 mg daily and had a prolonged steroid suggest that CRs may be more common in PDL-1-positive taper (for six months). PET/CT following discontinuation tumors and may be associated with the development of irAEs of therapy showed no evidence of disease (NED). Nivolumab (Table 1) [9]. was not restarted as he was in complete remission, and it was Predicting which patients will respond to checkpoint deemed that the risks of nivolumab rechallenge outweighed inhibitors is an evolving area of research. The current predic- its benefits. Repeat PET/CT scans (Figure 2) continued to tive markers of response to immunotherapy in NSCLC show sustained complete remission, which lasted 14 months remain imperfect and can be divided into two main groups. after discontinuation of nivolumab, until March 2017 when The first group includes host and tumor/microenvironment his tumor recurred in a 1.1 cm subcarinal node (biopsy factors that already exist prior to the initiation of immuno- proven, PDL-1 positive 80%; 22C3 pharmDX kit). Molecular therapy. These factors include male gender [10], PDL-1 studies showed RET rearrangement (10q11) in 84% of the expression [11, 12], smoking status [13, 14], tumor mutation cells (Leica BioSystems) and were negative for MET amplifi- burden [15], microsatellite instability [16], presence or cation and BRAF and HER2 mutations. Given local recur- absence of CD8+ tumor-infiltrating lymphocytes (TILs) rence with very low disease burden, decision was made to [11, 17], KRAS mutation or EGFR wild type [18], previous treat the subcarinal node with RT (3000 cGy, 10 daily frac- radiotherapy [19] or bevacizumab use [20], and baseline tions of 300 cGy), with a resultant complete response. Nine neutrophil-to-lymphocyte (NLR) ratio [21] and platelet-to- months later, PET/CT showed a new hypermetabolic focus lymphocyte ratio [22]. The second group of predictors (SUV 8.7) in the right paratracheal lymph node (LN, belongs to “evolving or developing” determinants that arise 1.2 cm from 0.6 cm previously) and a new hypermetabolic concurrently with immunotherapy treatment, which may focus (SUV 3.7) in the right middle paratracheal LN be subject to exploitation by external factors. These predic- (0.7 cm). Given limited disease, RT was administered to the tive markers include but are not limited to change in gut paratracheal LNs (3000 cGy), and complete response was microbiome [23], change in NLR [24] and lymphocyte-to- again achieved until 12 months later, when his disease monocyte ratio [25], and immune-related adverse events recurred in the lungs with new and growing bilateral subcen- (irAEs) [26, 27]. Based on current data, no new biomarkers timeter nodules. He was rechallenged with nivolumab and have been identified in long-term survivors specifically. In has achieved a partial response after two months of therapy. the aforementioned nivolumab phase I CA209-003 trial [6], He has no evidence of immune-mediated adverse events the majority of the long-term survivors were current smokers after 10 cycles. Of note, his SIADH has not recurred since (14 out of 16 patients). In subgroup analysis, the 5-year OS the initial nivolumab therapy, and he continues to be asymp- rate was higher in patients with PDL‐1 expression > 50% tomatic with excellent performance status. (43% vs. 20% in PDL‐1< 1, and 23% in PDL‐1 ≥ 1%). Most Case Reports in Oncological Medicine 3 Erlotinib Carbo/Pem+Bev followed by Pem+Bev Docetaxel RT 3000 cGy to LUL tumor Vinorelbine Nivolumab Time 0 4 12 16 23 26 (month) SIADH SIADH resolved resolved 2.1 cm Metastatic PD SD PD PD LUL NSCLC liver mets SIADH SIADH nodule diagnosed RT 3000 cGy to LN RT 3000 cGy to LNs Off therapy Nivolumab 31 45 51 56 59 68 70 72 CR for 14 months CR CR PR Now Immune- Recurrence #1 Recurrence #2 Recurrence #3 mediated (post nivolumab) 1.2 cm, 0.7 cm Subcentimeter hepatitis 1.1 cm subcarinal LN paratracheal LNs lung nodules PDL-1 80% Figure 1: Treatment timeline. The numbers below the axis represent the number of months since the initial presentation. Abbreviations: NSCLC—non-small-cell lung cancer; Carbo—carboplatin; Pem—pemetrexed; Bev—bevacizumab; LUL—left upper lobe of the lung; PD—progression of disease; SD—stable disease; CR—complete response; PR—partial response; LN—lymph node; PDL-1—programmed death ligand-1; SIADH—syndrome of inappropriate antidiuretic hormone secretion. (a) (b) (c) (d) Figure 2: PET/CT images showing increased metabolic activity in the mediastinum (a) and in the liver (b) prior to initiating nivolumab. Resolution of FDG-avid lesions in the mediastinum (c) and in the liver (d) 10 months after discontinuation of nivolumab. 4 Case Reports in Oncological Medicine Table 1: Long-term outcomes of patients treated with immune checkpoint inhibitors in metastatic NSCLC. Characteristics Outcomes and exceptional responders Clinical trials (5 yr data) Phase 1 (CA 209-003) Median OS 9.9 m 5-year OS 16% (43% for PDL‐1 ≥ 50%) Nivolumab 129 patients For 5-year survivors: 2nd line; Ref. [6] Median follow-up: 58 m 14/16 current or former smokers, 10/16 had received prior RT, 12/16 no further tx after stopping Nivo and without PD PDL‐1 ≥ 1% in 7, ≥50% in 5, <1% in 3 pts Phase Ib (Keynote 001) Treatment naïve: Median DOR 16.8 m; CR 3% (3 patients) Median OS 22.3 m 101 tx naïve Pembrolizumab 5-year OS 23.2% (29.6% for PDL‐1 ≥ 50%) 449 previously treated 1st line or later; Ref. [8] Previously treated: Median follow-up: 60.6 m Median DOR 38.9 m; CR 1.1% (5 patients) Median OS 10.5 m (15.5 m for PDL‐1 ≥ 50%) 5-year OS 15.6% (25% for PDL‐1 ≥ 50%) Clinical trials (3 yr data) Phase III (CheckMate 017, 057) Median DOR 23.8 m Nivolumab vs. Doc 854 patients CR 6% for those alive at 3 years 2nd line; Ref. [35] Median follow-up: 40.3 m 3-year OS: 17% (vs. 8% Doc), 8% (vs. 2%) for patients with liver metastases Phase III (Keynote 010) PDL‐1 ≥ 50%: Median OS 16.9 m (vs. 8.2 m Doc) Pembrolizumab vs. Doc 1033 patients 3-year OS: 35% (vs. 13% Doc) 2nd line or later; Ref. [49] Median follow-up: 42.6 m PDL‐1 ≥ 1‐49%: Median OS 11.8 m (vs. 8.4 m Doc) 3-year OS: 23% (vs. 11% Doc) Phase II (POPLAR) Median DOR: 22.3 m (vs. 7.2 m docetaxel) 3-year OS: Atezolizumab vs. Doc 287 patients ITT 16.6% (vs. 10% docetaxel) 2nd line; Ref. [50] Minimum 3-year follow-up IHC TC3 or IC3 37.5% (vs. 14.9%) IHC TC 2/3 or IC 2/3 21.2% (vs. 9.9%) Case reports 67 male; squamous cell ca Nivolumab-induced pneumonitis after 3 doses; Nivolumab PDL‐1 TPS > 50% following discontinuation of the drug, the patient continued to 3rd line; Ref. [28] TMB 87-91 Mut/Mb have complete remission for 14 months 80 male; squamous cell ca Nivolumab Radiation-induced pneumonitis RT (3 months prior to Nivo) 2nd line; Ref. [29] CR after 6 cycles, ongoing after 2 years of continuous nivolumab PDL‐1 positive > 5% 47 male; adenocarcinoma PR after 6 cycles; CR after 13 cycles (10 weeks after RT) Nivolumab Current smoker Nivo discontinued after cycle 17 due to pancreatitis; 2nd line; Ref. [31] SBRT to LNs while on Nivo still in CR almost 2 years since discontinuation Abbreviations: OS—overall survival; m—months; tx—treatment; DOR—duration of response; CR—complete response; PD—progressive disease; ITT—intention to treat; Nivo—nivolumab; doc—docetaxel; LN—lymph node; ca—carcinoma; NSCLC—non-small-cell lung cancer; RT—radiotherapy; SBRT—stereotactic body radiation therapy; IHC—immunohistochemistry; TC—tumor cells; IC—tumor-infiltrating immune cells; Mut/Mb—mutations per megabase; PDL-1—programmed death ligand-1. interestingly, 75% of the long-term survivors received nivolu- months). Majority of this cohort (75%) had partial response mab for no more than two years, required no further cancer as their best response, and none had a CR. therapy afterwards, and remained without disease progres- Case reports of exceptional responders to ICI in NSCLC sion as of their last follow-up visit (median follow-up of 58 are rare and possibly underreported (Table 1) [28–33]. Our Case Reports in Oncological Medicine 5 duration (87 patients) nivolumab in advanced NSCLC case is unique in several aspects. First, it is a real-world sce- nario of an exceptional responder to immunotherapy outside (CheckMate 153, n = 220) showed significant improvement of a clinical trial. Second, our patient has been diagnosed with in progression-free survival (hazard ratio (HR) 0.42, 95% confidence interval (CI): 0.25, 0.71) and a trend towards metastatic lung cancer more than 5.5 years and continues to do well with very limited disease burden following eight lines better OS (HR 0.63, 95% CI: 0.33, 1.20) favoring the contin- of therapy, including RT. Third, he exhibited many of the uous nivolumab arm [39]. However, it should be noted that predictive markers mentioned above, including high PDL-1 the continuous arm had a higher percentage of PDL‐1 expression (80%), smoking history, prior RT and bevacizu- expression > 50% (28% vs. 23%) and higher rates of CR (10% vs. 2%) at baseline (1-year randomization mark) com- mab use, and development of immune-mediated hepatitis requiring nivolumab to be held. Although he continues to pared to the 1-year fixed duration arm. Notably, two smoke daily, it currently remains unclear if active smoking patients who achieved CR in the 1-year treatment arm has any role in potentiating response to ICI. Interestingly, recurred 6 and 13 months after stopping treatment. Retreat- unlike what is reported in the literature on poor responses ment with nivolumab after disease progression while off therapy resulted in response in the majority of patients, to ICI in liver metastasis [34], our patient had a CR to nivo- lumab and his disease never recurred in his liver despite hav- although the duration of response to the rechallenge was ing a relatively large liver metastasis (Figure 2), possibly due short for those with early progression (<6 months) [39]. to the activation of the immune system that resulted in hep- Immune-related adverse events are major causes of ICI atitis. Notably, in phase III CheckMate 017 and 057 trials, interruption or discontinuation, complicating the subse- quent management of patients, particularly those who have nivolumab resulted in improved OS compared with doce- taxel in patients with liver metastases, and their immune- achieved durable clinical benefit. irAEs have been generally mediated hepatic adverse events were higher than the overall associated with better ICI efficacy as well as increased over- pooled population (10% vs. 6%) [35]. Fourth, the clinical all survival [26, 27, 40]. Although the optimal oncologic course following nivolumab discontinuation is interesting management of patients who discontinue therapy due to irAEs is unknown, current data [6, 28], including our case as he achieved CR lasting 14 months after a short course of nivolumab. Notably, the prolonged course of steroid taper report, suggest that patients who achieve a CR are more for his hepatitis did not affect his duration of response nor likely to have prolonged duration of response off therapy. Whether resuming immunotherapy (if prior irAE grade ≤ 2) did it affect his second response to nivolumab upon rechal- lenge. Ongoing responses following discontinuation of or adding chemotherapy in the absence of measurable metastatic disease further extends duration of response or immunotherapy is a well-known phenomenon and has been documented in clinical trials, including the nivolumab trial even achieves the ultimate goal of cure is currently above [6, 36]. Fifth, he was noted to have a RET rearrange- unknown. Limited data at this time suggest that it may be reasonable to rechallenge patients with immunotherapy ment on repeat biopsy. In contrast to our case, a recent case series by Offin et al. [37] showed that majority of RET- upon recurrence [6, 33, 41–44], or treat oligometastatic recurrences with surgery or radiation therapy, with lower rearranged lung cancers have low PDL-1 expression and low TMB, and exhibit poor responses to ICIs. However, only threshold to initiate systemic therapy following multiple one patient in that series had PDL‐1 expression > 50%, and recurrences or in those with higher burden of disease [6]. Furthermore, increased use of liquid biopsies (such as cir- hence no conclusions as to how to sequence targeted thera- pies in such patients can be drawn. In an ongoing global reg- culating tumor DNA) [45, 46], tumor markers (such as CEA, CA125) [47, 48], and blood parameters (such as istry (IMMUNOTARGET), it was noted that ICI efficacy in oncogenic-driven lung cancers is inconsistent and depends NLR) [46] as biomarkers of response or relapse in ICI- on smoking history, PDL-1 expression, and the type of treated patients will further identify early responders, discern CRs from occult disease, and guide therapy in patients with mutation (less benefit in RET/EGFR/ALK patients) [38]. In our case, we did not use a RET inhibitor as the patient’s can- early progression. cer recurrences were mostly localized, and it was thought that radiotherapy would provide the best local control with potential for greater disease-free and treatment-free inter- 4. Conclusion vals. Upon his last relapse, immunotherapy rechallenge was also more appealing given the patient’s initial complete Exceptional responders to immune checkpoint inhibitors are durable response and high PDL-1 expression. As expected, uncommon in metastatic NSCLC. Additionally, the optimal his local disease recurrences were successfully treated with duration of immunotherapy in patients who achieve complete radiation therapy, with responses lasting 9 and 12 months remission remains unknown. Our case report adds to the after each RT. Finally, rechallenge with nivolumab follow- limited data in the management of exceptional responders ing his third tumor recurrence resulted in rapid partial following discontinuation of immunotherapy. Treatment response after four cycles. In the future, we plan to use a of oligometastatic recurrences with localized therapy and RET inhibitor as the next line of therapy once he progresses rechallenge with immunotherapy may increase disease con- on nivolumab. trol and extend overall survival. Further understanding of Optimal duration of immunotherapy in responders tumor microenvironment and tumor/immune system inter- remains unclear and is an area of active investigation. A actions may help identify better predictors of response and randomized trial of continuous (76 patients) vs. 1-year fixed further improve patients’ outcomes. 6 Case Reports in Oncological Medicine [14] H. Borghaei, L. Paz-Ares, L. Horn et al., “Nivolumab versus Conflicts of Interest docetaxel in advanced nonsquamous non-small-cell lung can- The authors declare that they have no conflicts of interest. cer,” The New England Journal of Medicine, vol. 373, no. 17, pp. 1627–1639, 2015. [15] N. A. Rizvi, M. D. Hellmann, A. 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