Pembrolizumab Increases Progression-Free Survival vs Chemotherapy in Ipilimumab-Refractory Advanced Melanoma

“In a randomized phase II KEYNOTE-002 trial reported in The Lancet Oncology, Ribas et al found that treatment with the anti–PD-1 antibody pembrolizumab (Keytruda) prolonged progression-free survival vs investigator-choice chemotherapy in patients with advanced melanoma progressing on ipilimumab (Yervoy) and, if BRAF V600 mutant–positive, a BRAF or MEK inhibitor.

“The open-label trial included 540 patients from 12 countries with progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant–positive, previous treatment with a BRAF or MEK inhibitor or both. Patients were randomly assigned 1:1:1 between November 2012 and November 2013 to receive pembrolizumab 2 mg/kg (n = 180) or 10 mg/kg (n = 181) every 3 weeks or investigator-choice chemotherapy (n = 179, including 42 to paclitaxel plus carboplatin, 28 to paclitaxel, 13 to carboplatin, 45 to dacarbazine, and 43 to temozolomide)…

“The investigators concluded: ‘These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma.’ “


KEYTRUDA Demonstrated Superiority to Chemotherapy for Primary Endpoint of Progression-Free Survival

The gist: The drug KEYTRUDA (pembrolizumab) might be better than chemotherapy for people with melanoma that is metastatic or can’t be surgically removed, and who tried treatment with the drug ipilimumab without success. That was the conclusion of a recent clinical trial with volunteer patients. KEYTRUDA is an immunotherapy drug, meaning that it boosts the immune system to fight cancer.

“Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today that a pre-specified analysis of investigational data from a pivotal Phase 2 study (KEYNOTE-002) showed KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, substantially improved the primary endpoint of progression-free survival (PFS, as assessed by RECIST 1.1, independent central review) (HR 0.57 and 0.50 for 2 mg/kg and 10 mg/kg every three week doses, respectively), compared to chemotherapy (P<0.0001 for both comparisons) in patients with ipilimumab-refractory advanced melanoma (n=540). At six months, the PFS rates for KEYTRUDA were 34 percent at the 2 mg/kg dose (95% CI, 27-41) (n=180) and 38 percent at the 10 mg/kg dose (95% CI, 31-45) (n=181), compared to 16 percent for chemotherapy (95% CI, 10-22) (n=179). The median duration of follow-up at the interim analysis was 10 months.

“These findings, including pre-specified analyses of overall response rate (ORR), duration of response, safety and health-related quality of life (HRQoL), were presented today in an oral session by Dr. Antoni Ribas, professor, Hematology/Oncology and Surgery, and director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles at the Society of Melanoma Research (SMR) 2014 International Congress in Zurich, Switzerland.”


Nivolumab Superior to Dacarbazine for Untreated Metastatic Melanoma

The gist: A recent clinical trial with volunteer patients compared two treatments for metastatic melanoma. It showed that one of the treatments might give longer survival times for people whose tumors do not have mutations in the BRAF gene. This treatment is a drug called nivolumab. It is an immunotherapy drug, meaning that it boosts a patient’s own immune system to fight cancer. In the trial, some patients took nivolumab and some took the chemotherapy drug dacarbazine. People who took nivolumab lived a few months longer than people who took dacarbazine. None of the patients had taken any previous treatments for their melanoma.

“Patients with treatment-naive, BRAF wild-type metastatic melanoma treated with nivolumab demonstrated longer OS and PFS than those treated with dacarbazine, according to phase 3 study results presented at the Society for Melanoma Research International Congress.

“Prior research showed nivolumab (Opdivo, Bristol-Myers Squibb) — a PD-1 immune checkpoint inhibitor — was associated with higher rates of objective response compared with chemotherapy in patients with ipilimumab (Yervoy, Bristol-Myers Squibb)-refractory disease.

“In the current study, Caroline Robert, MD, PhD, head of the Dermatology Unit at the Institut Gustave-Roussy in Paris, and colleagues compared the efficacy of nivolumab vs. chemotherapy in 418 previously untreated patients.

“Researchers assigned patients 3 mg/kg nivolumab every 2 weeks plus a dacarbazine-matched placebo, or 1,000 mg/m2dacarbazine every 3 weeks plus a nivolumab-matched placebo.”


Nivolumab Superior to Chemotherapy in Metastatic Melanoma

The gist: The drug nivolumab (aka Opdivo) appears to be more effective than chemotherapy for certain people with metastatic melanoma. That was the conclusion of a recent clinical trial—a research study with volunteer patients. The study involved people whose disease worsened after treatment with drugs known as anti-CTLA-4 therapies or drugs known as BRAF inhibitors, such as ipilimumab (aka Yervoy).

“Nivolumab induced a greater rate of overall response than chemotherapy in patients with metastatic melanoma who progressed on or after anti-CTLA–4 therapy or treatment with BRAF inhibitors, according to phase 3 study results presented at the European Society for Medical Oncology Annual Congress in Madrid.

“ ‘For those who failed [on] ipilimumab (Yervoy, Bristol-Myers Squibb) and a BRAF inhibitor, there are no therapies known to prolong survival,’ researcher HemOnc Today. ‘This is the first phase 3 study of a PD-1 inhibitor, and first evidence that a PD-1 inhibitor is superior to any other therapy for ipilimumab-refractory melanoma…’

“The next step will be to conduct research designed to evaluate proper ways to combine nivolumab with other agents, Weber said.”


Anti–PD-1 Antibody Pembrolizumab Is Active in Ipilimumab-Refractory Advanced Melanoma

The gist: A drug called pembrolizumab (brand name Keytruda) is effective for treating people with melanoma that does not respond to treatment with the drug ipilimumab (Yervoy). That is the conclusion of a recent clinical trial—a research study with volunteer patients. Based on the study, the U.S. Food and Drug Administration (FDA) has already approved Keytruda for treating melanoma that is advanced or unresectable (can’t be removed by a surgeon) and is not responding well to other drugs.

“As reported in The Lancet by Robert et al, the anti–programmed-death receptor-1 (PD-1) antibody pembrolizumab (Keytruda) produced durable responses in a phase I trial in patients with ipilimumab (Yervoy)-refractory melanoma. The study provided the basis for the recent accelerated approval of pembrolizumab for treatment of patients with unresectable or metastatic melanoma with disease progression following treatment with ipilimumab and, in BRAF V600 mutation–positive patients, treatment with a BRAF inhibitor. Pembrolizumab is the first PD-1 inhibitor to be approved for use in the United States…

“In this open-label, international, multicenter expansion cohort of a phase I trial, 173 patients aged ≥ 18 years with advanced melanoma progressing after at least two ipilimumab doses were randomly assigned to receive pembrolizumab intravenously at 2 mg/kg (n = 89) or 10 mg/kg (n = 84) every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was overall response rate. Overall, 97% of patients were white, 17% had BRAF V600 mutant disease, and 73% had received at least two prior therapies for advanced or metastatic disease.”


Exclusive: U.S. Approval of Merck Cancer Immunotherapy Expected Soon

Editor’s note: Before a new cancer drug can be prescribed by oncologists in the U.S., it must be approved by the U.S. Food and Drug Administration (FDA). The FDA may soon approve a new melanoma drug called pembrolizumab. Pembrolizumab is an immunotherapy, meaning that it boosts a patient’s own immune system to fight cancer. It may be particularly helpful for people whose melanoma does not respond to treatment with another immunotherapy drug called ipilimumab (Yervoy).

“U.S. regulators are likely to approve Merck & Co’s highly anticipated immuno-oncology drug, pembrolizumab, as a treatment for melanoma well ahead of a late October deadline, according to three sources familiar with the situation.

“If approved by the Food and Drug Administration, the drug would be the first in a promising new class designed to help the body’s own immune system fend off cancer by blocking a protein known as Programmed Death receptor (PD-1), or a related target known as PD-L1, used by tumors to evade disease-fighting cells.

“Companies including Bristol-Myers Squibb, Roche Holding AG and AstraZeneca Plc are racing to develop similar treatments for a variety of cancers. Some analysts expect the new class could generate more than $30 billion in annual sales worldwide by 2025.”


Safety, Efficacy, and Biomarkers of Nivolumab With Vaccine in Ipilimumab-Refractory or -Naive Melanoma

Purpose: Nivolumab, a human immunoglobulin G4–blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma. Patients and Methods: In this phase I study, 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy (cohorts 1 to 3, 34 patients) or experienced progression after prior ipilimumab (cohorts 4 to 6, 56 patients) received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. Results: Nivolumab with vaccine was well tolerated and safe at all doses. The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25%. Median duration of response was not reached at a median of 8.1 months of follow-up. High pretreatment NY-ESO-1 and MART-1–specific CD8+ T cells were associated with progression of disease. At week 12, increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression. PD-L1 tumor staining was associated with responses to nivolumab, but negative staining did not rule out a response. Patients who experienced progression after nivolumab could respond to ipilimumab. Conclusion: In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab.”