ASCO 2011, New Drugs for Melanoma|August 14, 2011 4:49 am

ASCO 2011 Plenary Part 2: Vemurafenib


The Melanoma Triple-Threat

 

I was going over my notes about Dr. Paul Chapman’s ASCO 2011 Plenary Session presentation on the Phase III Vemurafenib study in metastatic melanoma and I came across an interesting phrase concerning the results: this is the first single drug to improve Overall Survival (OS), Progression Free Survival (PFS), and Response Rate (RR) in metastatic melanoma.

[Wow.]

I’m not sure if Paul said it that way or I just paraphrased, but either way its power and significance are singular and immense. For years, regardless of the setting, all of us who see patents with metastatic melanoma have polished a variation of the following statement: There is no drug that predictably and effectively treats advanced melanoma…

Every other drug with activity in advanced melanoma has always come with a qualifier. DTIC doesn’t do much, that often, but nothing else did either, and at least there was some measurable response rate. Intron A improves PFS (technically relapse free survival) in the adjuvant setting but not OS. The same for its newly approved longer acting cousin, Sylatron. Interleukin-2, approved for treatment of Stage IV melanoma, can cause impressive if infrequent responses without improving OS or PFS on a significant scale. Even Ipi (Yervoy), just approved for the treatment of advanced melanoma, improves OS without increasing RR. The PFS data for Ipi is interesting because the median PFS is not improved (in other words over half of all treated patients progress around the first assessment point) but the “tails” of the curve diverge, resulting in a statistically significant 24% reduction in the risk of progression. Approvable but less than ideal…

But now there is a drug with unequivocal, across the board, benefit. A Melanoma “Triple Threat”. Or at least, once the FDA approves the drug, there will be. Vemurafenib, which at press time still doesn’t have a catchy trade name. So I have decided to call it VFib.

During the plenary session at ASCO this year, Dr. Chapman presented data from the BRIM-3 Phase III trial comparing treatment with VFib (Vemurafenib) vs. DTIC for patients with unresectable Stage III or Stage IV melanoma. The pace and scope of this achievement is remarkable and exciting. The initial Phase I data was only presented two years ago in 2009. The Phase II study accrued so quickly, its (positive but of lesser importance) data were only presented the day before the plenary session. The Phase III trial was able to complete accrual in a little less than one year. I’m not sure there have been too many cancer drugs that have ever had a shorter development cycle.

Then, another truly amazing thing happened; the FDA demanded a rewrite of the approved statistical plan, followed by an earlier interim analysis of the results before the overall survival data were really mature. The positive results were announced earlier this year (apparently at the FDA’s urging) and then all patients on the trial were immediately allowed to crossover to the VFib arm.

I believe the FDA was reacting to a NY Times article about the ethics of patients on the trial being randomized to DTIC when VFib was so obviously effective. As a political animal, the FDA is very sensitive to these sorts of things.

As a result of the FDA’s meddling, the PFS data became final at the time of the early stoppage, because the instant crossover ended any further analysis of progression. The trial data were analyzed and reported before the OS data became finalized, and at the time of the plenary session the OS and response rate data remains preliminary.

On to the study and its specific results:

This was a large scale randomized trial in patients with either unresectable Stage III or Stage IV melanoma. All patients had to have a mutated BRAF gene in their melanoma, as determined by a single, central laboratory, to eliminate the possibility of lab-to-lab variation. Of the patients screened for the trial, 47% had the mutation, consistent with earlier studies. Most of the mutations were of the V600e type although a small number of V600k type mutations were also treated and appeared to do well.

Patients were randomized to either receive VFib at 960 mg twice a day by mouth or standard dose DTIC intravenously every three weeks, the longterm (if disappointingly ineffective) standard of care for advanced melanoma. In less than one year, 675 patients were enrolled (!!) and data cutoff was a fairly early, on Dec 30, 2010. The reason for this early data cutoff was to allow the mandated early/interim evaluation to take place earlier this year. However as a result of this early data cutoff, several endpoints will need to be reassessed at a later date for completeness, although that will not affect the overall conclusions.

The most striking side effect has been reported previously: fairly frequent development of low grade squamous cell type skin cancers and pre-cancers, in up to about 35% of treated patients. In theory, this could be due to unanticipated malignant transformation of BRAF wild-type or un-mutated skin cells, but this is unproven at present. These skin changes did not cause dose delays or adjustments, which mostly occurred due to rashes, fatigue, light sensitivity, joint pain, or liver test elevations.

The results are nothing short of spectacular! About 90% of patients treated with VFib has some tumor shrinkage, with at least 48% reaching “measurable” thresholds. This data is best shown in a “waterfall plot” which I will attempt to get a copy of for the website. This number is lower than what will be the final result because of the early data cutoff which prevented some patients from having their response evaluated/included in the results. The responses were seen quite quickly, on average only about six weeks after treatment was begun. Only 5 % of patients treated with DTIC had measurable tumor shrinkage and the difference between the two drug treatments was highly statistically significant.

The only final result based on the data cutoff point is the PFS or progression free survival. Patients treated with VFib had a median PFS of 5.3 months vs. 1.6 months for DTIC. Statistically, this translates to a highly significant 74% reduction in the risk of melanoma progression when treated with VFib.

Finally, overall survival was improved with VFib treatment, resulting in a statistically significant 63% reduction in the risk of death relative to treatment with DTIC. Due to the early data cutoff, median survival in the VFib treated group cannot yet be estimated, but the curves predict that 84% of patients will be alive at 6 months, well above the older standards for patients with advanced melanoma.

As I said, VFIb is the new triple threat against advanced melanoma. It improves overall survival, progression free survival and tumor response rate in patients with the deadliest stage of this cancer. There are no negatives in this study. It even overcame the “tougher” statistical barriers imposed by the FDA.

So what’s next? Why isn’t it approved by the FDA yet?

I’m not sure. The drug has met every statistical requirement imposed. There are no red flags in its safety profile. The data was reviewed early at the FDA’s request and still hit all the endpoints.

Thus by every reasonable criteria the drug has done everything “asked” of it for FDA approval. My only possible conclusions are that the FDA must be completing an independent internal verification of the reported data, and that full approval must be just around the corner. My prediction is for full approval in September 2011.

Stay tuned for a discussion of how the Ipi and VFib data change the treatment of melanoma, coming soon.

Eric D. Whitman, MD
Senior Editor, TheMelanomaCenter.com


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3 Comments

  • Dr. Whitman describes “spectacular” results presented at the last ASCO. The Vemurafenib, indeed, seems to be a very impressive drug against advanced melanoma. Dr. Whitman unambiguously indicates that : ” this is the first single drug to improve Overall Survival (OS), Progression Free Survival (PFS), and Response Rate (RR) in metastatic melanoma”. I must disagree with this statement and admit that one is even a bit disappointed from the oversight regarding the impressive results (in terms of melanoma treatment) of the adoptive cell therapy (ACT) technology demonstrated by groups applying it with tumor infiltrating limphocytes (TILs). This technology has improved significantly the response rates as well as progression free survival of patients, and predicted to improve significantly the overall survival of the treated patients. Recent review of Rosenberg et al at Nat Rev Clin Oncol (2011) describes: ” Cancer immunotherapy using the adoptive transfer of autologous tumor-infiltrating lymphocytes results in objective cancer regression in 49-72% of patients with metastatic melanoma. In a pilot trial combining cell transfer with a maximum lymphodepleting regimen, complete durable responses were seen in 40% of patients, with complete responses ongoing beyond 3 to 7 years. To the best of my knowledge, up to date complete durable response is exclusive to the TILs technology concerning melanoma treatment. Indeed, TILs are not a “classical” drug, but rather a technology and as such, tends to be underestimated and sometimes ignored.

    • Thank you for your note. I must respectfully disagree with your contention. Dr. Rosenberg’s work, while unique, creative, and impressive, has never been tested in a large scale Phase III format. The papers you refer to are PILOT studies with small numbers of patients. The results, while interesting, should mostly be considered “hypothesis-generating,” in that they lead us to contemplate how this therapy could actually be compared against other therapies, which would now include ipilimumab and/or vemurafenib.

      I stand by my statement. These are spectacular results. There never has been another drug to show across the board effects in Stage IV melanoma patients.

      Eric Whitman, MD
      Senior Editor, TheMelanomaCenter.com

  • Dear Dr. Whitman. The results demonstrated with the TIL technology are indeed phase II clinical trials. Nevertheless, I must indicate that to define this therapy as a pilot study does not serve properly the patients. This technology is currently applied in four different medical centers (USA: NIH, Aurora, MD Anderson and in Israel: Sheba medical center) and overall accumulated over 200 treated patients. All centers achieve similar response rates!! As you know, both Ipilimumab and Vemurafenib give great clinical results, however do not CURE melanoma, since almost all treated patients experience relapse in a short period of time.
    I understand your caution with regard to this still experimental treatment, but I plead you as a clinician to help us bring this option to the patients and philanthropists knowledge. Adoptive cell therapy is not financed by any pharmaceutical company and as such, will be difficult to finance the standard regulatory approval. Moreover, the TIL treatment has been offered only to patients who failed other approved treatments and are deemed to die. Let’s save some of these people lives (many of them very young)- this is what medicine is all about!
    Last few years have shown there still is a lot of improvement potential for ACT and therefore the joining of additional hospitals to the effort is very important to further develop a technology that proved a lot of promise in the fight against cancer.
    Sincerely yours,
    Melanoma cures team.

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