Presenter: P. B. Chapman Presenter's Institution: Memorial Sloan Kettering Cancer Center
Dacarbazine (DTIC) was approved for melanoma in 1975; the overall response rate has been reported at 7-12% and median OS after starting the drug is less than 8 months.
High dose IL-2 was approved in 1998, with a durable CR of 5-7%. IL-2 is a toxic drug, and use requires that patients have excellent performance status to tolerate the treatment.
About 50% of melanomas have an activating V600EBRAF mutation; in 80-90% of patients, this consists of a mis-sense mutation with substitution of glumatine for valine at position 600. Understanding of these genetic changes has led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit.
Phase I and II trials with Vemurafenib (previously PLX4032/RO5185426), an orally available small molecule inhibitor of oncogenic BRAF kinase, showed response rates (RR= CR+PR) >50% in V600EBRAF- mutated melanoma patients. Phase I data demonstrated antitumor activity and dose-limiting toxicity, with arrival at a dose of 960 mg twice daily.
The authors conducted a phase III trial to determine whether Vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with V600EBRAF mutation, the results of which are described here.
Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for V600EBRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to Vemurafenib (960 mg po bid) or DTIC (1,000 mg/m2, IV, q3w).
Randomization was stratified by PS, stage, LDH, and geographic region.
Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks.
The randomization was not blinded and cross-over was not allowed initially.
Co-primary endpoints were OS and PFS on the intent-to-treat population.
Secondary endpoints included RR, response duration, and safety. The final analysis was planned at 196 deaths.
Based on evolving phase II data, it was felt that the design of the trial underestimated the treatment effect, therefore in Oct 2010, the statistical plan was resolved.
Originally, the target hazard ratio was 0.75 which would have required 468 events (deaths) with a single primary endpoint of overall survival;
The revised plan had two primary endpoints, OS and PFS, and the OS target hazard ratio was changed to 0.65, requiring only 196 events.
675 pts were enrolled at 104 centers from 12 countries worldwide between Jan and Dec 2010.
Treatment cohorts were well-balanced:
2/3 of patients had M1C disease.
Pts were stratified by stage, LDH, ECOG PS, and geographic region.
Entry criteria included ECOG PS of 0-1 and no active CNS metastases.
All pts were previously untreated.
Data presented are from the pre-planned interim analysis in Dec 2010.
At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios for OS and PFS were 0.37 (95% CI 0.26 to 0.55; p<0.0001) and 0.26 (95% CI 0.20 to 0.33; p<0.0001), respectively, both in favor of Vemurafenib.
The confirmed RR was 48.4% and 5.5% to Vemurafenib and DTIC, respectively, among the 65% of pts evaluable for RR to date.
The estimated 6 month survival was 64% for dacarbazine, whereas it was 84% for Vemurafenib.
Median PFS for dacarbazine at interim analysis was 1.6 months, compared to 5.3 months for Vemurafenib which was highly statistically significant. For all groups in the subset analysis, there was a benefit in PFS after treatment with Vemurafanib (p=SS).
Beyond 7 months, there were too few patients with long enough follow-up to report longer-term findings.
In susbset analysis, stages M1C, IIIC, and elevated LDH subsets derived the most benefit from Vemurafenib.
Due to these data, the DTIC cohort has been allowed, and recommended, to cross over to Vemurafenib. At the time of data analysis, 66% of Vemurafenib pts and 25% DTIC pts were still on treatment.
The most common toxicities of Vemurafenib were diarrhea, rash, alopecia, photosensitivity, fatigue, arthralgia, and keratoacanthoma/skin squamous cell carcinoma.
Fewer than 10 percent of patients who received Vemurafenib experienced grade three or worse toxicity.
Approximately 20 percent to 30 percent of patients developed a low-grade skin cancer, squamous cell carcinoma. There were no other malignancies observed.
Discontinuations due to AEs were uncommon: 6% for Vemurafenib and 4% for dacarbazine.
The authors conclude that Vemurafenib is associated with significantly improved OS (63% decrease in hazard of death) and PFS (74% decrease in hazard of progression, with a benefit seen in all subgroups) compared to DTIC in pts with previously untreated, V600EBRAF-mutated metastatic melanoma. There were few drug discontinuations.
Vemurafenib is the first drug to improve overall survival when compared to standard chemotherapy in patients with advanced melanoma. It is also the first drug to improve progression-free survival (PFS) and response rate in these patients. If approved by the FDA, as is expected, Vemurafenib could become a new standard treatment for patients with melanoma who have this gene mutation. However, because of the short follow-up, the results, at this point, should not be considered definitive.
The development of other skin cancers in patients taking Vemurafenib has been postulated to be due to paradoxical stimulation of CRAF. With longer follow-up, we will want to know if this pathway could promote development of other malignancies.
The authors plan to next test Vemurafenib in combination with other agents in patients with advanced melanoma. A Phase I trial has already begun with Vemurafenib and Ipilimumab, the first drug to show an overall survival benefit for patients with metastatic melanoma. Ipillimumab is a CLA-4 monoclonal antibody that augments T cell activation, which received approval from the U.S. Food and Drug Administration earlier this year. The results of this trial will be of great interest.
Vemurafenib is not effective for patients without BRAF gene mutation. For example, most acral lentiginous and mucosal melanomas have KITrather thanBRAF mutations and would not respond to Vemurafenib. KIT-mutated, BRAF-mutated and NRAS-mutated melanomas will require different regimens, so histological and molecular diagnostics will be of utmost important in determining treatment regimens.
Even with excellent responses such as those observed in this study, many melanomas relapse, and there are several possible mechanisms of BRAF resistance, highlighting the need for research into resistance mechanisms.
Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809-819.
Jun 7, 2011 - The addition of ipilimumab to dacarbazine appears to improve survival in patients with previously untreated metastatic melanoma, and vemurafenib appears to improve survival in patients with metastatic melanoma and the BRAF V600E mutation, according to two studies published online June 5 in the New England Journal of Medicine to coincide with the annual meeting of the American Society of Clinical Oncology, held from June 3 to 7 in Chicago.