Checkpoint inhibitors in the first-line treatment of non-small cell lung cancer

380 Checkpoint inhibitors in the first-line treatment of non-small cell lung cancer L. Decoster, MD 1, K. Vekens, MD 2, S. Mignon, MD 1, D. Schallier, MD, PhD 1, J. De Grève, MD, PhD 1 SUMMARY Antibodies against programmed cell death-1 (PD-1) and its ligand (PD-L1) have become standard-of-care in the second-line treatment for advanced non-small cell lung cancer after failure of first-line chemotherapy. The observed durable responses as well as the favourable toxicity profile have moved these agents to firstline studies for advanced non-small cell lung cancer. In tumours with high PD-L1 expression, pembrolizumab is registered as the preferred first-line treatment. Further studies are currently focusing on combination strategies. The major future challenge will be selecting the optimal treatment strategy for the patient. (BELG J MED ONCOL 2017;11(8):380-385) INTRODUCTION In locally advanced or metastatic non-small-cell lung cancer (NSCLC) without targetable driver mutations, platinum-doublet chemotherapy has been the standard-of-care for the past three decades. The proportion of patients who achieve response to first-line chemotherapy is 25-35%, but these responses are rarely durable with a median progression free survival (PFS) of four to six months and a median overall survival (OS) of eight to ten months. 1 In addition, chemotherapy is associated with moderate to severe toxicities. Immune checkpoints inhibitors, such as antibodies targeting the cytotoxic T-lymphocyte associated protein 4 (ctla4) and the programmed cell death-1 (PD-1) protein or the PD ligand 1 (PD-L1), are rapidly reshaping the therapeutic landscape of different tumour types, including NSCLC. Four randomised phase III studies in NSCLC have demonstrated superior activity of the PD-1 inhibitors nivolumab (CheckMate 017 and 057) and pembrolizumab (Keynote 010) and the PD-L1 inhibitor atezolizumab (OAK) over docetaxel chemotherapy in second-line and beyond, with response rates of approximately 20% and significant improvements in OS. 2-5 In addition, treatment with an anti- PD-(L)1 inhibitor resulted in durable responses, decreased toxicity and improved quality-of-life when compared to docetaxel. As a result, PD-1 blockade has become a new standard-of-care for patients with advanced NSCLC who experience progression on or after a platinum-based chemotherapy. The observed activity and improved tolerability of PD-1/ PD-L1 inhibitors in second-line setting for NSCLC have increased the interest in moving these agents to the front-line setting. This review summarises the current knowledge on first-line immunotherapy treatment for advanced NSCLC (Table 1). 1 Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel, Brussel, Belgium, 2 Department of Pulmonology, UZ Brussel, Vrije Universiteit Brussel, Brussel, Belgium. Please send all correspondence to: L. Decoster, MD, Oncologisch Centrum, Department of Medical Oncology, Laarbeeklaan 101, 1090 Brussel, Belgium, tel: +32 2 477 60 40, email: lore.decoster@uzbrussel.be. Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. Keywords: checkpoint inhibitors, first-line, non-small cell lung cancer. VOLUME11DECEMBER2017

PHARMACOTHERAPY 381 TABLE 1. Overview of the reported first -line studies in non-small cell lung cancer with immunotherapy. Study drug(s) Study Name (reference) Phase Compared with Patient selection Patient number Response (%) PFS OS AE Anti-PD-(L)1 monotherapy Pembrolizumab Keynote 024 (7) 3 CT Yes, PD- L1 50% 305 44.8 vs 27.8 mpfs 10.3 m vs 6 m; 6mOS 80% vs 72% Any grade: 73 vs 90% Grade 3/4: 27 vs 53% Nivolumab Checkmate 012 (8) 1 No 52 23 mpfs 3.6m PFS24w 41% mos 19.4m 1y0S 73% Any grade: 71% Grade 3/4: 19% Nivolumab Checkmate 026 (9) 3 CT Yes PD- L1 1% 541 mpfs 4.2 vs 5.9m Durvalumab 1108 study (10) 1/2 NA No 59 27 NR NR Any grade: 56% Grade 3/4 : 10% Avelumab Javelin solid tumour (11) 1 NA No 156 22 mpfs 4m PFS 24w 37% NR Any grade: 66% Grade 3/4: 11% Anti-cTLA4/anti PD-(L)1 combination Ipilimumab/ Nivolumab CheckMate 012 (15) 1 NA No 77 38-47 mpfs 3.9-8.1 m PFS 24w 47-68% 1yOS 69% Any grade: 72-82% Grade 3/4: 33-37% Anti-cTLA4/chemotherapy combination Ipilimumab/ carboplatinum/paclitaxel (18) 2 Concurrent vs Phased vs CT No 204 21 vs 32 vs 14 mpfs 4.1 vs 5.1 vs 4.2m mos 9.7 vs 12.2 vs 8.3m 1yOS 42 vs 50 vs 39% Any grade: 76% vs 82 % vs 80% Grade 3/4: 41% vs 39% vs 37% Anti-PD-(L)1/chemotherapy combination Nivolumab/ platinum- doublet CheckMate 012 (19) 1 NA No 56 33-47 mpfs 4.8-7.1m PFS24w 38-71% mos 11.6-19.2m 1y0S 5à-87% Any grade: 95% Grade 3/4: 45% Pembrolizumab/ carboplatinum/ pemetrexed Keynote-021 (20) Atezolizumab/ platinum doublet GP28328 (21) 2 CT No 123 55 vs 29 mpfs 13 vs 8.9m NR Any grade: 94% vs 90% Grade 3/4: 40% vs 25% 1b NA No 58 50-76.5 NR NR Any grade: 98% Grade 3/4 : 78% Abbreviations: PFS: Progression Free Survival; OS: Overall Survival; AE: Adverse Events; NA: Not applicable; NR: Not Reported; m: months; y: year; vs: versus; CT: chemotherapy. MECHANISM OF ACTION OF CHECKPOINT INHIBITORS To mediate anti-tumour responses, T cells must be specific for cancer cells and activated into an effector state. The process of T cell activation involves an antigen presentation to the corresponding T cell receptor on naïve T cells. In addition, a second co-stimulatory signal by interaction of B7 on an antigen-presenting cell with CD28 on the T cell is required for full activation of the T cells. This is regulated by inhibitory checkpoints to avoid collateral damage and autoimmunity. In the lymph nodes, the ctla4 receptor on activated T cells competes with CD28 for B7 ligands and subsequently down- VOLUME11DECEMBER20178

382 FIGURE 1. Overall survival for pembrolizumab versus platinum-doubled in the first line treatment of non-small cell lung cancer. regulates the T cell function. The anti-ctla4 antibodies reactivate T cells by facilitating the CD28-B7 binding. In the tumour microenvironment, the PD1 checkpoint receptor, expressed by activated T cells, will bind with the PD-L1 receptor expressed by the tumour cells in order to suppress T cell activation. In NSCLC, approximately 60% of patients present with a PD-L1 expressing tumour. 6 Antibodies blocking either PD-1 or PD-L1 can unleash the activated tumour-reactive T cells. IMMUNE CHECKPOINTS AS MONOTHERAPY IN FIRST-LINE FOR NSCLC Two first-line phase III studies have compared an anti-pd1 antibody to platinum-based chemotherapy with variable success. In the randomised, open-label phase III Keynote-024 trial, pembrolizumab was compared to first-line platinum-doublet chemotherapy for patients with advanced NSCLC and a PD-L1 tumour proportion score of 50% or greater. 7 In this trial, there was an increase of the objective RR (45% versus 28%) and a prolongation of the median PFS (10.3 months versus 6.0 months; HR 0.50; p<0.001). In addition, although median OS was not reached in either group there was a significant prolongation of the OS at six months in the pembrolizumab group (80.2% versus 72.4%, HR 0.60; p=0.005) (Figure 1). As in the second-line studies, all grades adverse events were less frequent for pembrolizumab (73% versus 90%) and grade 3-4 treatment-related adverse events occurred in twice as many patients in the chemotherapy group (53% versus 27%). This also means that more than a quarter of patients on immunotherapy have no toxicity at all. Immune related adverse events were more frequent with pembrolizumab (29% with 10% grade 3-4) and cytopaenias (anaemia 44%, neutropenia VOLUME11DECEMBER2017

PHARMACOTHERAPY 383 23% with 13% grade 3-4 and thrombocytopenia 11%) were more frequent with chemotherapy, consistent with the mechanism of action of each treatment. Since pembrolizumab was associated with longer PFS and OS and fewer treatment-related adverse events than platinum-based chemotherapy, this treatment received FDA and EMA registration as first-line treatment for NSCLC with high PD-L1 expression of 50% and is currently reimbursed in Belgium for this indication. Interestingly, the same success was not observed in the CheckMate 026 trial. In this randomised phase III trial nivolumab was compared to first-line platinum-doublet chemotherapy for patients with advanced NSCLC and a PD-L1 expression of 1%. In addition PD-L1 expression of <5% versus 5% was a stratification factor at randomisation. A prior phase I study (CheckMate 012) demonstrated clinical activity with nivolumab in the first line treatment for NSCLC regardless of PD-L1 expression but with higher RR in patients whose tumours expressed PD-L1 and with a trend toward greater response as PD-L1 expression level increased. 8 In the phase III trial, CheckMate 026, nivolumab did not improve PFS compared to platinum-based chemotherapy (4.2 versus 5.9 months; HR 1.15; p=0.25). 9 The anti-pdl-1 antibodies durvalumab and avelumab have also been studied in early phase first-line trials. In the 1108 study, durvalumab monotherapy led to an objective RR of 27% and a disease control rate at 24 weeks of 42%. 10 In this trial the RR was higher for tumours with high PD-L1 expression ( 25%) versus tumours with lower PD-L1 expression (RR 29% versus 11%). In the phase I Javelin solid tumour trial the objective RR for avelumab monotherapy in the NSCLC cohort was 22% with a PFS at 24 weeks of 37%. 11 Different trials investigating the efficacy of an anti-pd-(l)1 antibody in the first-line setting versus chemotherapy are still ongoing, including Keynote 042 of pembrolizumab in patients with advanced NSCLC with a PD-L1 expression 1% (NCT 02220894), IMpower 110 and 111 with atezolizumab in respectively PD-L1 positive non-squamous NSCLC (NCT 02409342) and squamous NSCLC (NCT 02409355) and Javelin Lung 100 with avelumab (NCT 02576574). 12 DUAL CHECKPOINT BLOCKADE ctla-4 and PD-1 inhibit anti-tumour immunity through complementary and non-redundant mechanisms. These non-overlapping mechanisms of action of anti-ctla4 and anti-pd-(l)1 antibodies make combination of these two classes of checkpoint inhibitors an interesting strategy. Preclinical models have shown that dual blockade, as compared with blockade of either pathway alone, synergistically improves anti-tumour responses. 13 In melanoma, the highest RR and PFS were observed with the combination of ipilimumab and nivolumab (RR 57.6% and PFS 11.5 months) in comparison with nivolumab monotherapy (RR 43.7% and PFS 6.9 months (HR 0.74)) and ipilimumab monotherapy (RR 19% and PFS 2.9 months (HR 0.42; p<0.001)). This improved PFS compared to nivolumab was mainly observed in the PD-L1 negative tumours (11.2 months versus 5.3 months). However, the observed increased activity was at the expense of a higher frequency of serious treatment-related adverse events (55% for the combination arm versus 16.3% for nivolumab monotherapy). 14 In the CheckMate 012 phase I trial, two cohorts combined nivolumab every two weeks with ipilimumab either every twelve weeks or every six weeks. 15 This combination resulted in a RR of 38-47%, a median PFS of four to eight months and a one-year survival of 69%. The RR of the nivolumab/ipilimumab combination was enhanced with increasing PD-L1 expression: 21% for a PD-L1 expression of <1%; 57% for a PD-L1 expression of 1% and 92% for a PD-L1 expression of 50%. In addition the one-year OS for this last group of patients was 100%. In this study grade 3-4 adverse events seemed more frequent than observed for anti-pd-1 monotherapy (33-37%). The first-line combination of nivolumab/ ipilimumab is currently under investigation in a phase III study, CheckMate 227 (NCT 02477826). 12 Two other ongoing trials investigating the combination of durvalumab with tremelimumab are ongoing (MYSTIC: NCT02453282 and NEPTUNE: NCT 02542293). 12 COMBINATION OF CHECKPOINT INHIBITOR WITH CHEMOTHERAPY IN FIRST-LINE Although conventional chemotherapy may be immunosuppressive because of the myelodepression, it may also stimulate anti-cancer immunity through various mechanisms: 1) induction of immunogenic cell death with tumour antigen release which can activate dendritic cells and consequently specific T cell response, 2) elimination of immunosuppressive cells and 3) sensibilisation of tumour cells to immune effector cells. 16,17 For this reason, there is a strong rationale to combine chemotherapy with checkpoint inhibitors. Early phase studies have combined chemotherapy with either anti-ctla4 or anti-pd-(l)1 antibodies. In a randomised phase II trial in NSCLC carboplatinum/paclitaxel chemotherapy was combined with ipilimumab in two different regimens: either concurrent ipilimumab (four doses of ipilimumab plus chemotherapy followed by two doses of placebo plus chemotherapy) or phased ipilimumab (two doses of placebo plus chemotherapy followed by four doses of ipilimumab plus chemotherapy). The study resulted in an improved PFS for the phased ipilimumab regimen (HR VOLUME11DECEMBER20178

384 KEY MESSAGES FOR CLINICAL PRACTICE 1. Pembrolizumab has become standard-of-care for the first-line treatment of advanced NSCLC with a PD- L1 expression of 50%. It is the only immunotherapy registered and reimbursed in the first line setting so far. 2. Phase III trials combining different types of immunotherapy or immunotherapy and chemotherapy are ongoing. 3. PD-L1 expression is an enrichment biomarker for response to immunotherapy in NSCLC, but other markers may be even more important for the immune response against the tumour. Predictive biomarkers are needed in order to select the optimal first-line treatment strategy for patients with advanced NSCLC. 0.69; p=0.02) but not for the concurrent regimen (HR 0.88; p=0.25). 18 In a phase I trial nivolumab was combined with four cycles of a platinum-doublet chemotherapy followed by nivolumab monotherapy. 19 In this trial, the RR varied from 33-47% and the median OS ranged from 11.1 to 19.2 months. In addition, no dose limiting toxicities were observed. In this small study no increased efficacy was observed with higher PD-L1 expression. The nivolumab/platinum-doublet chemotherapy combination is currently being investigated in the Check- Mate 227 trial (NCT 02477826). 12 In the randomised phase II study Keynote-021, patients with advanced non-squamous NSCLC were treated with carboplatin-pemetrexed chemotherapy with or without pembrolizumab. 20 Both objective RR (55 versus 29%, p=0,0016) and median PFS (13,0 versus 8,9 months; HR 0.53; p=0,01) favoured the pembrolizumab-chemotherapy combination over chemotherapy alone but there was no difference in OS between the two groups (HR 0.90; p=0.39) possibly because of a cross over in the chemotherapy alone group. In this phase II study the incidence of both any grade and grade 3-4 adverse events was similar for both groups (93% versus 90% and 39% versus 26%, respectively). Based on these results the FDA granted accelerated approval to pembrolizumab for use in combination with carboplatin plus pemetrexed as front line treatment for patients with metastatic or advanced non-squamous NSCLC, regardless of PD-L1 expression in May 2017. A phase III trial (Keynote-189) combining platinum-pemetrexed chemotherapy with pembrolizumab in non-squamous NSCLC is ongoing (NCT 02578680). The anti-pd-l1 antibody atezolizumab also demonstrated a promising RR (50-76%) in combination with chemotherapy. 21 Different phase III trials combining atezolizumab with chemotherapy are ongoing (IMpower 130 in non-squamous NSCLC (NCT 02367781), IMpower 131 in squamous NS- CLC (NCT02367794)). 12 CONCLUSION The emergence of immunotherapy in NSCLC has drastically changed the landscape of the management of this deadly disease, offering the potential for a durable response and a prolonged survival. Based on the results of the Keynote-024 trial, pembrolizumab has become the new standard-of-care for the firstline treatment of NSCLC with a high PD-L1 expression of 50%. 7 Pembrolizumab is currently the only immunotherapy approved and reimbursed in the first-line setting. Other immunotherapy drugs have so far not demonstrated any benefit over chemotherapy in the first-line setting. Combination strategies are under investigation in an attempt to further increase the number of patients potentially benefiting from immunotherapy. 12 In May 2017, the combination of pembrolizumab with chemotherapy carboplatin and pemetrexed received accelerated approval based on phase II results. However, this combination also seems to increase the toxicity and is further being explored in a phase III trial For this reason, the challenge in advanced NSCLC in the coming years will be the identification of an individualised optimal treatment strategy in the first-line setting. Patient selection will be crucial. So far PD-L1 expression seems to be an enrichment biomarker for the response to immunotherapy in NSCLC. However other factors beyond PD-L1 expression such as tumour mutational load or patient s immune profile may be important for the immune response against the tumour and research should therefore continue to focus on the identification of potential biomarkers. 22,23 REFERENCES 1. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Eng J Med. 2002;346:92-8. 2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Eng J Med. 2015;373:123-35. 3. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Eng J Med. 2015;373:1627-39. VOLUME11DECEMBER2017

PHARMACOTHERAPY 385 4. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1 positive, advanced non-small-cell lung cancer (KEY- NOTE-010): a randomised controlled trial. Lancet. 2016;387:1540-50. 5. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicenter randomised controlled trial. Lancet. 2017;389:255-65. 6. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of nonsmall-cell lung cancer. N Eng J Med. 2015;372:2018-28. 7. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Eng J Med. 2016;375:1823-33. 8. Gettinger S, Rizvi NA, Chow LQ, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2016;34:2980-7. 9. Sonciski M, Creelan B, Horn L, et al. CheckMate 026: A Phase 3 trial of nivolumab vs Investigator s choice (IC) of platinum-doublet chemotherapy (PT- DC) as first line therapy for stage IV/recurrent programmed death ligand 1 (PD- L1) positive NSCLC. Ann of Oncol. 2016;27, suppl 6: abstract LBA7_PR (ESMO 2016). 10. Antonia SJ, Brahmer JR, Khleif S, et al. Phase 1/2 study of the safety and clinical activity of durvalumab in patients with non-small cell lung cancer. Ann of Oncol. 2016;27, suppl 6:416-54. 11. Jerusalem G, Chen F, Spigel D, et al. Javelin solid tumour: safety and clinical activity of avelumab (anti-pd-l1) as first line treatment in patients with advanced NSCLC. J Thorac Oncol. 2017; 12 (suppl):s252. 12. www.clinicaltrials.gov 13. Selby MJ, Engelhardt JJ, Johnston RJ, et al. Preclinical development of ipilimumab and nivolumab combination immunotherapy: mouse tumour models, in vitro functional studies, and cynomolgus macaque toxicology. PLoS One. 2016;11(11):e0167251. 14. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Eng J Med. 2015;373:23-34. 15. Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017;18:31-41. 16. Apetoh L, Ladoire S, Coukos G, et al. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol. 2015;26:1813-23. 17. Galluzzi L, Buque A, Kepp O, et al. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28:690-714. 18. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatinum as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomised, double-blind, multicenter phase II study. J Clin Oncol. 2012;30(17):2046-54. 19. Rizvi NA, Hellmann MD, Brahmer J, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-smallcell lung cancer. J Clin Oncol. 2016;34(25):2969-79. 20. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatinum and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508. 21. Liu S, Powderly JD, Camidge DR, et al. Safety and efficacy of MPDL3280A (anti-pdl1) in combination with platinum-based doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2015:33 (abstract 8030). 22. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8. 23. Tiseo M, Veneziani M, Gelsomino F, et al. Circulating immune-profile as predictor of outcome in NSCLC patients treated with nivolumab. Ann of Oncol. 2017;28 (suppl 2):ii9-ii13. Call for Oncothesis Share your thesis with your colleagues! At the Belgian Journal of Medical Oncology (BJMO) we are constantly looking for interesting doctoral theses in oncology. The BJMO is an ideal platform to share your research with your colleagues and peers. The BJMO is the official platform of the Belgian Society of Medical Oncology (BSMO) and the Belgian Association for Cancer Research (BACR) and as such offers optimal visibility in the Belgian oncology community. All article submissions or requests for additional information are most welcome at editor@bjmo.be VOLUME11DECEMBER20178