Checking in on Checkpoint Inhibitors

March 12, 2014
Special Reports, Immunotherapy (Issue 2), Volume 2, Issue 1

Survival rates for patients with cancer have consistently increased in past decades. However, a gap remains in treatment options, particularly for patients with a history of treatment for advanced or recurrent solid-tumor cancers.

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Immune checkpoints are critical immune system pathways responsible for both maintenance of self-tolerance and protection of tissues from damage resulting from infection. In some cancers, tumors are able to suppress or entirely evade the immune system by exploiting these naturally occurring immune tolerance pathways.2This process results in suboptimal control of tumors.3However, inhibitors of checkpoints in the immune system pathway may prevent cancer cells from evading these processes. Examples of agents that work in this way are ipilimumab, nivolumab, MK-3475, and NLG919.

Ipilimumab

Ipilimumab (Bristol-Myers Squibb Co.) is a monoclonal antibody that works to block cytotoxic T-lymphocyte antigen-4 (CTLA-4) and was approved by the FDA in 2011. Two phase III trials of patients with advanced melanoma, one of previously treated patients and the other of previously untreated patients, were recently completed. Overall survival (OS) was the endpoint for both studies. Ipilimumab was shown to “significantly prolong survival” in patients.4

Harriet Kluger, MD, on How Immunotherapies are Changing the Treatment of Melanoma

Kluger is the associate director of the Hematology/Oncology Fellowship Program at Yale Cancer Center.

The first placebo-controlled, phase III trial included 676 patients randomly assigned to one of three treatment groups: ipilimumab (3 mg/kg) plus glycoprotein 100 (gp100) vaccine, ipilimumab (3 mg/kg) alone, or gp100 alone. Four intravenous (IV) doses were given, one dose administered every 3 weeks over a 12-week period. Results indicated a significant increase in survival rates in patients given ipilimumab. The OS rates were as follows: ipilimumab plus gp100, 44% at 12 months, 22% at 24 months; ipilimumab alone, 46% at 12 months, 24% at 24 months; and gp100 alone, 25% at 12 months, 14% at 24 months. Additionally, objective response rates were significantly improved in both the ipilimumab (10.9%) and ipilimumab plus gp100 (5.7%) groups when compared with gp100 alone (1.5%).4

The second phase III trial included 502 patients with metastatic melanoma randomly assigned to one of two treatment groups: ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m2) or placebo plus dacarbazine (850 mg/m2). Patients who experienced no disease progression or significant toxicity received one dose of IV dacarbazine every 3 weeks for 24 weeks. Results indicated a significant increase in survival rates in patients given ipilimumab plus dacarbazine (median 11.2 months) in comparison to patients given placebo plus dacarbazine (median 9.1 months). Additionally, survival rates in patients treated with ipilimumab plus dacarbazine were consistently higher at 1 (47% vs 36%), 2 (29% vs 18%), and 3 years (21% vs 12%).4

Adverse events (AEs), including those of grade 3 or 4 toxicity, were reported in patients treated with ipilimumab. Hepatic toxicity was reported more frequently in patients given combination therapy of ipilimumab plus dacarbazine than in those in the other phase III trial who received ipilimumab alone. However, the occurrence of colitis, rash, and hypophysitis was less frequent than observed in patients receiving ipilimumab alone.4

Brian Daniels, MD

Nivolumab Plus Ipilimumab

A pooled analysis of 12 studies, presented in September 2013 at the European Cancer Congress, provided additional support of long-term survival benefits, extending at least 10 years, for this group of patients. Brian Daniels, MD, senior vice president of Bristol, Global Development and Medical Affairs, Bristol-Myers Squibb Company, said: “The durability and consistency of long-term survival observed in this analysis are encouraging as we continue to advance the research and development of our immune-oncology portfolio.”5Nivolumab (Bristol-Myers Squibb Co.) is a monoclonal antibody that works to block ligand activation of programmed death cell 1 (PD-1) receptors. The drug releases the “brakes” established when ligand proteins bind to PD-1 on T cells, thereby allowing T cells to effectively target cancer cells. Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center, together with colleagues from Memorial Sloan Kettering, Yale University School of Medicine and Smilow Cancer Hospital, and Bristol-Myers Squibb, published findings in theNew England Journal of Medicinesupporting combined treatment with nivolumab and ipilimumab in patients with advanced melanoma. This phase I trial of 86 patients, treated from December 2009 to February 2013, was designed to assess safety and efficacy of the combination therapy and included concurrent-regimen and sequenced-regimen cohorts. The five concurrent-regimen cohorts (53 patients) received therapy consisting of IV nivolumab followed by IV ipilimumab. Thirty-eight patients assigned to these cohorts had received prior treatment. Nivolumab and ipilimumab were given every 3 weeks, for a total of four escalating IV doses of both medications (between 0.3 mg/kg to 10 mg/kg of nivolumab and between 3 mg and 10 mg of ipilimumab). This was followed by nivolumab once every 3 weeks, for four doses. Up to eight doses of combined treatment, given every 12 weeks, were administered. Clinical activity was observed in 65% of patients in this group (95% confidence interval [CI], 51-78). Thirty-one percent of patients in this group with clinical response had a minimum 80% tumor regression by week 12.6

The two sequence-regimen cohorts, consisting of 33 total patients, received IV nivolumab (between 1 mg/kg and 3 mg/kg) only, every 2 weeks, for up to 48 doses. All patients assigned to these cohorts had received prior systemic treatment. The objective response rate of patients in this group was 20% (95% CI, 8-39).6

Serious treatment-related AEs occurred in 49% of patients in the concurrent-regimen groups and in 73% of patients in the sequenced-regimen group. AEs included pneumonitis, hepatic events, gastrointestinal events, and renal events.

MK-3475

Results from this trial suggest clinical benefits from combined therapy. There is an ongoing phase III clinical trial designed to evaluate efficacy of nivolumab alone, ipilimumab alone, and combined treatment.6MK-3475 (Merck & Co., Inc.) is a highly selective, monoclonal antibody therapy targeting PD-1. Like nivolumab, MK-3475 releases the ‘brakes’ established when ligand proteins bind to PD-1 on T cells.7 Researchers, led by Edward B. Garon, MD, from the University of California, Los Angeles Jonsson Comprehensive Cancer Center, presented data regarding a separate phase I study of MK-34757 at the Joint Conference on Molecular Origins of Lung Cancer 2014.

The study enrolled 38 patients with previously treated non-small cell lung cancer (NSCLC). Patients had a minimum of one measurable tumor in addition to a recent tumor biopsy before treatment initiation. Each patient received 10 mg/kg every 3 weeks. Imaging to assess tumor progression was performed every 9 weeks and was discontinued after confirmation of disease progression. Progression was confirmed using both Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related response criteria (irRC). Objective response rates were 21% (RECIST) and 24% (irRC) at 9 weeks. Results from pretreatment measurement of programmed cell death 1 ligand 1 (PD-L1) protein expression (N = 33) indicated higher PD-L1 levels were a predictor of more favorable response to treatment. High PD-L1 group response rate was 57% (RECIST) and 67% (irRC).7,8

NLG919

Overall, 53% of patients experienced some AEs (commonly rash); one grade 3 pulmonary edema was reported. There were no treatment-related deaths. MK-3475 was well tolerated with durable responses. There are 10 ongoing clinical trials of MK-3475, designed to test the efficacy of the drug as a monotherapy and as one component of combination therapy.9“A significant percentage of patients with growing disease after two prior treatments had substantially reduced tumor volume in response to MK-3475,” Garon said, “and the potential of this antibody drug to induce long-lasting responses in these patients is certainly exciting and promising.”8NLG919 (NewLink Genetics Corporation) is a novel, small-molecule indoleamin 2,3-dioxygenase (IDO) pathway inhibitor. The IDO pathway, which is thought to be active in a number of cancers, can be targeted using checkpoint inhibitors that disrupt the tumor’s ability to escape the immune system. The body’s immune response is then reactivated, allowing effective reaction of natural killer cells and T cells.10

NLG919 is in a phase I dose-escalation study of 36 adult patients with recurrent advanced solid malignancies.11The study began in February 2014, with an expected completion date of April 2015. It is designed to evaluate safety, toxicity, and maximum tolerated dose of the medication. Initial dosage is oral 50 mg every 12 hours, given daily for 21 days, followed by 7 days of no medication (dose escalation up to oral 800 mg every 12 hours).

Charles Link, MD

Conclusion

“[NLG919] has demonstrated encouraging preclinical activity on its own, and interesting synergy in combination with indoximod, [NewLink Genetic’s] most advanced IDO product candidate,” noted Charles Link, MD, Chairman, Chief Executive Officer, and Chief Scientific Officer of NewLink Genetics Corporation.11Significant progress has been made in the development and evaluation of checkpoint inhibitors. These treatments offer new options for patients with difficult-to-treat cancers. Adverse events, also known in this setting as “immune-related adverse events,” include rash, pneumonitis, hepatic events, and dermatitis. Although combination therapies require further assessment, there appear to be advantages to the addition of a second checkpoint inhibitor to the treatment regimen.4

References

  1. NewLink Genetics Corporation. IDO inhibitor study for advanced solid tumors. http://clinicaltrials.gov/ct2/show/NCT02048709. Published (Dec 10, 2013). Accessed February 25, 2014.
  2. Pardoll D. The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer. 2012;12(4):252-264.
  3. Stagg J, Allard B. Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects.Ther Adv Med Oncol. 2013;5(3):169-181.
  4. Sosman J. Immunotherapy of advanced melanoma with immune checkpoint inhibition. In: UpToDate, Rose BD (ed), UpToDate, Waltham, MA, 2014.
  5. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. Presented at: European Cancer Congress 2013 (ECCO-ESMO-ESTRO); September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 24.
  6. Wolchok J, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013;369:122-133.
  7. Garon E, Balmanoukian A, Hamid O, et al. MK-3475 monotherapy for previously treated non-small cell lung cancer (NSCLC): Preliminary safety and clinical activity. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; Jan 6-9, 2014; San Diego, CA. Philadelphia (PA): AACR.Clin Cancer Res. 2014;20(suppl 2): Abstract A20.
  8. American Association of Cancer Research. Immune checkpoint inhibitor shows early promise in previously treated lung cancer patients. http://www.aacr.org/home/public--media/aacr-in-the-news.aspx?d=3254. Published January 7, 2014. Accessed March 10, 2014.
  9. Merck initiates rolling submission of U.S. biologics license application for MK-3475, an investigational anti-PD-1 immunotherapy, in patients with advanced melanoma [news release]. Whitehouse Station, NJ: Business Wire. January 13, 2014. http://www.mercknewsroom.com/print/node/583. Accessed February 26, 2014.
  10. Hayes E. Oncology is next destination for Innate’s checkpoint inhibitor after return from Novo.The Pink Sheet: Prescription pharmaceuticals and biotechnology. 76(6):21.
  11. NewLink Genetics initiates phase I clinical trial of NLG919, a novel immune checkpoint inhibitor for cancer immunotherapy. [news release]. Ames, IA: Marketwired. Dec 10, 2013. http://investors.linkp.com/releasedetail.cfm?ReleaseID=812763. Accessed February 25, 2014.