Combination Immunotherapy Makes Progress in Advanced Melanoma

August 2016 Vol 9, Special Issue: Payers' Perspectives in Oncology
Phoebe Starr

Evidence is mounting that 2 immunotherapies are better than 1 as first-line treatment of patients with advanced melanoma. A phase 3 clinical trial showed that nivolumab plus ipilimumab was superior to ipilimumab or nivolumab alone, and a phase 1 trial suggests that pembrolizumab can be safely and effectively used in combination with other drugs as first-line treatment in this setting. Both studies were presented at ASCO 2016.

CheckMate 067

Updated results of the phase 3 CheckMate 067 trial showed that progression-free survival (PFS), response rates, and the duration of response were significantly better with the combination of nivolumab and ipilim­umab compared with either drug alone. In this study, nivolumab alone was also more effective than ipilimumab alone.

“Nivolumab plus ipilimumab continue to demonstrate superior clinical activity versus ipilimumab monotherapy, with greater efficacy than with either drug alone, regardless of PD ligand 1 [PD-L1] expression or BRAF mutation status,” said lead investigator Jedd D. Wolchok, MD, PhD, Chief of the Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. The updated analysis showed a pattern similar to an earlier analysis of the trial at 9 months of follow-up, he added.

At 18 months, an intent-to-treat analysis demonstrated PFS rates of 46% for the combination, 39% for nivolu­mab, and 14% for ipilimumab (P <.001 for both comparisons).

CheckMate 067 randomized 945 patients with untreated advanced melanoma to the combination of nivolumab and ipilimumab, to nivolumab alone, or to ipilimumab alone; the patients received treatment until disease progression. The study was powered to compare the combination therapy with ipilimu­mab monotherapy but not with nivolumab alone. The overall survival data were immature at the time of the meeting.

The overall response rate was significantly better with the combination, and with nivolumab alone versus ipilimu­mab alone. “Response rates haven’t changed over time, but some partial responses became complete responses at a median follow-up of 20.7 months,” Dr Wolchok said.

The median duration of response has not yet been reached in the combination arm versus 22 months with nivolumab alone and 14 months with ipilimumab alone.

In the updated analysis, the majority of adverse events were immune-mediated, and higher rates of grade 3 and 4 events were reported with the combination.

The data show that patients who withdraw from treatment can have a response. In fact, of the 40% of patients who discontinued combination therapy because of treatment-related adverse events, 68% had a response, and 50% had a response after discontinuing therapy.

“This is important to discuss in conversations with patients and families who want to discontinue therapy,” Dr Wolchok said.

Endocrine-related adverse events were treated with hormone replacement therapy, he noted.

Pembrolizumab plus Ipilimumab

The combination of pembrolizumab and ipilimumab had manageable toxicity and strong antitumor activity in 153 patients with untreated advanced melanoma who were enrolled in an expansion cohort of the phase 1 KEYNOTE-029 study.

“Standard-dose pembrolizumab combined with ipilimumab 1 mg/kg is tolerable. Seventy-two percent of patients were able to get all 4 ipilimumab doses, with no treatment-related deaths. Twenty-five percent of patients had grade 3 or 4 immune-mediated events. Overall the response rate was 57%, and 78% of patients are progression-free at 6 months,” said lead investigator Georgina V. Long, PhD, MBBS, FRACP, of the Melanoma Institute Australia, Wollstonecraft.

At the time of data cutoff, 91% of responders retained their response and 93% were alive. Response to the combination therapy was not dependent on PD-L1 status or on lactate dehydrogenase level.

Immune-mediated adverse events of any grade were reported in 58% of patients, and grade 3 or 4 events were reported in 25% of patients. Hypothyroidism, hyperthyroidism, and colitis, respectively, were reported in <10% of patients.

Of the 145 immune-mediated events that were reported, 76% resolved with treatment (mainly corticosteroids); 81% of grade 3 or 4 immune-mediated events resolved with treatment.


Discussant Marc S. Ernstoff, MD, Chairman of the Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, noted that the future lies with combination therapy. He also saw little difference, if any, between pembro­lizu­mab and nivolumab when comparing their use in combination therapies.

“Even though studies suggest that anti–PD-1 therapy is preferred as first-line immunotherapy over targeted therapy in advanced melanoma, the sequence of immunotherapy and targeted therapy remains to be established,” he said. He asked attendees to enroll their patients in the ECOG 6134 trial, which will evaluate the best therapy sequence.

There are remaining questions, Dr Ernstoff continued, including whether ipilimumab is of benefit after failure with pembrolizumab or nivolumab therapy.

“Also, we didn’t learn whether to continue treatment past disease progression. What is the optimal number of doses of ipilimumab?” he asked. Finally, the cost of immunotherapy will also need to be addressed, he said.

Related Items
MONALEESA-7 Sets New Standard of Care for Premenopausal Advanced Breast Cancer: Adding CDK4/6 to Endocrine Therapy Extends Survival
Phoebe Starr
August 2019, Vol 12, Special Issue: Payers’ Perspectives In Oncology: ASCO 2019 Highlights published on August 16, 2019 in Breast Cancer
Practice-Changing Results: Olaparib Maintenance Therapy Extends Progression-Free Survival in Metastatic Pancreatic Cancer with Germline BRCA Mutation
Phoebe Starr
August 2019, Vol 12, Special Issue: Payers’ Perspectives In Oncology: ASCO 2019 Highlights published on August 16, 2019 in Pancreatic Cancer
FDA Unveils Oncology-Specific “Project Facilitate,” Expanding Access to Investigational Cancer Drugs
Phoebe Starr
August 2019, Vol 12, Special Issue: Payers’ Perspectives In Oncology: ASCO 2019 Highlights published on August 16, 2019 in Value-Based Care
Enfortumab Vedotin Promising Third-Line Option for Metastatic Urothelial Cancer
Phoebe Starr
August 2019, Vol 12, Special Issue: Payers’ Perspectives In Oncology: ASCO 2019 Highlights published on August 16, 2019 in Emerging Therapies
Fixed-Duration Targeted Therapy with Venetoclax plus Obinutuzumab New Front-Line Standard for Patients with Chronic Lymphocytic Leukemia
Phoebe Starr
August 2019, Vol 12, Special Issue: Payers’ Perspectives In Oncology: ASCO 2019 Highlights published on August 16, 2019 in Leukemia
Last modified: August 19, 2016
  •  Association for Value-Based Cancer Care
  • Oncology Practice Management
  • Value-Based Cancer Care
  • Value-Based Care in Rheumatology
  • Rheumatology Practice Management
  • Urology Practice Management
  • Lynx CME