Targeted Roche Drug Scores Again in Melanoma for Patients with Advanced Melanoma
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By Charles Bankhead, Staff Writer, MedPage Today
Published: February 22, 2012
· Approximately 50% of melanomas harbor activating mutations in the serine-threonine protein kinase B-RAF.
· Point out that in this study, vemurafenib induced clinical responses in more than half of patients with previously treated BRAF-mutant metastatic melanoma.
Half of patients with previously treated metastatic melanoma responded to the targeted agent vemurafenib (Zelboraf), data from a phase II trial showed.
Treatment with the BRAF inhibitor was associated with a median progression-free survival of 6.8 months and a median overall survival of 16 months.
The results corroborated those from a phase I trial and were consistent with results from a phase III study that showed a high response rate in previously untreated metastatic melanoma.
"Most responses were rapid, with less than 15% of patients having had disease progression at their first evaluation," Jeffrey A. Sosman, MD, of Vanderbilt University in Nashville, Tenn., and co-authors wrote in conclusion in the Feb. 23 issue of the New England Journal of Medicine.
"Therefore this trial shows that vemurafenib has clinically evident antitumor activity in metastatic melanoma and that response rates are higher than those associated with previously used treatments."
"The long follow-up period in our study provides critical information on long-term overall survival, not yet shown in the phase III trial comparing vemurafenib and dacarbazine," they added.
A decade ago, laboratory studies showed that more than 60% of melanomas had the BRAF V600E mutation, which activated the MAP kinase pathway to promote cell proliferation and inhibit apoptosis (Nature 2002; 417: 949-954, Nature 2007; 445: 851-857).
Those observations led to development of vemurafenib, a tyrosine kinase inhibitor that targets the BRAF V600E mutation in cancer cells. A phase I clinical study showed that 26 of 32 patients with previously-treated melanoma had responses to vemurafenib, including 18 confirmed responses (N Engl J Med 2010; 363: 809-819).
The encouraging results of the phase I trial led to the phase II investigation by Sosman and colleagues. The study involved patients with histologically confirmed stage IV melanoma that had progressed after one or more prior systemic therapies for advanced disease.
The final analysis included 132 patients who had a median age of 52. Men accounted for 61% of the total population. Half the patients had received one prior regimen for advanced melanoma, 27% had received two, and 22% had received three or more.
Patients underwent baseline tumor imaging, and follow-up assessments occurred every six weeks and at final visit. A blinded independent review committee assessed response to therapy.
All patients received vemurafenib daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate.
The study population had a median follow-up of 12.9 months at the cutoff for efficacy data, and follow-up for the entire cohort ranged from 0.6 to 20.1 months.
By independent review, eight patients (6%) had a complete response to vemurafenib, and 47% had a partial response, resulting in an overall response rate of 53%. Investigator assessment showed an overall response rate of 57% (5% complete response rate).
The 70 patients with confirmed responses had a median response duration of 6.7 months. Although most responses occurred by the time of the first follow-up imaging assessment at six weeks, some occurred after more than six months of treatment.
At efficacy cutoff, 62 patients remained alive and the median overall survival was 15.9 months. The authors noted that 32 (24%) patients received ipilimumab (Yervoy) after disease progressed. An unplanned post hoc analysis showed that median overall survival remained at 15.9 months after exclusion of the 32 patients.
Providing context for the results, the authors wrote that metastatic melanoma has a median overall survival of six to 10 months and that, historically, few patients have responded to systemic therapy. Trials of ipilimumab, also approved for treatment of metastatic melanoma, showed an overall survival of 10.1 months in treated patients and 11.2 months in untreated patients.
Experience with vemurafenib has shown that non-melanoma skin cancer is a potential side effect of treatment. In the phase trial, 26% of patients developed cutaneous squamous-cell carcinoma or keratoacanthoma.
"Lesions usually manifested in the first eight to 12 weeks of treatment and were effectively managed with simple resection without discontinuation of vemurafenib," the authors wrote. "This suggests differential effects of vemurafenib on cells without oncogenic BRAF."
Adverse effects occurred in most patients but usually were mild or moderate in severity, the authors reported. In addition to skin cancer, the most common events were arthralgia (59%), rash (52%), photosensitivity (52%), fatigue (42%), alopecia (36%), pruritus (29%), skin papilloma (29%), nausea (17%), peripheral neuropathy (10%), and hand-foot syndrome (10%).
Survival in BRAF V600-Mutant Advanced Melanoma Treated with Vemurafenib
Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial.
We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point.
A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients.
Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months.
Treatment options for patients with advanced melanoma are limited.22 Since its discovery in 2002, the BRAF V600E mutant kinase has been considered a promising therapeutic target for this disease. The previously reported phase 1 study with vemurafenib in patients with BRAF V600-mutant metastatic melanoma provided evidence that inhibition of the oncogenic MAPK pathway resulted in significant antitumor activity.15,23 The major objective of the current phase 2 clinical trial was to define, in a larger number of patients, the overall response rate with vemurafenib in advanced melanoma. We report a confirmed response rate of over 50% in patients with previously treated metastatic melanoma bearing the V600E or V600K BRAF mutations. Most responses were rapid, with less than 15% of patients having had disease progression at their first evaluation. Therefore, this trial shows that vemurafenib has clinically evident antitumor activity in metastatic melanoma and that response rates are higher than those associated with previously used treatments.1-8,22 Reanalysis of the response rate in the phase 1 study according to the response criteria used in our phase 2 study yielded a similar overall response rate of 56%. Furthermore, although the median durations of response and progression-free survival were less than 7 months, some responses were delayed, with one fourth of patients remaining progression-free after a median follow-up period of 13 months. The median overall survival was nearly 16 months in this group of patients with melanomas expressing the relevant mutation. The patients did not have favorable baseline characteristics (61% with stage M1c disease and 49% with elevated LDH level) as compared with those in other large, phase 2 and phase 3 studies of melanoma. In fact, the BRAF mutation has been associated with shortened survival in patients with metastatic disease.24 The long median overall survival was not simply due to post-progression ipilimumab use in some patients, because exclusion of these patients from the analysis did not change the median overall survival.
Toxic effects were common but not severe or life-threatening in most instances. Although some patients required dose interruptions or reductions, patients were able to receive most of their intended daily dose. The toxic effects were largely related to the skin. As reported previously, the BRAF inhibitor vemurafenib, as with other RAF inhibitors, is associated with the development of cutaneous squamous-cell carcinoma or keratoacanthoma but not squamous-cell carcinoma derived from other organs.15,25,26 Lesions usually manifested in the first 8 to 12 weeks of treatment and were effectively managed with simple resection without discontinuation of vemurafenib. This suggests differential effects of vemurafenib on cells without oncogenic BRAF. Preclinical models have shown that BRAF inhibitors can paradoxically enhance activation of the MAPK pathway in cancer cells with wild-type BRAF that carry upstream RAS mutations.27-30 This mechanism may play a role in the development of cutaneous squamous-cell carcinomas.30
As with most targeted therapies that block a driver oncogene, cancer cells can develop acquired resistance with continuous dosing. The molecular mechanisms of vemurafenib resistance are under investigation. The currently available data suggest that reactivation of the MAPK pathway through the emergence of truncated hyperactive forms of BRAF,31 secondary mutations in NRAS (the neuroblastoma RAS viral oncogene homologue)32 or MEK (MAP kinase kinase),33 up-regulation of COT (also known as TPL2 or MAP3K8),34 or activation of alternative survival pathways induced by increased expression of receptor tyrosine kinases but not by secondary point mutations in BRAF32,35 are all mechanisms of resistance. Elucidating approaches that can overcome or prevent acquired resistance is critical to further advances in the treatment of melanoma.
In conclusion, this trial shows a high rate of response to vemurafenib in patients with metastatic melanoma and activating BRAF mutations. These results independently confirm the high response rate and response duration shown in a phase 1 trial. The long follow-up period in our study provides critical information on long-term overall survival, not yet shown in the phase 3 trial comparing vemurafenib with dacarbazine.19 Targeted therapy aimed at oncogenic BRAF V600 induces responses in half the patients and a median survival of 16 months.
Supported by Hoffmann-La Roche.
Between October 2009 and March 2010, a total of 344 patients were screened for study entry at 13 centers (10 in the United States and 3 in Australia). Overall, 328 patients had tumor tissue tested for BRAF V600 mutations, and 184 (56%) tested positive (Fig. A in the Supplementary Appendix). The most common reason for exclusion was a negative test for BRAF V600 (in 143 patients), followed by the presence of central nervous system metastases (in 23 patients) on brain screening by means of MRI or CT. A total of 132 patients received the study drug and made up the intention-to-treat population. We enrolled more patients than the 90 originally planned because at the time the enrollment target was met, additional patients were already being screened; they were subsequently enrolled if determined to be eligible. At the efficacy data cutoff date (July 1, 2011), the median follow-up was 12.9 months (range, 0.6 to 20.1). At the safety data cutoff date (January 31, 2011), the median follow-up was 10.4 months (range, 0.6 to 14.7).
Of the 132 patients enrolled and treated in the study, the majority were men under 65 years of age with stage M1c disease (Table ). In all, 49% of patients had an elevated LDH level. Only 7 patients had received prior anti-CTLA4 therapy; 1 other had a history of stable brain metastases.
After screening for BRAF V600E by means of PCR-based testing, a BRAF V600E mutation was confirmed by Sanger sequencing or pyrosequencing in 122 patients, and BRAF V600K mutations were identified in the remaining 10 patients (Fig. B in the Supplementary Appendix).
According to the IRC, a complete response was achieved in 8 patients (6%) and a partial response in 62 patients (47%), for an overall response rate of 53% (95% confidence interval [CI], 44 to 62) (Figure 1, and Fig. C in the Supplementary Appendix). The rate of stable disease was 29% (in 38 of the 132 patients; 95% CI, 21 to 37). Six patients had missing assessments or data that were not able to be assessed. Only 18 patients (14%; 95% CI, 8 to 21) had primary progressive disease (Fig. C in the Supplementary Appendix). The investigator-assessed overall response rate was 57% (partial response, 52% of patients; complete response, 5%), representing an 83% concordance with the IRC assessments. In all the predefined subgroups comprising more than 25 patients, the overall response rate was greater than 30%, meeting the target rate in the protocol (Fig. D in the Supplementary Appendix). Patients with an LDH level more than 1.5 times the upper limit of the normal range had an overall response rate of 33% (15 of 46 patients; 95% CI, 19 to 48) - the lowest among the subgroups. Among the 10 patients with BRAF V600K mutations, 4 had a partial response, 3 had stable disease, 2 had progressive disease, and 1 had data that could not be assessed.
Twenty-three of 70 patients with a response had a maintained response at the date of efficacy data cutoff (July 1, 2011). The median duration of response according to the IRC was 6.7 months (95% CI, 5.6 to 8.6) (Figure 2). Most objective responses were evident at the time of the first set of scans (week 6), but in some patients, responses did not appear until the patient had been receiving the drug for more than 6 months. Thirty-three of the 132 patients (25%) were progression-free at the time of the data cutoff. The median progression-free survival, as assessed by the IRC, was 6.8 months (95% CI, 5.6 to 8.1). The 6-month progression-free survival rate was 56% (95% CI, 47 to 64) (Figure 3A).
Of the 132 patients enrolled in the study, 62 (47%) were alive as of July 1, 2011, and the median overall survival was 15.9 months (95% CI, 11.6 to 18.3) (Figure 3B). The overall survival rate at 6 months was 77% (95% CI, 70 to 85), 58% at 12 months (95% CI, 49 to 67), and estimated to be 43% at 18 months (95% CI, 33 to 53). During the follow-up period, 32 patients (24%) received ipilimumab after they had disease progression while receiving vemurafenib. In an unplanned post hoc analysis, median overall survival remained at 15.9 months (95% CI, 8.0 to not reached) even when these 32 patients were not included.
The safety data cutoff was January 31, 2011. Most patients had at least one adverse event related to the study drug (Table 2). The most commonly reported adverse events were arthralgia, rash, a photosensitivity reaction, fatigue, and alopecia. Several patients had asymptomatic, transient elevations in liver-enzyme levels. Four patients discontinued treatment because of adverse events, including retinal-vein occlusion in one. One patient died owing to rapid progression of melanoma and acute renal failure, possibly related to the study drug. Three patients had transient palsies of the seventh cranial nerve (with one patient having both synchronous and bilateral palsies). After resolution, these patients were able to resume vemurafenib.
Fifty-nine (45%) of the 132 patients had their dose reduced; dose interruptions were required in 85 patients (64%). The adverse events that most frequently led to dose modification or interruption included rash, arthralgia, elevated liver-enzyme levels, and photosensitivity reactions. Patients received a median dose of 1740 mg per day, which represents 91% of the intended dose of 1920 mg per day.
Development of cutaneous squamous-cell carcinoma or keratoacanthoma was reported in 34 patients (26%), typically consisting of only one lesion (in 20 patients) or two lesions (in 6 patients). Three lesions developed in 4 other patients, and four, five, six, and seven lesions developed in 1 patient each. The median time to development of the first cutaneous squamous-cell carcinoma or keratoacanthoma lesion was 8 weeks (range, 2 to 36) (Fig. E in the Supplementary Appendix). On central pathological review, 39 of 43 cutaneous squamous-cell carcinoma lesions were either keratoacanthoma or mixed keratoacanthoma type; the remaining 4 were invasive cutaneous squamous-cell carcinoma. Eight cases of basal-cell carcinoma were identified. No mucosal squamous-cell carcinoma or metastases of cutaneous squamous-cell carcinoma were observed.