Results from long-term follow-up of an expanded phase I study, supported by Bristol-Myers Squibband Ono Pharmaceutical,which was presented at the 50th Annual Meeting of the American Society of Clinical Oncology(ASCO), being held May 30 – June 3, 2014 in Chicago, Ill, shows that concurrent treatment with ipilimumab (MDX-010, MDX-101, marketed as Yervoy?; Bristol-Myers Squibb Company (BMS), Princeton, NJ 08543 U.S.A.) and nivolumab, an investigational, fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 (programmed death-1) expressed on activated T-cells being developed by Bristol-Myers Squibb Company, produces an unprecedented median survival of roughly three and a half years (40 months) for patients with advanced melanoma. In the study, the combination treatment nearly doubled the median overall survival found in previous studies of either agent alone.
Melanoma is a form of skin cancer characterized by the uncontrolled growth of melanocytes, the pigment-producing cells located in the skin. Metastatic melanoma is considered the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to other organs, such as the lymph nodes, lungs, brain or other areas of the body. Based on data from the American Cancer Society,the incidence of melanoma has been increasing for at least 30 years. In 2012, an estimated 232,130 melanoma cases were diagnosed globally. In 2014 in the United States alone, the ACS estimates that about 76,100 new melanoma patients will be diagnosed (about 43,890 in men and 32,210 in women) and about 9,710 people are expected to die of melanoma (about 6,470 men and 3,240 women). Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate has historically been just six months with a one-year mortality rate of 75%, making it one of the most aggressive forms of cancer.
Just a few years ago, median survival for patients diagnosed with advanced melanoma was as little as a year or less, and only approximately 20-25% survived two years…
Median Survival
?Just a few years ago, median survival for patients diagnosed with advanced melanoma was as little as a year or less, and only approximately 20-25% survived two years, so it?s truly remarkable that we?re seeing a median survival over three 
years in this trial. Even in the latest era of targeted and immunotherapy agents, the median survival is on average only about 16-18 months with any new treatment alone,? said lead study author Mario Sznol, MD, a professor of medical oncology, clinical research program leader (melanoma program) and co-director, Yale SPORE in Skin Cancer at Yale School of Medicine in New Haven, CT. ?While we?re encouraged by what we?re seeing with the use of these two drugs together, this trial was small, so a randomized phase III trial will be important to validate our initial results.?
Targeting “Gatekeepers”
Nivolumab and ipilimumab are antibody drugs that target and block two different ?gatekeepers? or checkpoints (PD-1 and CTLA-4, respectively) on T cells, disarming the tumor?s defense against the immune system and boosting the immune system?s ability to fight melanoma. Ipilimumab is FDA-approved for the treatment of metastatic melanoma. Lasting antitumor effects have been observed with nivolumab as a single-agent therapy.
Study design
In the study, 94 patients with inoperable stage III or IV melanoma who had undergone up to three prior systemic therapies received concurrent treatment with ipilimumab and nivolumab. Approximately 53% of patients had very advanced disease (stage M1c), and 55% had no prior systemic treatments.
Long-term follow-up data on the 53 patients enrolled in the initial four concurrent dosing cohorts are being reported. Those patients received ipilimumab and nivolumab every three weeks for four cycles, followed by nivolumab alone every three weeks for four cycles. At week 24, patients who did not have disease progression or severe side effects could continue nivolumab plus ipilimumab every 12 weeks for eight cycles.
Overall, 22 out of 53 patients (41%) responded to the treatment, and nine (17%) had complete remissions. Tumor shrinkage was rapid and extensive ? 42% of the patients had a greater than 80% tumor reduction by week 36 ? and the responses were durable, with 18 of 22 responses (82%) ongoing at time of analysis. Across doses, the one-year and two-year median overall survival rates were 85% and 79%, respectively, and the median survival duration was 39.7 months. (In an unrelated, ongoing trial Phase II/III trial, the drugs were being tested in with nivolumab 1 mg/kg and ipilimumab 3 mg/kg dose. These results showed one- and two-year overall survival rates were 94 and 88%, respectively). The rate of side effects related to induction of immune reactivity against normal tissues was higher than previously observed for either single agent, but side effects were manageable and reversible in almost all patients.
Combination more effective
Clinical responses were seen regardless of tumor BRAF mutation status or PD-L1 status, and across all dose levels. According to the authors, the activity of the combination in the PD-L1 negative subgroup was higher than observed in prior trials of nivolumab alone, and therefore supports the observation that the combination is more effective than nivolumab by itself. In addition, the authors stated, if the activity is validated in the phase III trial, patients with melanomas that test positive for a BRAF mutation would have an even more effective immunotherapy option in addition to targeted therapy for treatment of their disease.
Follow-up
Researchers will continue following patients in all cohorts of this study, including a separate cohort of 41 patients who received the combination treatment every three weeks for four cycles, followed by nivolumab alone every two weeks for up to two years.
A separate, ongoing phase III study comparing nivolumab plus ipilimumab versus nivolumab or ipilimumab alone, and a phase II randomized study comparing nivolumab plus ipilimumab to ipilimumab alone, completed accrual; findings have not yet been reported.
Commenting on the results of this long-term follow up, Steven O?Day, MD, ASCO Expert and a clinical associate professor of medicine at the University of Southern California, Keck School of Medicine, noted:?Anti CTLA-4 and anti PD1 single-agent therapies for metastatic melanoma have made significant contributions in recent years. This study combines the two checkpoint inhibitors concurrently in efforts to improve clinical outcomes further. This update on the initial group of 53 patients treated with ipilimumab and nivolumab confirm continued excitement, with remarkable clinical benefit and longer survival than we?ve typically seen. Phase III trials will be necessary to determine the benefit of combination checkpoint therapy versus sequential single-agent therapy and delineate the price of additional toxicities.?
For more inform
ation:
Sznol M, Kluger HM, Callahan MK, Postow MA, Gordon RA, Segal NH, Rizvi NA, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL).Oral Abstract Session, ASCO 2014, Monday June 2, 3:00 PM to 6:00 PM, Abstract No: LBA9003^ Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9003^) [Abstract]
Photo: Mario Sznol at the American Society of Clinical Oncology Annual Meeting, Monday June 2, 2014. Photo Courtesy: ?ASCO/Zach Boyden-Holmes 2014
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