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Ipilimumab: its potential in non-small cell lung cancer:

Ipilimumab: its potential in non-small cell lung cancer: 431718 TAM421758834011431718P Tomasini, N KhobtaTherapeutic Advances in Medical Oncology Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Ipilimumab: its potential in (2012) 4(2) 43 –50 DOI: 10.1177/ non-small cell lung cancer 1758834011431718 © The Author(s), 2011. Reprints and permissions: Pascale Tomasini, Nataliya Khobta, Laurent Greillier and Fabrice Barlesi http://www.sagepub.co.uk/ journalsPermissions.nav Abstract: Ipilimumab is a fully human monoclonal antibody that enhances antitumor immunity by way of cytotoxic T-lymphocyte antigen 4 blockade. It has already been approved by the US Food and Drug Administration for the treatment of metastatic melanoma and is being investigated for treating other solid tumors such as renal cell, prostate and lung cancers. This review details the potential of ipilimumab in the management of non-small cell lung cancer (NSCLC). In particular, ipilimumab showed promising results in a first-line NSCLC phase II study combining carboplatin/paclitaxel chemotherapy with concurrent or phased ipilimumab. The median immune-related progression-free survival was 5.68 months for the phased ipilimumab arm versus 4.63 months for chemotherapy alone (hazard ratio [HR] = 0.68, p = 0.026) and 5.52 months for the concurrent ipilimumab arm versus 4.63 months for chemotherapy alone (HR = 0.77, p = 0.094). The main adverse events were immune related, such as hypophysitis, enterocolitis, and hyperthyroidism. These adverse events may be improved with high-dose glucocorticoids and may be correlated with tumor response. Phase III studies are ongoing. Future studies may investigate ipilimumab in the management of early stage lung cancer. Strategies for potential translational research studies are also discussed to identify prognostic and predictive biomarkers for the use of ipilimumab in the treatment of patients with NSCLC. Keywords: biomarkers, immunotherapy, ipilimumab, lung cancer, targeted therapy Corresponding to: Introduction signal mediated by the engagement of CD28 on Fabrice Barlesi, MD, PhD Ipilimumab is a fully human immunoglobulin G the T-cell surface by members of the B7 family Service d’Oncologie Multidisciplinaire et and anti-cytotoxic T-lymphocyte antigen 4 on APCs. Both signals result in the activation Innovations Thérapeutique, (CTLA-4) monoclonal antibody. It has already and interleukin-2 (IL-2)-dependant clonal pro- Hôpital Nord, Chemin des Bourrely, 13915 Marseille been studied in several solid malignancies and liferation of T cells. This proliferation needs to Cedex 20, France has been approved by the US Food and Drug be regulated to avoid autoimmunity. After acti- fabrice.barlesi@ap-hm.fr Association (FDA) for the treatment of advanced vation, T cells express CTLA-4, a member of the Pascale Tomasini, MD, Laurent Greillier, MD melanoma. Studies of ipilimumab for the treat- immunoglobulin super family and homologue to Multidisciplinary Oncology ment of lung cancer are described in this CD28 first cloned in 1987 [Brunet et al. 1987]. and Therapeutic Innovations Department, Aix Marseille review, and the clinical potential of ipilimumab is CTLA-4 binds members of the B7 family with a University – Assistance discussed. much higher affinity than CD28 and downregu- Publique Hôpitaux de Marseille; Aix Marseille lates the T-cell response. It has been proven that University – Inserm U911, one reason for the poor immunogenicity of many Marseille, France Biological background: mechanisms of action tumors such as lung cancer is CTLA-4 activity Nataliya Khobta, MD Multidisciplinary The adaptive immune response requires two sig- and that in vivo administration of antibodies to Oncology and Therapeutic nals between the antigen-presenting cells (APCs) CTLA-4 can enhance antitumor immunity Innovations Department, Aix Marseille University – and the effector T cells. The first signal is medi- [Leach et al. 1996]. Assistance Publique ated by the T-cell receptor and the major histo- Hôpitaux de Marseille, Marseille, France compatibility complex classes I or II antigenic CTLA-4 also regulates tumor immunity via peptide. The second signal is a costimulatory Tregs. Tregs are a suppressive CD4+ T-cell http://tam.sagepub.com 43 Therapeutic Advances in Medical Oncology 4 (2) population that expresses high levels of surface Melanoma CTLA-4. Tregs have nonspecific immunosup- Hodi and colleagues conducted a phase III study pressive functions through several mechanisms. of ipilimumab in the treatment of metastatic mel- Among these mechanisms is upregulation of anoma. Overall, 676 patients with HLA-A0201- CTLA-4 on the surface of Tregs, which can sup- positive unresectable stage III or IV melanoma press the activation and expansion of effector cells whose disease had progressed after a first-line [Gabriel and Lattime, 2007]. Therefore, whereas therapy were randomized to receive ipilimumab CTLA-4-expressing Tregs may play a critical role 3mg/kg every 3 weeks plus gp100 or ipilimumab in maintaining self-tolerance, they may also facili- alone or gp100 alone. Ipilimumab alone improved tate nonresponsiveness to tumor antigens. Tregs overall survival (OS) in comparison with gp100 have been shown to be present in tumors and alone (HR for survival = 0.66, p = 0.003). coexist with primed effector T cells. Thus, block- Similarly, ipilimumab plus gp100 improved OS in ade of Tregs function via anti-CTLA-4 antibodies comparison with gp100 alone (HR = 0.68, p < has the potential to remove Tregs suppression and 0.001). There was no difference in OS between enhance antitumor immunity. the ipilimumab groups (p = 0.76) [Hodi et al. 2010] or across subgroups [Lebbé et al. 2010; O’Mahony and colleagues studied the biological Haanen et al. 2010; Lawrence et al. 2010]. consequences of the administration of ipilimumab 3 mg/kg and then 1.5 mg/kg monthly in patients with advanced malignancies after cancer vaccine Renal cell carcinoma failure. The first hypothesis for the biological Yang and colleagues conducted a phase II study mechanism of action of ipilimumab was that of ipilimumab monotherapy 3 mg/kg followed by blockade of CTLA-4 on CD8+ T cells would 1 mg/kg or 3 mg/kg every 3 weeks in patients with result in an expansion of vaccine-specific T-cell metastatic renal cell carcinoma (RCC). Overall, responses. However, no increase in peripheral 15% of patients with the higher dose had partial blood CD3+, CD8+ T cells or vaccine-specific response according to the Response Evaluation CD8+ T cells was detected. These data, consist- Criteria for Solid Tumors (RECIST) criteria ent with previous studies, suggest that the increase [95% confidence interval (CI) for cohort response in CD8+ T-cell response through blockade of rate 4–27%) [Yang et al. 2007]. CTLA-4 signaling is not the major mechanism of tumor response [O’Mahony et al. 2007]. However, Yang and colleagues published a retrospective Prostate cancer analysis of four phase II studies of ipilimumab in Fong and colleagues published a phase I study of stage IV melanoma. Patients with clinical benefit 24 patients with metastatic castration-resistant had a statistically significant increase in CD8+ T prostate cancer treated with granulocyte mac- cells in comparison with patients without clinical rophage colony-stimulating factor (GM-CSF) and benefit (p = 0.0294) [Yang et al. 2010]. The sec- increasing doses of ipilimumab. Three of the six ond hypothesis was the potential for ipilimumab patients with the highest dose had prostate-specific to deplete Tregs. Flow cytometry was used to antigen declines of more than 50%. Expansion quantitate Tregs number. The authors showed a of activated circulating CD25+ CD69+ CD8+ significant decrease of Tregs at 1–4 days after each T cells was greater than in patients from two administration of ipilimumab. But the number of separate clinical trials who received ipilimumab or Tregs had increased above baseline at the time of GM-CSF as monotherapy [Fong et al. 2009]. next administration. This suggests that modula- tion of Tregs plays a role in tumor regression and that the transient decrease in Tregs allows for Ipilimumab in lung cancer immune activation [Yang et al. 2010]. Despite recent advances in lung cancer treatment with third-generation chemotherapies and targeted therapies, the prognosis of patients with lung can- Proof of concept of ipilimumab activity cer remains poor and there is a need for new thera- in solid malignancies peutic strategies to improve lung cancer patients’ Ipilimumab has been studied in several solid survival. Lung cancer in not known to be an immu- malignancies, and the main results are summa- nogenic-mediated malignancy. Ding and colleagues rized here to allow comparison with the NSCLC performed DNA sequencing of a large number of development of ipilimumab. genes in 188 lung cancer samples and identified 44 http://tam.sagepub.com P Tomasini, N Khobta et al. 26 genes mutated at significantly high frequencies chemotherapy may increase antigen exposure to and thus potentially involved in lung cancer car- immunotherapy but may also decrease the popu- cinogenesis [Ding et al. 2008]. None of the genes lation of immune cells mediating the response to were involved in immunity. However, immunother- immunotherapy. This is the reason why phasing apy remains an attractive therapeutic approach with chemotherapy is also of importance. Actually, because of its theoretical specificity and potential low-dose intravenous infusions of cyclophospha- long-term disease control. Consequently, several mide may overcome the immune suppression immunotherapies are under investigation in seen in carcinomas, and cyclophosphamide has NSCLC and some of them already showed promis- shown, in various animal models, its ability to ing results. Some immunotherapies have a specific augment delayed-type hypersensitivity responses, immune target; for example, MAGE-A3, Lucanix increase antibody production, abrogate tolerance, (belagenpumatucel-L, a transforming growth and potentiate antitumor immunity [Bass and factor β2-based vaccine, NovaRx, San Diego, CA, Mastrangelo, 1998]. To date, use of ipilimumab USA), Stimuvax (BLP25 liposome vaccine, a with pretreatment cyclophosphamide remains to vaccine targeting mucin 1, Oncothyreon, Seattle, be studied. WA, USA) and Saccharomyces-CEA vaccine. Some immunotherapies do not have identified tar- Ipilimumab showed promising results in the get, such as GVAX (GM-CSF vaccine), talactofer- treatment of NSCLC in a phase II study. The rin (a genetically engineered form of the human CA184-041 phase II study randomized previously protein lactoferrin), and ipilimumab [Morgensztern untreated patients with advanced NSCLC to et al. 2010]. As an example, a randomized phase II receive chemotherapy with carboplatin (area study of talactoferrin versus placebo in patients with under the curve 6) and paclitaxel (175 mg/m ) advanced NSCLC that progressed after chemo- alone or in association with concurrent ipilimumab therapy showed an improvement in OS (HR for (10 mg/kg from cycle 1 to cycle 4) or with phased survival = 0.68; p = 0.04) [Parikh et al. 2011]. In ipilimumab (10 mg/kg from cycle 3 to cycle 6) (see the same way, a phase II study of MAGE-A3 Figure 1 for design) [Lynch et al. 2010]. Overall, immunotherapy as adjuvant therapy in stage IB/II 204 patients were included in the study with com- NSCLC showed a positive trend for activity of mon characteristics for patients with advanced MAGE-A3 in NSCLC with a relative improve- NSCLC (74% men, 79% stage IV disease, 51% ment of disease-free survival of 27% [Vansteenkiste adenocarcinoma, and 71% European Cooperative et al. 2007]. However, there has been no vaccine or Oncology Group performance status 1). The pri- other immune-related therapy, FDA or European mary endpoint was immune-related progression- Medicines Agency (EMEA) approved, for NSCLC. free survival (irPFS), according to the guidelines Furthermore, Stimuvax, talactoferrin, MAGE-A3, for the evaluation of immune therapy activity and ipilimumab are still actively being investigated in solid tumors [Wolchok et al. 2009]. Clinical for the treatment of patients with NSCLC through response to immunotherapeutic agents is some- ongoing phase III studies. times represented by an initial increase in tumor size or even appearance of new lesions, therefore The rationale for the use of ipilimumab in associa- considered as a disease progression according to tion with chemotherapy is based on the assump- RECIST or World Health Organization (WHO) tion that tumor-specific antigen released during criteria. This novel pattern of clinical response chemotherapy-induced tumor necrosis may limits the use of the RECIST or WHO criteria increase tumor-specific immunity and therefore when using immunotherapy. Therefore, immune- enhance ipilimumab or other immunotherapeutic relative response criteria were defined in an efficacy. This hypothesis may explain the trend in attempt to capture additional response patterns favor of the sequential association of ipilimumab observed in immunotherapy. In the CA184-041 and chemotherapy in comparison with the con- study, irPFS was improved in the ipilimumab arms current association as highlighted in several in comparison with chemotherapy alone. Indeed, phase II studies, including lung cancer studies as the median irPFS was 5.68 months for the phased reported below. In addition, a randomized phase I ipilimumab arm versus 4.63 months for chemo- study assessed the pharmacokinetic interaction therapy alone (HR = 0.68, p = 0.026) and was between ipilimumab and paclitaxel/carboplatin in 5.52 months for the concurrent ipilimumab arm patients with untreated advanced melanoma and versus 4.63 months for chemotherapy alone (HR = there was no clinically relevant pharmacokinetic 0.77, p = 0.094). However, there was no signifi- interaction [Weber et al. 2010]. Complete-dose cant difference between the arms in terms of OS http://tam.sagepub.com 45 Therapeutic Advances in Medical Oncology 4 (2) Figure 1. Study design of the CA184-041 phase II study investigating the potential of concurrent and phased ipilimumab (IPI) versus placebo (p) with concomitant carboplatin (C, Carbo) plus paclitaxel (P, Pac) as first-line treatment in advanced stages of non-small cell lung cancer (NSCLC). q3w, every 3 weeks; q12w, every 12 weeks. (p = 0.104) but a trend seemed to favor the of patients in the placebo arm). The more specific sequential combination of ipilimumab plus chem- immune-related toxicities are detailed below. otherapy. Indeed, OS was 8.3 months in the placebo arm versus 9.7 months in the concurrent In 2011, Lynch and colleagues presented the arm (HR = 0.98, p = 0.47) and 12.2 months in results of a subgroup analysis of the CA184-041 the phased arm (HR = 0.86, p = 0.23). The dis- phase II study looking at efficacy by histological ease control rate (DCR) seemed also to favor the subtypes [Lynch et al. 2011]. This subgroup phased combination of ipilimumab with chemo- hypothesis-generating analysis suggested that therapy with a DCR of 57.1 versus 77.9 and 72.7 patients with squamous NSCLC might derive a for chemotherapy alone, phased and concurrent greater benefit of the ipilimumab plus chemother- ipilimumab, respectively. Although the absolute apy combination when compared with patients difference in irPFS seems small (1 month), it is with nonsquamous NSCLC, especially for the statistically significant and we have to focus on HR phased combination. Indeed, the median irPFS (0, 68). In this disease with such a poor prognosis, was 6.2 and 5.7 months for the phased ipili- there are very few immune therapies showing such mumab arms versus 4.2 and 5.3 months for chem- promising results. Furthermore, some patients otherapy alone in squamous and nonsquamous experienced almost complete and longlasting NSCLC, respectively (HR = 0.55 and 0.82, responses (Figure 2), highlighting the need for respectively). The retrospective nature of this phase III studies and assessment for potential pre- analysis and the small sample size warrants cau- dictive biomarkers. The association of ipilimumab tion in interpretation. and chemotherapy was generally well tolerated and ipilimumab did not potentiate chemotherapy- related toxicity. However, safety results suggest a Safety profile in solid malignancies moderate added toxicity in the arms containing The major toxicities due to ipilimumab are ipilimumab (grade 3–4 adverse events were immune-related adverse events (irAEs). The most observed in 58% of patients in the concurrent arm common major toxicity was enterocolitis (21% of and 52% of patients in the phased arm versus 42% patients) [Beck et al. 2006], defined by diarrhea 46 http://tam.sagepub.com P Tomasini, N Khobta et al. Figure 2. Thoracic computed tomography scans showing baseline (left panels) and current (right panels) scans of a patient with stage IV non-small cell lung cancer participating in the CA184-041 phase II study, and showing an almost complete and long-lasting response to the combination of ipilimumab plus concurrent carboplatin plus paclitaxel chemotherapy. or biopsy documentation (neutrophilic and Thus, the early screening and treatment of auto- lymphocytic inflammation). The major risk is immune endocrinopathies is recommended in represented by bowel perforation. Most patients patients undergoing clinical trials with ipili- with enterocolitis respond to high-dose systemic mumab. Ipilimumab can also induce uveitis and corticosteroids, without affecting tumor response, hepatitis that may be severe and corticosteroid but a significant association between irAEs and resistant [Chmiel et al. 2011]. tumor regression (response rate 30% with irAEs versus 0% without irAEs) was also shown [Yang In the CA184-041 phase II study dedicated to et al. 2007]. Weber and colleagues conducted a patients with NSCLC, irAEs were more fre- double-blind placebo-controlled phase II study quent in the ipilimumab arms (19% and 15% of prophylactic budesonide in the management of grade 3–4 irAEs for concurrent and phased grade ≥2 diarrhea in patients with unresectable arms, respectively, versus 6% in the placebo advanced melanoma receiving ipilimumab. arm) [Lynch et al. 2010]. There were mostly Budesonide did not affect the rate of grade ≥2 grade 3 irAEs, with dermatologic and gastroin- diarrhea (32.7% versus 35%) [Weber et al. 2009]. testinal irAEs the most frequent. A fatal grade 5 Immune-related endocrinopathies have also been toxic epidermal necrolysis was observed in described. Autoimmune hypophysitis has been a patient treated in the concurrent arm. No reported in 17% (all grades) of patients with hypopituitarism or adrenal insufficiency was melanoma and RCC treated with ipilimumab. observed, but two patients experienced a grade Furthermore, cases of hypopituitarism have been 1–2 hypothyroidism. described in patients with prostate cancer under- going experimental therapy with ipilimumab. In most cases, high-dose glucocorticoid treatment Perspectives improved symptoms [Dillard et al. 2010]. In The results of the CA184-041 study actually led the same way, cases of hyperthyroidism after to the design of a phase III study of the association ipilimumab therapy for patients with advanced of ipilimumab with paclitaxel/carboplatin in melanoma have been described [Min et al. 2011]. previously untreated advanced NSCLC with http://tam.sagepub.com 47 Therapeutic Advances in Medical Oncology 4 (2) Table 1. Immune-related response criteria (irRC) [Wolchok, 2009]. Complete response All lesions gone Partial response ≥ 50% decrease in SPD of index + new* lesions Stable disease SPD of index + new* lesions not irCR, irPR or irPD Progressive disease SPD of index + new* lesions increases ≥25% SPD, sum of products of perpendicular diameters; irCR, immune related Complete Response; irPR, immune related Partial Response; irPD, immune related Progressive Disease;*, differences between irRC and modified World Health Organization response criteria. squamous histology (clinicaltrials.gov, NCT discovery, evaluation and clinical application of 01285609 and NCT00527735). immune biomarkers [Bedognietti et al. 2011]. In addition, Breunis and colleagues provide data However, the potential efficacy of ipilimumab in suggesting that genetic variations in CTLA-4 NSCLC together with its particular mechanism could influence response to CTLA-4 blockade of action might also lead to investigation in earlier [Breunis et al. 2008], representing a first step in stages of the disease, such as the early stages of biomarker development in the field of ipili- NSCLC in the adjuvant or neoadjuvant setting, mumab studies. but also in all the situations when a maintenance treatment might be useful (response after induc- tion chemotherapy in NSCLC, management of Conclusions unresectable stage III, etc.). The investigation of Ipilimumab is an anti-CTLA-4 antibody. A ipilimumab in early stage lung cancer may expose phase II study of ipilimumab in the first-line patients to long-term irAEs. Long-term results of treatment of metastatic NSCLC in association a phase III trial of ipilimumab in metastatic mela- with chemotherapy showed an improvement of noma describe only 1% of irAEs in the ‘ipili- irPFS in comparison with chemotherapy alone, mumab alone’ arm, mostly grade 1 or 2, with no without major added toxicity. Phase III studies, grade 4 or 5 toxicities. The long-term benefit of especially in the squamous-NSCLC population, ipilimumab on OS has been demonstrated are ongoing. In the future, ipilimumab should be [Haanen et al. 2010]. Furthermore, in compari- investigated in early stage or locally advanced son with adjuvant chemotherapy for resected lung lung cancer, such as other immunotherapies. cancer, the long-term results of the International There is also a need for the research of biomark- Adjuvant Lung Cancer Trial on OS favor adju- ers to individualize and optimize the use of vant chemotherapy, but not significantly, after ipilimumab in NSCLC. 5 years even if non-lung cancer mortality is increased in the chemotherapy arm [Arriagada Funding et al. 2010]. This research received no specific grant from any funding agency in the public, commercial, or not- In addition, predictive and prognostic biomark- for-profit sectors. ers to drive the use of ipilimumab should be investigated in tumor or blood. We already know Conflict of interest statement that increased tumor-infiltrating lymphocytes in The authors have participated in clinical trials patients with squamous disease were correlated based on ipilimumab in lung cancer. with improved survival in NSCLC [Hiraoka et al. 2006]. Several other biomarkers are under investigation, such as the increase in CD8+ T cells or the decrease of CTLA-4-expressing References Arriagada, R., Dunant, A., Pignon, J.P., Bergman, Tregs, but these studies frequently face the com- B., Chabowski, M., Grunenwald, D. et al. (2010) plexity of interactions between tumor and host Long-term results of the International Adjuvant that impact on antitumor immune responses. Lung Cancer Trial evaluating cisplatine-based Although assessing predictors of response to chemotherapy in resected lung cancer. J Clin Oncol immunotherapies is difficult, recommendations 28: 35–42. are available in the cancer immunotherapy bio- markers resource document [Bedognietti et al. 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Abstract

431718 TAM421758834011431718P Tomasini, N KhobtaTherapeutic Advances in Medical Oncology Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Ipilimumab: its potential in (2012) 4(2) 43 –50 DOI: 10.1177/ non-small cell lung cancer 1758834011431718 © The Author(s), 2011. Reprints and permissions: Pascale Tomasini, Nataliya Khobta, Laurent Greillier and Fabrice Barlesi http://www.sagepub.co.uk/ journalsPermissions.nav Abstract: Ipilimumab is a fully human monoclonal antibody that enhances antitumor immunity by way of cytotoxic T-lymphocyte antigen 4 blockade. It has already been approved by the US Food and Drug Administration for the treatment of metastatic melanoma and is being investigated for treating other solid tumors such as renal cell, prostate and lung cancers. This review details the potential of ipilimumab in the management of non-small cell lung cancer (NSCLC). In particular, ipilimumab showed promising results in a first-line NSCLC phase II study combining carboplatin/paclitaxel chemotherapy with concurrent or phased ipilimumab. The median immune-related progression-free survival was 5.68 months for the phased ipilimumab arm versus 4.63 months for chemotherapy alone (hazard ratio [HR] = 0.68, p = 0.026) and 5.52 months for the concurrent ipilimumab arm versus 4.63 months for chemotherapy alone (HR = 0.77, p = 0.094). The main adverse events were immune related, such as hypophysitis, enterocolitis, and hyperthyroidism. These adverse events may be improved with high-dose glucocorticoids and may be correlated with tumor response. Phase III studies are ongoing. Future studies may investigate ipilimumab in the management of early stage lung cancer. Strategies for potential translational research studies are also discussed to identify prognostic and predictive biomarkers for the use of ipilimumab in the treatment of patients with NSCLC. Keywords: biomarkers, immunotherapy, ipilimumab, lung cancer, targeted therapy Corresponding to: Introduction signal mediated by the engagement of CD28 on Fabrice Barlesi, MD, PhD Ipilimumab is a fully human immunoglobulin G the T-cell surface by members of the B7 family Service d’Oncologie Multidisciplinaire et and anti-cytotoxic T-lymphocyte antigen 4 on APCs. Both signals result in the activation Innovations Thérapeutique, (CTLA-4) monoclonal antibody. It has already and interleukin-2 (IL-2)-dependant clonal pro- Hôpital Nord, Chemin des Bourrely, 13915 Marseille been studied in several solid malignancies and liferation of T cells. This proliferation needs to Cedex 20, France has been approved by the US Food and Drug be regulated to avoid autoimmunity. After acti- fabrice.barlesi@ap-hm.fr Association (FDA) for the treatment of advanced vation, T cells express CTLA-4, a member of the Pascale Tomasini, MD, Laurent Greillier, MD melanoma. Studies of ipilimumab for the treat- immunoglobulin super family and homologue to Multidisciplinary Oncology ment of lung cancer are described in this CD28 first cloned in 1987 [Brunet et al. 1987]. and Therapeutic Innovations Department, Aix Marseille review, and the clinical potential of ipilimumab is CTLA-4 binds members of the B7 family with a University – Assistance discussed. much higher affinity than CD28 and downregu- Publique Hôpitaux de Marseille; Aix Marseille lates the T-cell response. It has been proven that University – Inserm U911, one reason for the poor immunogenicity of many Marseille, France Biological background: mechanisms of action tumors such as lung cancer is CTLA-4 activity Nataliya Khobta, MD Multidisciplinary The adaptive immune response requires two sig- and that in vivo administration of antibodies to Oncology and Therapeutic nals between the antigen-presenting cells (APCs) CTLA-4 can enhance antitumor immunity Innovations Department, Aix Marseille University – and the effector T cells. The first signal is medi- [Leach et al. 1996]. Assistance Publique ated by the T-cell receptor and the major histo- Hôpitaux de Marseille, Marseille, France compatibility complex classes I or II antigenic CTLA-4 also regulates tumor immunity via peptide. The second signal is a costimulatory Tregs. Tregs are a suppressive CD4+ T-cell http://tam.sagepub.com 43 Therapeutic Advances in Medical Oncology 4 (2) population that expresses high levels of surface Melanoma CTLA-4. Tregs have nonspecific immunosup- Hodi and colleagues conducted a phase III study pressive functions through several mechanisms. of ipilimumab in the treatment of metastatic mel- Among these mechanisms is upregulation of anoma. Overall, 676 patients with HLA-A0201- CTLA-4 on the surface of Tregs, which can sup- positive unresectable stage III or IV melanoma press the activation and expansion of effector cells whose disease had progressed after a first-line [Gabriel and Lattime, 2007]. Therefore, whereas therapy were randomized to receive ipilimumab CTLA-4-expressing Tregs may play a critical role 3mg/kg every 3 weeks plus gp100 or ipilimumab in maintaining self-tolerance, they may also facili- alone or gp100 alone. Ipilimumab alone improved tate nonresponsiveness to tumor antigens. Tregs overall survival (OS) in comparison with gp100 have been shown to be present in tumors and alone (HR for survival = 0.66, p = 0.003). coexist with primed effector T cells. Thus, block- Similarly, ipilimumab plus gp100 improved OS in ade of Tregs function via anti-CTLA-4 antibodies comparison with gp100 alone (HR = 0.68, p < has the potential to remove Tregs suppression and 0.001). There was no difference in OS between enhance antitumor immunity. the ipilimumab groups (p = 0.76) [Hodi et al. 2010] or across subgroups [Lebbé et al. 2010; O’Mahony and colleagues studied the biological Haanen et al. 2010; Lawrence et al. 2010]. consequences of the administration of ipilimumab 3 mg/kg and then 1.5 mg/kg monthly in patients with advanced malignancies after cancer vaccine Renal cell carcinoma failure. The first hypothesis for the biological Yang and colleagues conducted a phase II study mechanism of action of ipilimumab was that of ipilimumab monotherapy 3 mg/kg followed by blockade of CTLA-4 on CD8+ T cells would 1 mg/kg or 3 mg/kg every 3 weeks in patients with result in an expansion of vaccine-specific T-cell metastatic renal cell carcinoma (RCC). Overall, responses. However, no increase in peripheral 15% of patients with the higher dose had partial blood CD3+, CD8+ T cells or vaccine-specific response according to the Response Evaluation CD8+ T cells was detected. These data, consist- Criteria for Solid Tumors (RECIST) criteria ent with previous studies, suggest that the increase [95% confidence interval (CI) for cohort response in CD8+ T-cell response through blockade of rate 4–27%) [Yang et al. 2007]. CTLA-4 signaling is not the major mechanism of tumor response [O’Mahony et al. 2007]. However, Yang and colleagues published a retrospective Prostate cancer analysis of four phase II studies of ipilimumab in Fong and colleagues published a phase I study of stage IV melanoma. Patients with clinical benefit 24 patients with metastatic castration-resistant had a statistically significant increase in CD8+ T prostate cancer treated with granulocyte mac- cells in comparison with patients without clinical rophage colony-stimulating factor (GM-CSF) and benefit (p = 0.0294) [Yang et al. 2010]. The sec- increasing doses of ipilimumab. Three of the six ond hypothesis was the potential for ipilimumab patients with the highest dose had prostate-specific to deplete Tregs. Flow cytometry was used to antigen declines of more than 50%. Expansion quantitate Tregs number. The authors showed a of activated circulating CD25+ CD69+ CD8+ significant decrease of Tregs at 1–4 days after each T cells was greater than in patients from two administration of ipilimumab. But the number of separate clinical trials who received ipilimumab or Tregs had increased above baseline at the time of GM-CSF as monotherapy [Fong et al. 2009]. next administration. This suggests that modula- tion of Tregs plays a role in tumor regression and that the transient decrease in Tregs allows for Ipilimumab in lung cancer immune activation [Yang et al. 2010]. Despite recent advances in lung cancer treatment with third-generation chemotherapies and targeted therapies, the prognosis of patients with lung can- Proof of concept of ipilimumab activity cer remains poor and there is a need for new thera- in solid malignancies peutic strategies to improve lung cancer patients’ Ipilimumab has been studied in several solid survival. Lung cancer in not known to be an immu- malignancies, and the main results are summa- nogenic-mediated malignancy. Ding and colleagues rized here to allow comparison with the NSCLC performed DNA sequencing of a large number of development of ipilimumab. genes in 188 lung cancer samples and identified 44 http://tam.sagepub.com P Tomasini, N Khobta et al. 26 genes mutated at significantly high frequencies chemotherapy may increase antigen exposure to and thus potentially involved in lung cancer car- immunotherapy but may also decrease the popu- cinogenesis [Ding et al. 2008]. None of the genes lation of immune cells mediating the response to were involved in immunity. However, immunother- immunotherapy. This is the reason why phasing apy remains an attractive therapeutic approach with chemotherapy is also of importance. Actually, because of its theoretical specificity and potential low-dose intravenous infusions of cyclophospha- long-term disease control. Consequently, several mide may overcome the immune suppression immunotherapies are under investigation in seen in carcinomas, and cyclophosphamide has NSCLC and some of them already showed promis- shown, in various animal models, its ability to ing results. Some immunotherapies have a specific augment delayed-type hypersensitivity responses, immune target; for example, MAGE-A3, Lucanix increase antibody production, abrogate tolerance, (belagenpumatucel-L, a transforming growth and potentiate antitumor immunity [Bass and factor β2-based vaccine, NovaRx, San Diego, CA, Mastrangelo, 1998]. To date, use of ipilimumab USA), Stimuvax (BLP25 liposome vaccine, a with pretreatment cyclophosphamide remains to vaccine targeting mucin 1, Oncothyreon, Seattle, be studied. WA, USA) and Saccharomyces-CEA vaccine. Some immunotherapies do not have identified tar- Ipilimumab showed promising results in the get, such as GVAX (GM-CSF vaccine), talactofer- treatment of NSCLC in a phase II study. The rin (a genetically engineered form of the human CA184-041 phase II study randomized previously protein lactoferrin), and ipilimumab [Morgensztern untreated patients with advanced NSCLC to et al. 2010]. As an example, a randomized phase II receive chemotherapy with carboplatin (area study of talactoferrin versus placebo in patients with under the curve 6) and paclitaxel (175 mg/m ) advanced NSCLC that progressed after chemo- alone or in association with concurrent ipilimumab therapy showed an improvement in OS (HR for (10 mg/kg from cycle 1 to cycle 4) or with phased survival = 0.68; p = 0.04) [Parikh et al. 2011]. In ipilimumab (10 mg/kg from cycle 3 to cycle 6) (see the same way, a phase II study of MAGE-A3 Figure 1 for design) [Lynch et al. 2010]. Overall, immunotherapy as adjuvant therapy in stage IB/II 204 patients were included in the study with com- NSCLC showed a positive trend for activity of mon characteristics for patients with advanced MAGE-A3 in NSCLC with a relative improve- NSCLC (74% men, 79% stage IV disease, 51% ment of disease-free survival of 27% [Vansteenkiste adenocarcinoma, and 71% European Cooperative et al. 2007]. However, there has been no vaccine or Oncology Group performance status 1). The pri- other immune-related therapy, FDA or European mary endpoint was immune-related progression- Medicines Agency (EMEA) approved, for NSCLC. free survival (irPFS), according to the guidelines Furthermore, Stimuvax, talactoferrin, MAGE-A3, for the evaluation of immune therapy activity and ipilimumab are still actively being investigated in solid tumors [Wolchok et al. 2009]. Clinical for the treatment of patients with NSCLC through response to immunotherapeutic agents is some- ongoing phase III studies. times represented by an initial increase in tumor size or even appearance of new lesions, therefore The rationale for the use of ipilimumab in associa- considered as a disease progression according to tion with chemotherapy is based on the assump- RECIST or World Health Organization (WHO) tion that tumor-specific antigen released during criteria. This novel pattern of clinical response chemotherapy-induced tumor necrosis may limits the use of the RECIST or WHO criteria increase tumor-specific immunity and therefore when using immunotherapy. Therefore, immune- enhance ipilimumab or other immunotherapeutic relative response criteria were defined in an efficacy. This hypothesis may explain the trend in attempt to capture additional response patterns favor of the sequential association of ipilimumab observed in immunotherapy. In the CA184-041 and chemotherapy in comparison with the con- study, irPFS was improved in the ipilimumab arms current association as highlighted in several in comparison with chemotherapy alone. Indeed, phase II studies, including lung cancer studies as the median irPFS was 5.68 months for the phased reported below. In addition, a randomized phase I ipilimumab arm versus 4.63 months for chemo- study assessed the pharmacokinetic interaction therapy alone (HR = 0.68, p = 0.026) and was between ipilimumab and paclitaxel/carboplatin in 5.52 months for the concurrent ipilimumab arm patients with untreated advanced melanoma and versus 4.63 months for chemotherapy alone (HR = there was no clinically relevant pharmacokinetic 0.77, p = 0.094). However, there was no signifi- interaction [Weber et al. 2010]. Complete-dose cant difference between the arms in terms of OS http://tam.sagepub.com 45 Therapeutic Advances in Medical Oncology 4 (2) Figure 1. Study design of the CA184-041 phase II study investigating the potential of concurrent and phased ipilimumab (IPI) versus placebo (p) with concomitant carboplatin (C, Carbo) plus paclitaxel (P, Pac) as first-line treatment in advanced stages of non-small cell lung cancer (NSCLC). q3w, every 3 weeks; q12w, every 12 weeks. (p = 0.104) but a trend seemed to favor the of patients in the placebo arm). The more specific sequential combination of ipilimumab plus chem- immune-related toxicities are detailed below. otherapy. Indeed, OS was 8.3 months in the placebo arm versus 9.7 months in the concurrent In 2011, Lynch and colleagues presented the arm (HR = 0.98, p = 0.47) and 12.2 months in results of a subgroup analysis of the CA184-041 the phased arm (HR = 0.86, p = 0.23). The dis- phase II study looking at efficacy by histological ease control rate (DCR) seemed also to favor the subtypes [Lynch et al. 2011]. This subgroup phased combination of ipilimumab with chemo- hypothesis-generating analysis suggested that therapy with a DCR of 57.1 versus 77.9 and 72.7 patients with squamous NSCLC might derive a for chemotherapy alone, phased and concurrent greater benefit of the ipilimumab plus chemother- ipilimumab, respectively. Although the absolute apy combination when compared with patients difference in irPFS seems small (1 month), it is with nonsquamous NSCLC, especially for the statistically significant and we have to focus on HR phased combination. Indeed, the median irPFS (0, 68). In this disease with such a poor prognosis, was 6.2 and 5.7 months for the phased ipili- there are very few immune therapies showing such mumab arms versus 4.2 and 5.3 months for chem- promising results. Furthermore, some patients otherapy alone in squamous and nonsquamous experienced almost complete and longlasting NSCLC, respectively (HR = 0.55 and 0.82, responses (Figure 2), highlighting the need for respectively). The retrospective nature of this phase III studies and assessment for potential pre- analysis and the small sample size warrants cau- dictive biomarkers. The association of ipilimumab tion in interpretation. and chemotherapy was generally well tolerated and ipilimumab did not potentiate chemotherapy- related toxicity. However, safety results suggest a Safety profile in solid malignancies moderate added toxicity in the arms containing The major toxicities due to ipilimumab are ipilimumab (grade 3–4 adverse events were immune-related adverse events (irAEs). The most observed in 58% of patients in the concurrent arm common major toxicity was enterocolitis (21% of and 52% of patients in the phased arm versus 42% patients) [Beck et al. 2006], defined by diarrhea 46 http://tam.sagepub.com P Tomasini, N Khobta et al. Figure 2. Thoracic computed tomography scans showing baseline (left panels) and current (right panels) scans of a patient with stage IV non-small cell lung cancer participating in the CA184-041 phase II study, and showing an almost complete and long-lasting response to the combination of ipilimumab plus concurrent carboplatin plus paclitaxel chemotherapy. or biopsy documentation (neutrophilic and Thus, the early screening and treatment of auto- lymphocytic inflammation). The major risk is immune endocrinopathies is recommended in represented by bowel perforation. Most patients patients undergoing clinical trials with ipili- with enterocolitis respond to high-dose systemic mumab. Ipilimumab can also induce uveitis and corticosteroids, without affecting tumor response, hepatitis that may be severe and corticosteroid but a significant association between irAEs and resistant [Chmiel et al. 2011]. tumor regression (response rate 30% with irAEs versus 0% without irAEs) was also shown [Yang In the CA184-041 phase II study dedicated to et al. 2007]. Weber and colleagues conducted a patients with NSCLC, irAEs were more fre- double-blind placebo-controlled phase II study quent in the ipilimumab arms (19% and 15% of prophylactic budesonide in the management of grade 3–4 irAEs for concurrent and phased grade ≥2 diarrhea in patients with unresectable arms, respectively, versus 6% in the placebo advanced melanoma receiving ipilimumab. arm) [Lynch et al. 2010]. There were mostly Budesonide did not affect the rate of grade ≥2 grade 3 irAEs, with dermatologic and gastroin- diarrhea (32.7% versus 35%) [Weber et al. 2009]. testinal irAEs the most frequent. A fatal grade 5 Immune-related endocrinopathies have also been toxic epidermal necrolysis was observed in described. Autoimmune hypophysitis has been a patient treated in the concurrent arm. No reported in 17% (all grades) of patients with hypopituitarism or adrenal insufficiency was melanoma and RCC treated with ipilimumab. observed, but two patients experienced a grade Furthermore, cases of hypopituitarism have been 1–2 hypothyroidism. described in patients with prostate cancer under- going experimental therapy with ipilimumab. In most cases, high-dose glucocorticoid treatment Perspectives improved symptoms [Dillard et al. 2010]. In The results of the CA184-041 study actually led the same way, cases of hyperthyroidism after to the design of a phase III study of the association ipilimumab therapy for patients with advanced of ipilimumab with paclitaxel/carboplatin in melanoma have been described [Min et al. 2011]. previously untreated advanced NSCLC with http://tam.sagepub.com 47 Therapeutic Advances in Medical Oncology 4 (2) Table 1. Immune-related response criteria (irRC) [Wolchok, 2009]. Complete response All lesions gone Partial response ≥ 50% decrease in SPD of index + new* lesions Stable disease SPD of index + new* lesions not irCR, irPR or irPD Progressive disease SPD of index + new* lesions increases ≥25% SPD, sum of products of perpendicular diameters; irCR, immune related Complete Response; irPR, immune related Partial Response; irPD, immune related Progressive Disease;*, differences between irRC and modified World Health Organization response criteria. squamous histology (clinicaltrials.gov, NCT discovery, evaluation and clinical application of 01285609 and NCT00527735). immune biomarkers [Bedognietti et al. 2011]. In addition, Breunis and colleagues provide data However, the potential efficacy of ipilimumab in suggesting that genetic variations in CTLA-4 NSCLC together with its particular mechanism could influence response to CTLA-4 blockade of action might also lead to investigation in earlier [Breunis et al. 2008], representing a first step in stages of the disease, such as the early stages of biomarker development in the field of ipili- NSCLC in the adjuvant or neoadjuvant setting, mumab studies. but also in all the situations when a maintenance treatment might be useful (response after induc- tion chemotherapy in NSCLC, management of Conclusions unresectable stage III, etc.). The investigation of Ipilimumab is an anti-CTLA-4 antibody. A ipilimumab in early stage lung cancer may expose phase II study of ipilimumab in the first-line patients to long-term irAEs. Long-term results of treatment of metastatic NSCLC in association a phase III trial of ipilimumab in metastatic mela- with chemotherapy showed an improvement of noma describe only 1% of irAEs in the ‘ipili- irPFS in comparison with chemotherapy alone, mumab alone’ arm, mostly grade 1 or 2, with no without major added toxicity. Phase III studies, grade 4 or 5 toxicities. The long-term benefit of especially in the squamous-NSCLC population, ipilimumab on OS has been demonstrated are ongoing. In the future, ipilimumab should be [Haanen et al. 2010]. Furthermore, in compari- investigated in early stage or locally advanced son with adjuvant chemotherapy for resected lung lung cancer, such as other immunotherapies. cancer, the long-term results of the International There is also a need for the research of biomark- Adjuvant Lung Cancer Trial on OS favor adju- ers to individualize and optimize the use of vant chemotherapy, but not significantly, after ipilimumab in NSCLC. 5 years even if non-lung cancer mortality is increased in the chemotherapy arm [Arriagada Funding et al. 2010]. This research received no specific grant from any funding agency in the public, commercial, or not- In addition, predictive and prognostic biomark- for-profit sectors. ers to drive the use of ipilimumab should be investigated in tumor or blood. 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(2007) Ipilimumab Visit SAGE journals online http://tam.sagepub.com Weber, J.S., Hamid, O., Wolchok, J., Amin, A., (anti-CTLA4 antibody) causes regression of Masson, E., Goldberg, S. et al. (2010) Assessment metastatic renal cell cancer associated with enteritis SAGE JOURNALS Online of pharmacokinetic interaction between ipilimumab and hypophysitis. J Immunother 30: 825–830. 50 http://tam.sagepub.com

Journal

Therapeutic Advances in Medical OncologySAGE

Published: Dec 14, 2011

Keywords: biomarkers; immunotherapy; ipilimumab; lung cancer; targeted therapy

References