ASCO 2011|June 2, 2011 3:33 am

New Drugs and Treatments for Melanoma from ASCO 2011


This year at ASCO will feature, as previously described, two plenary session blockbuster presentations on positive results for ipilimumab and vemurafenib, respectively.

When looking through the abstracts accepted in the melanoma sections, there are many that feature supplemental results about those two drugs: mechanisms of resistance, genetic markers of response, genetic profiles by age etc., and early looks at combination therapies. Other abstracts sadly report negative results from large scale studies, or provide updates on studies already reported. However, as with each year, there are some abstracts that look at new drugs or new combinations of drugs that show early promise. Perhaps these drugs or regimens will graduate to a plenary session in the future!

I thought it would be interesting to preview the oral abstracts and poster-discussion abstracts (General posters to be previewed and reported another time)  that present treatment data on either new drugs or combinations. Conveniently, there are ten abstracts that fit that bill, and therefore, in their presentation order, here are the top ten new drugs or combinations for melanoma treatment, ASCO vintage 2011.

1. A phase I trial of ipilimumab plus bevacizumab in patients with unresectable stage III or stage IV melanoma. This study combines Ipi (10 mg/kg dose) with bevacizumab (Avastin) at escalating doses. From data on 21 patients, the interesting points appear to be that 14/21 patients had either a PR or SD, all durable, that toxicities are what would be expected from ipi alone, and that correlative studies show anti-angiogenic effects in tumors not seen with ipi alone. These are promising Phase I results.

2. Results from the first-in-human (FIH) phase I study of the oral RAF inhibitor RAF265 administered daily to patients with advanced cutaneous melanoma. This is an early Phase I study of a new drug in development by Novartis, RAF265. It is both a mutant BRAF inhibitor and also a VEGFR2 inhibitor. There were some significant side effects, including pulmonary embolism in 2 patients, and dosing is still being finalized. Interestingly, patients with both mutant and wild type (unmutated) BRAF responded to the drug at about the same frequency. This is in contrast to the Plexxikon and GSK BRAF inhibitors that elicit responses in mutant BRAF only.

3. Targeting histone deacetylase to overcome resistance of B-RAFV600Emelanoma cells to apoptosis. I find this a very interesting study. Histone deacetylase inhibitors (sometimes called HDAC) target the epigenome, the structure surrounding DNA. This study, which appears to be in vitro, appears to show that HDAC inhibition can partially undo the survivability of cells that become resistant to BRAF inhibitor drugs (even though they still harbor the otherwise sensitive mutation). This pathway may become important some day, as acquired resistance to the BRAF inhibitors has been important in all studies to date.

4. The effect of beta-blocker treatment in patients with cutaneous melanoma. This is a retrospective study that suggests that patients who take beta blockers for other reasons (high BP, etc) had a reduced risk of recurrent melanoma. If this finding is confirmed and supplemented, wouldn’t that be great? Almost all patients can be safely given beta blocker therapy…

5. Assessment of clinical activity of E7080, a multitargeted kinase inhibitor, in patients with advanced melanoma treated in two phase I trials. There are multiple posters looking at various aspects of therapy with E-7080, a drug being investigated for treatment of metastatic melanoma (and in Phase III testing for thyroid cancers too). We will be opening these trials at the Atlantic Melanoma Center.

6. A phase II clinical/translational trial of sequential axitinib/carboplatin/paclitaxel in melanoma. This is a small (8 patient) Phase II trial combining axitinib with taxol/carbo. 5/8 patients had some response, and 4/5 had wild type BRAF gene, again relating back to the emphasis on BRAF mutation status, particularly in anticipation of FDA approval of Vemurafenib.

7. MLN4924, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients (pts) with metastatic melanoma: Results of a phase I study. This is another Phase I study, of an agent that works on the NEDD8 pathway and felt to promote apoptosis. This is a “new” pathway for melanoma investigation. The results of this limited study are interesting enough to encourage further evaluation (19 patients, 1 PR, 9 SD).

8. Final results of phase I/II study of decitabine (DAC) combined with temozolomide (TMZ) in metastatic melanoma (MM). This study combines extended dose temozolomide (75 mg/m^2 x 4/6 weeks) with DAC, a DNA repair enzyme inhibitor. The principle is to prevent temozolomide-damaged DNA from being repaired. Of 33 evaluable patients in the Phase II portion of the trial, 1 had CR, 4 had PR and 13 had SD (RR=15%). The median OS was 15.2 months, which is impressive (Ipi trial last year had OS of 10 months). Also, this trial included patients with brain metastases (42% of patients) although the abstract does not break out how those patients did.

9. A randomized phase II trial of temozolomide (TMZ) and bevacizumab (BEV) or nab-paclitaxel (nab-P)/carboplatin (CBDCA) and bevacizumab (BEV) in patients with unresectable stage IV metastatic melanoma: A North Central Cancer Treatment Group Study (N0775). This is a Phase II randomized comparison of temozolomide plus avastin vs Abraxane/carbo/avastin. The Abraxane arm had better 6 month PFS rate, the primary endpoint. As with the last abstract the median OS was 15 months. Like the previous study, this regimen seems to deserve further investigation.

10. Combination immunotherapy for high-risk and advanced melanoma patients. This study looks at a new melanoma vaccine, called HyperAcute Melanoma vaccine (NLG-12036, NewLink Genetics), in combination with peg-Interferon or Sylatron. The results are ok but not great, although it is difficult to evaluate due to low numbers and a mixed group of patients. I include it because it is a new agent and there is considerable interest in combining immunotherapeutic agents for possible synergy.

These brief comments are previews only; full reports (and tweets) to follow during ASCO.

Eric D. Whitman, MD

Senior Editor, TheMelanomaCenter.com

 

 

 

 

 

 

 

 

 

 

 


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