The U.S. Food and Drug Administration (FDA) has approved the immunotherapy Tecentriq (atezolizumab), in combination with Cotellic (cobimetinib) and Zelboraf (vemurafenib), for the treatment of BRAF V600 mutation-positive advanced melanoma.
The decision comes after promising findings from IMSPIRE150 (NCT02908672), a Phase 3 trial in which the triple combination significantly extended the time patients lived without signs of disease progression, compared with a combination of Cotellic and Zelboraf.
“Today’s FDA approval of this Tecentriq combination represents an important step forward for many patients living with advanced melanoma,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Genentech — which makes all three medications — said in a press release.
The company’s submission was reviewed under priority review and Project Orbis, an initiative created to allow simultaneous submission and review of cancer medications among international regulatory partners.
Melanoma is a type of skin cancer. About half of melanomas have mutations in the gene BRAF, the most common being V600 mutations (mutations at position 600 in the protein chain, where there is usually the amino acid valine). These mutations lead to the production of an overly active BRAF protein, which drives cancer cell growth.
Zelboraf is an inhibitor of the BRAF protein, and Cotellic inhibits MEK, a related protein that is involved in BRAF-driven cancer cell growth. The combination of these two medications was approved for the treatment of BRAF V600 mutation-positive melanoma in 2015.
Tecentriq is an immune checkpoint inhibitor, a type of immunotherapy that works by blocking signals that cancer cells use to avoid destruction by the immune system — thus allowing the immune system to eliminate the cancer cells more easily.
IMSPIRE150 enrolled 514 people with an advanced melanoma that could not be removed surgically, who had not previously been treated. About 60% of participants were male, about three-quarters were older than 65, and 95% were white.
Participants were randomized to receive Tecentriq, plus Cotellic and Zelboraf (the Tecentriq group, consisting of 256 participants) or a placebo with Cotellic and Zelboraf (the control group, 258 participants).
The trial’s primary outcome, or its main measurement of efficacy, was progression-free survival (PFS), which is the time in which patients live without evidence of disease progression (e.g., no measurable tumor growth).
Results of the trial were published in The Lancet, in the study, “Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial.”
The median PFS, as determined by the study investigators, was significantly longer in the Tecentriq group (15.1 months) than in the control group (10.6 months).
An independent committee also assessed PFS and found results that favored the Tecentriq group, though the difference it found between the groups was not considered statistically significant. Closer evaluation of the data revealed that the committee had tended not to score events as PFS in cases where the study’s investigators had, which likely explains the discrepancy.
“When receiving a cancer immunotherapy combined with targeted therapies, patients with BRAF V600 mutation-positive advanced melanoma were able to live for more than 15 months without their disease worsening,” said Garraway.
Overall response rates were similar (about 66%) in both groups, though the median duration of the response was markedly longer in the Tecentriq group (21 months vs. 12.6 months).
The estimated two-year overall survival rates were 60% in the Tecentriq group and 53% in the control group.
Of note, for both PFS and overall survival, significant differences between the groups were generally seen relatively late into the study, which followed participants for a median of 18.9 months. This suggests that a longer follow-up “might reveal more clinically meaningful benefit and inform the optimal treatment paradigm,” the investigators wrote.
The most commonly reported adverse events in the Tecentriq group were rash (75%), musculoskeletal pain (62%), fatigue (51%), liver toxicity (50%), fever (49%), nausea (30%), itch (26%), edema (26%), inflammation of the mouth (23%), hypothyroidism (22%), and photosensitivity reaction (21%).
Genentech is offering patient assistance programs for people prescribed Tecentriq plus Cotellic and Zelboraf by their doctor through Genentech Access Solutions; more information can be found on its website or by calling (866) 422-2377.
Genentech is planning additional research for Tecentriq, including studies of the medication (both alone and in combination with other therapies) in lung, genitourinary, skin, breast, gastrointestinal, gynecological, and head and neck cancers.
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