Immuno-oncology

Med Learning Group

Current and Emerging Immunotherapies

Oncology is a rapidly evolving field with new therapeutic agents constantly in development. There are several approved immune checkpoint inhibitors currently on the market and several other novel agents are under investigation. Below you will find brief summaries of recent clinical trials for immune checkpoint inhibitors and links to relevant journal articles.

Ipilimumab

Anti-CTLA-4 monoclonal antibody

Recent clinical trials

  • Patients with stage III and IV metastatic melanoma that progressed on chemotherapy saw improvements in median overall survival (OS) on ipilimumab (10 months) vs. gp100 (6.4 months). Grade 3 or 4 immune-related adverse events (AEs) occurred in 10 to 15% of patients treated with ipilimumab and in 3% of patients treated with gp100 alone. There were 14 deaths related to the study drug (2.1%), and 7 were associated with immune-related adverse events.1
  • Patients with complete resections of stage III cutaneous melanoma and who received 10 mg/kg ipilimumab had significantly higher rates of overall survival (65.4% vs 54.4%), recurrence-free survival (40.8% vs 30.3%) and distant metastasis-free survival (48.3% vs 38.9%) compared to placebo. Higher rates of grade 3 or 4 adverse events (54.1% vs. 26.2%) as well as immune-related adverse events (41.6% vs 2.7%) occurred in the ipilimumab group compared to placebo.2

Nivolumab

Anti-PD-1 monoclonal antibody

Recent clinical trials

  • Nivolumab was investigated in patients with metastatic DNA mismatch repair deficient/microsatellite instability-high colorectal cancer. At median follow-up of 12 months, 23 of 74 patients achieved an objective response and 69% of patients had disease control for 12 or more weeks. The most common grade 3 or 4 adverse events were increases in lipase (8%) and amylase (3%). 23 patients died during the study due to non-treatment related causes.3
  • In patients with recurrent squamous-cell carcinoma of the head and neck whose disease progressed after 6 months of platinum-based chemotherapy, nivolumab significantly improved median OS (7.5 months vs 5.1 months) and 1-year survival rates (36% vs 16.6%) compared to standard chemotherapy. The rate of PFS at 6 months (19.7% vs 9.9%) and response rate (13.3% vs 5.8%) were significantly improved for nivolumab versus chemotherapy.4
  • A dose escalation trial of nivolumab in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis found an objective response rate of 20% in the dose-expansion phase and 15% in the dose-escalation phase.5
  • An objective response rate of 87% was observed in patients receiving nivolumab with relapsed or refractory Hodgkin’s lymphoma. The rate of PFS at 24 weeks was 86%.6
  • Median OS (12.2 months vs 9.4 months) and the OS rate at 1 year (51% vs 39%) were significantly higher for patients with advanced non-squamous non-small cell lung cancer who received nivolumab compared to docetaxel. With additional follow-up, the OS rate at 18 months was 39% for nivolumab compared to 23% for docetaxel.7
  • In patients with advanced renal cell carcinoma, nivolumab was associated with a longer median OS (25.0 months vs 19.6 months) and higher objective response rate (25% vs 5%) than everolimus monotherapy. Grade 3 or 4 adverse events occurred in 19% of patients receiving nivolumab and 37% of patients receiving everolimus.8
  • An investigation on the efficacy of nivolumab in patients with metastatic or unresectable urothelial carcinoma whose disease progressed on platinum-based therapy found that a confirmed objective response was achieved in 19.6% of patients, irrespective of PD-L1 expression levels.9
  • In patients with melanoma refractory to ipilimumab and BRAF inhibition, nivolumab led to higher objective responses (31.7% vs 10.6%) and 6-month progression free survival (48% vs 36%) compared to chemotherapy. The nivolumab safety profile was tolerable with manageable side effects, including fatigue, pruritus, and diarrhea, compared to nausea, fatigue, alopecia, and anemia most commonly in the chemotherapy group.10
  • Nivolumab was compared to dacarbazine in individuals without a BRAF Nivolumab had a superior OS (72.9% vs 42.1%) and median PFS (5.1 vs 2.2 months) compared to chemotherapy. Drug-related AEs of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine.11

 

Nivolumab plus Ipilimumab

Combination therapy with an anti-PD1 and anti-CTLA-4 monoclonal antibodies

Recent clinical trials

  • At median follow-up of 13.4 months, combination therapy of nivolumab plus ipilimumab resulted in an objective response rate of 55% and a disease control rate >12 weeks in 80% of patients with DNA mismatch repair deficient/microsatellite instability-high colorectal cancer.12
  • In patients with melanoma metastatic to the brain, nivolumab plus ipilimumab produced a complete response in 26% of patients and a partial response rate of 30%. The rate of intracranial benefit was 57% and the rate of extracranial benefit was 56%. Grade 3 or 4 adverse events were reported in 55% of patients.13
  • Nivolumab plus ipilimumab resulted in longer PFS and higher objective response rate than ipilimumab alone in patients with advanced melanoma. The OS at 3 years was 58% in the combination group, 52% in the nivolumab group, and 34% in the ipilimumab group. The rate of grade 3 or 4 adverse events was higher in the combination group (59%) than in the nivolumab (21%) or ipilimumab (28%) monotherapy groups.14
  • In a comparison of nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma, the 18-month OS was longer for the combination therapy compared to sunitinib (75% vs 60%). The objective response rate was 42% and the median OS was not reached for the nivolumab plus ipilimumab treatment arm, compared to an ORR of 27% and a median OS of 26.0 months for sunitinib.15
  • A dose escalation study in patients with recurrent small-cell lung cancer found that various doses of nivolumab plus ipilimumab resulted in an objective response rate in 21% of patients, and nivolumab monotherapy resulted in an ORR of 10%16

 

Pembrolizumab

Anti-PD-1 monoclonal antibody

Recent clinical trials

  • Pembrolizumab monotherapy demonstrated an ORR of 11.6% and a median response duration of 8.4 months in patients with previously treated advanced gastric and gastroesophageal junction cancer.17
  • In patients with ipilimumab-refractory melanoma, pembrolizumab was associated with improved 6-month PFS (34-38%) compared to standard chemotherapy (16%).18
  • In patients with previously treated, PD-L1 positive, advanced non-small cell lung cancer, median OS was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. PFS was approximately 1 month longer for patients receiving pembrolizumab compared to docetaxel.19
  • Treatment naïve patients with metastatic non-small cell lung cancer were randomly assigned to receive either pembrolizumab or placebo. Both treatment groups received pemetrexed and a platinum-based chemotherapy regimen. The OS at 12 months was 69.2% for pembrolizumab compared to 49.4% for the placebo arm. Median PFS was significantly higher for pembrolizumab than for placebo (8.8 months vs 4.9 months).20
  • In patients with advanced uroepithelial carcinoma that progressed after platinum-based chemotherapy, pembrolizumab resulted in a longer median OS (10.3 months vs 7.4 months) compared to chemotherapy. Fewer treatment related adverse events were associated with pembrolizumab use (60.9%) than with chemotherapy (90.2%).21

 

Cemiplimab

Anti-PD-1 monoclonal antibody

Recent clinical trials

  • Cemiplimab demonstrated a positive risk/benefit profile and produced antitumour activity in patients with advanced CSCC in primary analyses with a median time to response of 1.9 months.22
  • Cemiplimab 3 mg/kg Q2W showed substantial antitumor activity, durable responses, and acceptable safety profile in patients with laCSCC.23 ORR by central review was 43.6% and investigator-assessed ORR was 52.6%. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.8%.

 

Atezolizumab

Anti-PD-L1 monoclonal antibody

Recent clinical trials

  • A study of atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic non-squamous non-small cell lung cancer who had not previously received chemotherapy found improved median PFS (8.3 months vs 6.8 months) and median OS (19.2 months vs 14.7 months) in patients in the treatment group compared to those who received chemotherapy plus bevacizumab.24
  • In patients with previously treated, advanced or metastatic non-small cell lung cancer, atezolizumab plus docetaxel increased OS (12.6 months vs 9.7 months) compared to docetaxel alone. Increasing improvements in OS were associated with increasing PD-L1 expression. There were significantly fewer treatment-related adverse events in the atezolizumab group compared to docetaxel alone.25
  • In patients with extensive-stage small cell lung cancer, atezolizumabplus carboplatin and etoposide was associated with longer median OS (12.3 months vs 10.3 months) and median PFS (5.2 months vs 4.3 months) compared to chemotherapy alone.26
  • Atezolizumab was studied in cisplatin-ineligible patients with metastatic urothelial cancer. At 17.2 months median follow-up, the objective response rate was 23%, and 19 of 27 responses were ongoing. Immune-related adverse events occurred in 12% of patients, and the most common adverse events were fatigue (30%), diarrhea (12%), and pruritis (11%).27

 

Avelumab

Anti-PD-L1 monoclonal antibody

Recent clinical trials

  • In patients with stage IV Merkel cell carcinoma that progressed after chemotherapy, 31.8% of patients achieved an objective response, with 8 complete responses and 20 partial responses. Serious treatment-related adverse events were reported in 6% of patients receiving avelumab, including enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis.28
  • In patients with locally advanced or metastatic urothelial carcinoma that had progressed after previous platinum-based chemotherapy, 17% of patients receiving avelumab achieved a complete or partial response. The most common treatment-related adverse events were infusion-related reaction (29%) and fatigue (16%). 8% of patients experienced serious AEs, with one death due to pneumonitis.29

 

Durvalumab

Anti-PD-L1 monoclonal antibody

Recent clinical trials

  • In patients with stage III, unresectable NSCLC, the OS (66.3% vs 55.6%) and PFS (17.2 months vs 5.6 months) were longer in the durvalumab group compared to placebo. Median time to death or distant metastases was 28.3 months for durvalumab compared to 16.2 months for the placebo group. Grade 3 or 4 adverse events occurred in 30.5% of the durvalumab group and 26.1% of the placebo group.30

References

  1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723
  2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy.N Engl J Med. 2016;375(19):1845-185
  3. Overman MJ, McDermott R, Leach JL, et al Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182-1191
  4. Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856-1867.
  5. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase ½ dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502
  6. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311-319
  7. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639
  8. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813
  9. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322.
  10. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375-384
  11. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330
  12. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol.2018;36(8):773-779
  13. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379(8):722-730
  14. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356.
  15. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290
  16. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol.2016 Jul;17(7):883-895
  17. Fuchs CS, Doi T, Jang RW, et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018;4(5):e180013
  18. Ribas A, Puzanov I, Dummer R, et al, Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-918
  19. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550
  20. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092
  21. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026
  22. Owonikoko TK, Papadopoulos KP, Gil-Martin M, et al. Phase I study of cemiplimab, a human monoclonal anti-PD-1, in patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Longer follow-up efficacy and safety data. Ann Oncology. 2018;29(8):mdy290.048.
  23. Migden M, Khushalani N, Chang A, et al. Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with locally advanced cutaneous squamous cell carcinoma (laCSCC).  JCO. 2019;37(150:6015.
  24. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301.
  25. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837-1846.
  26. Horn L, Mansfield AS, Szczęsna A, et al; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer [published online September 25, 2018]. N Engl J Med. 2018.
  27. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017; 389(10064):67-76.
  28. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicenter, single-group, open-label, phase 2 trial. Lancel Oncol. 2016;17(10):1374-1385.
  29. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial [published correction appears in Lancet Oncol. 2018;19(7):e335]. Lancet Oncol. 2018;19(1):51-64
  30. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC [published online September 25, 2018]. N Engl J Med. 2018