by Dr. C.H. Weaver M.D. 8/2020
Researchers have reported that BRAF V600E mutated advanced melanoma patients survive longer without their cancer progressing when immunotherapy is combined with two precision cancer medicines that block the BRAF mutation. The results of clinical trials explaining how “checkpoint inhibitor” immunotherapy improved the performance of standard precision medicines targeting BRAF and MEK were published in the journal Nature Medicine and the U.S. Food and Drug Administration (FDA) approved the checkpoint inhibitor Tecentriq® (atezolizumab) for combination with Cotellic® (cobimetinib) and Zelboraf® (vemurafenib) for the treatment of BRAF V600 mutation-positive advanced melanoma patients in July 2020. (1-3)
Metastatic melanoma refers to skin cancer that has spread from its site of origin to distant and/or several locations in the body. Historically, advanced melanoma has had a poor outlook and only a few patients achieved long-term survival. However, recent treatments that target specific genetic mutations, as well as those that stimulate the immune system have resulted in significantly improved outcomes for many patients. There are over 250,000 individuals with advanced melanoma diagnosed worldwide each year, the majority of whom can benefit from treatment with newer precision cancer medicines and immunotherapy. (4,5)
Precision Cancer Medicines & Immuno-oncology
Treatment of melanoma with precision cancer medicines has progressed considerably over the past few decades. The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in melanoma. Approximately half of all melanomas carry a specific BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Some melanomas carry another mutation known as V600K. BRAF and MEK inhibitors block the activity of the V600E and V600K mutations respectively and the combination of a BRAF and MEK Inhibitor is standard treatment for individuals with advanced melanoma and these cancer driving mutations.
The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.
Checkpoint inhibitors are a novel precision cancer immunotherapy that help to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. Checkpoint inhibitors block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells.
Currently available checkpoint inhibitors:
- Keytruda® (pembrolizumab)
- Opdivo (nivolumab)
- Imfinzi (durvalumab)
- Tecentriq® (atezolizumab)
UCLA scientists initially published results of adding the checkpoint inhibitor Keytruda to BRAF and MEK inhibitors in 15 people with BRAF-mutated metastatic melanoma. In 11 patients the tumors shrank and remained stable and did not grow again for 12 to 27 months. Additional patients who received the three-drug combination had progression-free survival — meaning that the disease did not worsen or progress — for an average of 16 months. Those who received a BRAF and MEK inhibitor alone lived for an average of 10.3 months without the disease progressing. According to Dr. Antoni Ribas of UCLA “utilizing the three drugs together sensitized the patient’s own immune system to bolster the power of immunotherapy and block the growth of two genes — BRAF and MEK — that cause cancer cells to reproduce and grow out of control.”
The U.S. FDA approved the checkpoint inhibitor Tecentriq® (atezolizumab) for combination with the BRAF-MEK inhibitors Cotellic® and Zelboraf® for the treatment of BRAF V600 mutation-positive advanced melanoma patients based on results from the IMspire150 clinical study which demonstrated that the addition of Tecentriq to Cotellic and Zelboraf prolonged patient survival and delayed cancer progression by 5 months.
About the IMspire150 study
The IMspire150 clinical trial directly compared Tecentriq plus Cotellic and Zelboraf to the combination of placebo plus Cotellic and Zelboraf in 514 previously untreated BRAF V600 mutation-positive metastatic or unresectable locally advanced melanoma. Patients treated with Tecentriq survived 15.1 months without cancer progression compared to10.6 months in individuals treated with the two-drug combination. These results are consistent with the UCLA researchers experience with the addition of Keytruda. The most common side effects with the three-drug combination were rash, musculoskeletal pain, fatigue, fever pyrexia, nausea, itching, pruritus, mouth sores, hypothyroidism and photosensitivity reactions.
Side effects that occur when immunotherapy is combined with a BRAF and MEK inhibitor are not insignificant. Patients should discuss the potential benefits and risks of adding checkpoint inhibitor immunotherapy to the BRAF MEK inhibitor combination with their treating oncologist.
Returning to an active life
One of the participants in the UCLA trial was Joanna, a former Wall Street trader and veteran hiker and snowboarder. In 2014, Joanna had golf ball–sized tumors throughout her body, and she was diagnosed with BRAF-mutated advanced melanoma. By the time the clinical trial began, she needed a wheelchair to get around, a far cry from the active life she was accustomed to.
“I was in really bad shape,” Joanna said. “I was bedridden and on pain killers, and I couldn’t really move. It’s no way to live. I was obviously scared, yet surprisingly optimistic before starting the treatment.”
Just days after she began the therapy, Joanna’s tumors began to disappear.
“I could actually see it working,” she said. “The tumors started dissolving and getting smaller almost immediately. Within a month I was back walking on my own, and three months later I was on a plane to the Canadian Rockies for a vacation with one of my best friends.”
Five years later, Joanna still has no evidence of the disease.
After the study’s first phase proved the drug combination to be safe, the next phase incorporated 120 people at 22 sites around the world. Half of the patients received the three-drug combination, and the other half received the two targeted drugs and a placebo instead of the immunotherapy drug.
Even though the trial was randomized, the three-drug group had more patients with a poorer prognosis than the placebo arm. Regardless, people in the three-drug group fared better, with their progression-free survival lasting an average of nearly six months longer than the average for those in the placebo arm.
“The results of the triple therapy is so much more encouraging than double-therapy combinations with these drug agents,” Ribas said. “With this triple combination, we’re doing two things at once: using the two inhibitors to block the cancer from spreading and stimulating the immune system. An immune response has the ability to remember foreign invaders and help protect the body from similar infections in the future, so enlisting an immune response to the cancer is aimed at having more durable responses to the therapy.
- Keep Current With The Melanoma Newsletter
- Connect With Others In The Skin Cancer Community To Share Information And Support
- FDA approves atezolizumab for BRAF V600 unresectable or metastatic melanoma
- Three-drug combination helps curb the growth of deadly type of skin cancer
- 5 Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F (2018). Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available here Last accessed: July 2020.
- Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.