“Ipilimumab was associated with long-term OS rates that plateaued after 3 years in patients with unresectable or metastatic melanoma, according to results from a pooled analysis of phase 2 and phase 3 trials.
“ ‘We observed an apparent plateau in the survival curve regardless of prior therapy, ipilimumab dose or treatment regimen,’ Dirk Schadendorf, MD, of the department of dermatology at the University Hospital Essen, Germany, and colleagues wrote. ‘In all analyses, including those with OS data from patients in the expanded access treatment protocol, the survival curves seemed to consistently begin around year 3 and extended up to 10 years in some patients.’
“Schadendorf and colleagues sought to provide an estimate of the long-term OS benefit associated with ipilimumab (Yervoy, Bristol-Myers Squibb), which was approved in 2011 for the treatment of unresectable or metastatic melanoma.
“Researchers evaluated data from 1,861 patients with advanced melanoma who were enrolled in 10 prospective and two retrospective clinical trials. Approximately two-thirds (n = 1,257) of the patients had received prior treatment.”
“More patients with advanced melanoma who had progressed on ipilimumab with or without a BRAF inhibitor were able to achieve an objective response when treated with the PD-1 immune checkpoint inhibitor nivolumab than with alternative chemotherapy options, according to the interim analysis results of the CheckMate 037 trial published recently in Lancet Oncology.
“In fact, the rate of objective response was about threefold greater with nivolumab compared with investigator’s choice of chemotherapy; however, no difference in progression-free survival in the intention-to-treat population was noted.
“These results were the basis of the December 2014 US Food and Drug Administration accelerated approval of nivolumab for this patient population.
“ ‘Findings from our study show that nivolumab leads to clinically meaningful improvements in the proportion of patients achieving an objective response and provide a manageable safety profile when compared with chemotherapy,’ wrote Jeffrey S. Weber, MD, of Moffitt Cancer Center, Tampa, Florida, and colleagues. ‘Nivolumab can now be considered as a new treatment option for patients that have progressed after ipilimumab, or a BRAF inhibitor and ipilimumab if their melanoma is BRAF V600–mutated.’ ”
“Continued use of vemurafenib, even after disease progression, can improve survival outcomes for patients with BRAF V600-mutated advanced melanoma.
“More than half of diagnosed melanomas harbor BRAF V600 mutations, and the introduction of targeted agents such as vemurafenib (Zelboraf, Hoffmann-La Roche) and dabrafenib (Tafinlar, GlaxoSmithKline) triggered a paradigm shift in the treatment of BRAF-mutated melanoma.
“However, standard treatment practice is to discontinue use of these targeted agents upon disease progression, not unlike classic regimens such as cytotoxic chemotherapy.
“Because BRAF-mutated melanoma progresses rapidly after treatment, John Haanen, PhD, of the division of immunology at Netherlands Cancer Institute, and colleagues conducted a single-institution retrospective study to determine whether continued use of vemurafenib after disease progression could extend OS in patients with BRAF V600-mutated advanced melanoma.
The gist: People with advanced melanoma who have not yet been treated might benefit from the drug nivolumab (Opdivo). In December, the U.S. Food and Drug Administration (FDA) approved Opdivo for people who had tried other treatments unsuccessfully. Now, a new clinical trial shows that patients without prior treatment survive longer on Opdivo than chemotherapy.
“The PD-1 inhibitor nivolumab significantly increased overall survival compared with chemotherapy in patients with previously untreated metastatic melanoma without a BRAF mutation. In addition, the drug more than doubled the progression-free survival among these patients.
“ ‘The risk of death decreased by 58% with nivolumab, as compared with dacarbazine, among previously untreated patients with advanced melanoma,’ wrote study author Caroline Robert, MD, PhD, of INSERM Unité 981, Gustave Roussy, and colleagues. ‘The survival benefit was consistent across all the prespecified subgroups, including patients with poor prognostic factors.’
“The results of the phase III double-blind study were published in the January 22 issue of the New England Journal of Medicine.”
The gist: A new immunotherapy drug called CM-24 will soon be tested in patients with various types of advanced or recurrent cancer, including melanoma and non-small cell lung cancer (NSCLC). CM-24 is meant to boost a patient’s own immune system to fight cancer. It works by targeting an immune system protein called CEACAM1.
“cCAM Biotherapeutics, a biopharmaceutical company focused on the discovery and development of novel cancer immunotherapies, has announced that it has received approval form the US Food and Drug Administration to commence a Phase 1 trial for CM-24, a first-in-class immunomodulatory monoclonal antibody (mAb) for the treatment of various types of cancers. The study is expected to commence during the first quarter of 2015.
“CM-24 is directed against CEACAM1, a novel immune checkpoint protein that is expressed on activated effector lymphocytes and a variety of cancer cells. CEACAM1 belongs to the Human CEA protein family, and preclinical data show that inhibition of CEACAM1-CEACAM1 homophilic interactions by CM-24 leads to enhanced activation of tumor specific immune cells.
“The Phase 1 trial is a first-in-human, open-label, multicenter, dose escalation study assessing the effect of the CM-24 mAb in cancer patients with selected advanced or recurrent malignancies, including melanoma, non-small cell lung adenocarcinoma (NSCLC) and bladder, gastric, colorectal or ovarian cancer. Primary objectives of the study are to assess the safety and tolerability of escalating multiple doses of CM-24 and to determine the recommended dose for Phase 2 trials with CM-24. Secondary objectives include characterization of the pharmacokinetic profile and immunogenicity of CM-24, and the evaluation of the preliminary efficacy of the drug on the basis of objective tumor response and duration of response in subjects treated with CM-24. The trial will be conducted at four sites including Yale and UCLA, and will be composed of a dose escalation stage and an expansion stage. The expansion stage will focus on subjects with cutaneous melanoma or additional malignancies that responded to treatment in the first stage of the study.”
“Some patients with advanced melanoma treated with ipilimumab continued to derive a survival benefit at least 5 years after treatment, according to study results.
“The results showed that, for certain patients, retreatment with ipilimumab (Yervoy, Bristol-Myers Squibb) can re-establish disease control while demonstrating a safety profile comparable to that observed during ipilimumab induction, researchers wrote.
“The analysis included patients treated with ipilimumab in one of six phase 2 clinical trials. In those trials, ipilimumab was administered in doses of 0.3 mg/kg, 3 mg/kg or 10 mg/kg.
“In the current companion study — conducted by Celeste Lebbé, MD, PhD, professor of dermatology at Hôpital Saint-Louis in Paris, and colleagues — patients underwent ipilimumab retreatment, extended maintenance therapy or follow-up for survival only.”
“The U.S. Food and Drug Administration today granted accelerated approval to Opdivo (nivolumab), a new treatment for patients with unresectable (cannot be removed by surgery) or metastatic (advanced) melanoma who no longer respond to other drugs.
“Melanoma is the fifth most common type of cancer in the United States. It forms in the body’s melanocyte cells, which develop the skin’s pigment. The National Cancer Institute estimates that 76,100 Americans will be diagnosed with melanoma and 9,710 will die from the disease this year.
“Opdivo works by inhibiting the PD-1 protein on cells, which blocks the body’s immune system from attacking melanoma tumors. Opdivo is intended for patients who have been previously treated with ipilimumab and, for melanoma patients whose tumors express a gene mutation called BRAF V600, for use after treatment with ipilimumab and a BRAF inhibitor.”
The gist: A combination of the drugs cobimetinib and vemurafenib (aka Zelboraf) might soon become a new treatment option for U.S. patients with advanced melanoma whose tumors have a V600 mutation in the BRAF gene. The drug company Genentech submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) asking for FDA approval of the combo. In a clinical trial, Genentech researchers found that patients who take cobimetinib along with vemurafenib do better than patients who take vemurafenib alone. Both drugs are targeted therapies.
“Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced the company has submitted a New Drug Application (NDA) for cobimetinib to the U.S. Food and Drug Administration (FDA) for treatment, in combination with Zelboraf® (vemurafenib), for people with BRAF V600 mutation-positive advanced melanoma. The submission is based on results of the coBRIM Phase III study, which showed people who received the MEK inhibitor cobimetinib plus Zelboraf lived significantly longer without their disease worsening or death (progression-free survival; PFS) compared to Zelboraf alone.
” ‘In the past several years we have made significant progress in treating advanced melanoma, but it remains a serious and difficult to treat cancer that affects more people each year,’ said Sandra Horning, M.D., chief medical officer and head of Global Product Development. ‘We look forward to working with the FDA as they review the NDA and hope the combination of cobimetinib and Zelboraf will soon become a new option for people with BRAF mutation-positive advanced melanoma.’
“In the coBRIM study, cobimetinib and Zelboraf reduced the risk of disease worsening or death by half (hazard ratio [HR]=0.51, 95 percent confidence interval [CI] 0.39-0.68; p<0.0001), with a median PFS of 9.9 months for cobimetinib plus Zelboraf compared to 6.2 months with Zelboraf alone. The safety profile was consistent with a previous study of the combination. The most common Grade 3 or higher adverse events in the combination arm included liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and diarrhea. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity and lab abnormalities. The most common Grade 3 or higher adverse events in the combination arm included liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and diarrhea.”
In the past 3 years, the treatment landscape for metastatic melanoma has changed dramatically. We saw the advent of drugs that inhibit mutant BRAF and activate MEK proteins (vemurafenib, dabrafenib, and trametinib) and drugs known as immune checkpoint inhibitors (ipilimumab, Keytruda, Opdivo, and others). These treatments are ‘systemic’; that is, they are taken by mouth or injected directly into the bloodstream and spread throughout the body. However, as I reported earlier this year, drugs that are injected directly into tumors—’intralesional drugs’—have recently gained some attention. Two of them were featured at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting. New data, and doubts, on these drugs have since emerged. Continue reading…