Combining Targeted Therapy with Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

Editor’s note: Targeted therapies that fight tumors with specific genetic mutations opened up a new era in cancer treatment, but many patients become resistant to these treatments, and their cancer grows back. A new type of treatment called immunotherapy boosts a patient’s own immune system to fight cancer. Researchers are hopeful that combining targeted drugs with immunotherapy drugs could be highly effective. This article discusses the idea of combining immunotherapy with targeted drugs developed to treat melanomas with mutations in the GRAF gene. It is a scientific article, but may interest some patients and caregivers dealing with BRAF-mutant melanoma.

“Hu–Lieskovan S, et al. – In this review,the authors present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

  • “Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer.
  • “Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high.
  • “Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma.
  • “These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration.
  • “Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors.
  • “However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities.”

Astrazeneca’s Medimmune Presents Encouraging Immunotherapy Data at ASCO 2014

“MedImmune, the global biologics research and development arm of AstraZeneca, presented results today from its novel investigational immunotherapy portfolio, focusing on MEDI4736, at the American Society of Clinical Oncology (ASCO) 2014 Annual Meeting.  Overall, studies demonstrated durable clinical activity and tolerability for MEDI4736 across a range of tumor types.

“This announcement follows the recent progression of the first Phase III study for MEDI4736, an investigational, engineered, human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. It is believed that by targeting PD-L1, MEDI4736 may block this ligand from sending out signals to T-cells to ‘ignore’ tumor cells, thereby countering cancer’s immune-evading tactics.

Editor’s note: Immunotherapy treatments that boost a patient’s own immune system to fight cancer are a promising area of cancer research. A new immunotherapy drug called MEDI4736 is being tested in volunteer patients with different cancer types, and has shown good results for some patients with advanced non-small cell lung cancer (NSCLC).


New System for Treating Cancer Seen as Hopeful

“Drugs that unleash the body’s immune system to combat tumors could allow patients with advanced melanoma to live far longer than ever before, researchers gathered at the nation’s largest cancer conference say.

“ ‘It’s a completely different world for patients with metastatic melanoma, to talk about the majority of patients being alive for years rather than weeks or months,’ said Dr. Jedd D. Wolchok, a melanoma specialist at the Memorial Sloan-Kettering Cancer Center, interviewed at the annual meeting of the American Society of Clinical Oncology here.”

Editor’s note: This is a good exploration of immunotherapy treatments for melanoma; immunotherapy for lung cancer is also discussed.


New System for Treating Cancer Seen as Hopeful

“Drugs that unleash the body’s immune system to combat tumors could allow patients with advanced melanoma to live far longer than ever before, researchers gathered at the nation’s largest cancer conference say.

“ ‘It’s a completely different world for patients with metastatic melanoma, to talk about the majority of patients being alive for years rather than weeks or months,’ said Dr. Jedd D. Wolchok, a melanoma specialist at the Memorial Sloan-Kettering Cancer Center, interviewed at the annual meeting of the American Society of Clinical Oncology here.”

Editor’s note: This is a good exploration of immunotherapy treatments for melanoma; immunotherapy for lung cancer is also discussed.


Long-Term Results Encouraging for Combination Immunotherapy for Advanced Melanoma

“The first long-term follow-up results from a phase 1b immunotherapy trial combining drugs for advanced melanoma patients has shown encouraging results—long-lasting with high survival rates—researchers report. First author Mario Sznol, M.D., professor of medical oncology at Yale Cancer Center, is presenting the updated data at the 2014 annual conference of the American Society of Clinical Oncology (ASCO) in Chicago.

“Sznol, clinical research leader of the melanoma research program at Yale Cancer Center, was the senior author on the original study of combination immunotherapy that was first published in the New England Journal of Medicine and presented at ASCO in 2013. Jedd Wolchok, M.D., of Memorial Sloan Kettering Cancer Center was first author of the earlier study, and senior author of this updated research.”

Editor’s note: Immunotherapy treatments boost a patient’s own immune system to fight cancer. This story describes a promising treatment that combines two immunotherapy drugs: nivolumab and ipilimumab (Yervoy).


T-cell Changes: Why Only Some Respond to Ipilimumab

“The immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb Company) works amazingly well in some patients, hardly at all in others. A groundbreaking study that used deep sequencing techniques offers some clues as to why.

“Ipilimumab, which is marketed for melanoma but is being explored in several other cancer types, including prostate cancer, acts as a checkpoint blocker by inhibiting cytotoxic T lymphocyte– associated antigen–4 (CTLA-4).

“Immune repertoire sequencing has confirmed that blocking CTLA-4 increased turnover and diversity of the T-cell repertoire in some patients with advanced prostate cancer or metastatic melanoma, but also showed that patients who survived longest maintained clones of high-frequency T-cells they had developed before starting treatment.”

Editor’s note: Ipilimumab is a drug that boosts a patient’s own immune system to fight cancer. It works by activating immune system cells called T cells, some subtypes of which may then attack tumors. Ipilimumab works very well for some patients, but not for others. This study found that patients who had certain tumor-fighting T cell subtypes already present before ipilimumab treatment were more likely to respond well and survive longer, possibly because these cells were readily available to fight cancer upon activation. The study also found that ipilimumab may prompt the immune system to “re-shuffle” the body’s T cell subtypes, allowing patients with only a small amount of tumor-fighting T cells to generate more. (This may explain why some patients take longer to respond to ipilimumab than others; their immune systems need more time to build up the right T cells.) Based on the results, doctors may be able to monitor a patient’s T cell subtypes (“immune repertoire sequencing”) to determine whether ipilimumab will work, or to keep tabs on the effectiveness of ongoing ipilimumab treatment.


T-cell Changes: Why Only Some Respond to Ipilimumab

“The immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb Company) works amazingly well in some patients, hardly at all in others. A groundbreaking study that used deep sequencing techniques offers some clues as to why.

“Ipilimumab, which is marketed for melanoma but is being explored in several other cancer types, including prostate cancer, acts as a checkpoint blocker by inhibiting cytotoxic T lymphocyte– associated antigen–4 (CTLA-4).

“Immune repertoire sequencing has confirmed that blocking CTLA-4 increased turnover and diversity of the T-cell repertoire in some patients with advanced prostate cancer or metastatic melanoma, but also showed that patients who survived longest maintained clones of high-frequency T-cells they had developed before starting treatment.”

Editor’s note: Ipilimumab is a drug that boosts a patient’s own immune system to fight cancer. It works by activating immune system cells called T cells, some subtypes of which may then attack tumors. Ipilimumab works very well for some patients, but not for others. This study found that patients who had certain tumor-fighting T cell subtypes already present before ipilimumab treatment were more likely to respond well and survive longer, possibly because these cells were readily available to fight cancer upon activation. The study also found that ipilimumab may prompt the immune system to “re-shuffle” the body’s T cell subtypes, allowing patients with only a small amount of tumor-fighting T cells to generate more. (This may explain why some patients take longer to respond to ipilimumab than others; their immune systems need more time to build up the right T cells.) Based on the results, doctors may be able to monitor a patient’s T cell subtypes (“immune repertoire sequencing”) to determine whether ipilimumab will work, or to keep tabs on the effectiveness of ongoing ipilimumab treatment.


Melanoma Treatment 2014: Emerging News


Immunotherapy may be patients’ biggest hope for transforming cancer treatment. This approach boosts a patient’s own immune system to fight cancer. More and more immunotherapy treatments are showing promise for more and more patients, and Science magazine named immunotherapies 2013’s Breakthrough of the Year. Continue reading…


At Last, Success Seen in Fighting Cancer with the Immune System

“Fundamental research — much of it done in Boston — has led to a shift in the scientific strategy for fighting some cancers, toward using drugs to activate a patient’s own immune system. An approach that was on the fringes of cancer therapy is suddenly the hottest trend in cancer drug development. On Monday, for example, Boston researchers presented data showing that nearly half of patients with advanced melanoma lived for two years after getting an experimental immune therapy called nivolumab, though multiple other therapies hadn’t worked for them. And drug companies have announced several deals recently to acquire companies developing immunotherapies. The frenzy of activity is an abrupt change for a field that had made big promises but failed to deliver for years.”