Array BioPharma Announces Positive Top-Line Results from Part 2 of the Phase 3 COLUMBUS Study of Binimetinib and Encorafenib for BRAF-Mutant Melanoma

Excerpt:

“Array BioPharma (Nasdaq: ARRY) today announced top-line results from Part 2 of the Phase 3 COLUMBUS study evaluating binimetinib, a MEK inhibitor, and encorafenib, a BRAF inhibitor, in patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The primary analysis of Part 2 compared progression free survival (PFS) in patients treated with binimetinib 45mg twice daily plus encorafenib 300mg daily (COMBO300) to patients treated with encorafenib 300mg daily as a single agent. The median PFS for patients treated with COMBO300 was 12.9 months compared to 9.2 months for patients treated with single agent encorafenib, with HR of 0.77 [95% CI 0.61-0.97, p=0.029]. COMBO300 was generally well-tolerated and reported dose intensity and adverse events were consistent with COMBO450 results in COLUMBUS Part 1. Part 2 was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300mg in the combination arm to allow for a comparison of equal doses across arms. Further results from Part 2 will be presented at a medical meeting during the second half of 2017.”

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Metastatic Melanoma: Not Quite Curable…But Getting There


By 2050, the number of deaths due to malignant melanoma in the U.S. could be three times lower than peak levels reached before 1960. Researchers presented the data behind this prediction at the 2017 European Cancer Congress in January.

It is unclear how much of this anticipated decline in deaths can be attributed to the availability of new, effective treatments. However, it is obvious that much-increased awareness of sunlight exposure as the single factor most responsible for the development of skin melanoma has contributed to lower incidence of the disease.

In any case, the armament of treatments available for metastatic melanoma is currently such that this diagnosis has transformed from being almost universally fatal (even just a few years ago) into a being largely treatable. Since 2011, the U.S. Food and Drug Administration (FDA) has approved eight new drugs for melanoma.

Now, the pressing questions are: Why do these drugs not work for all patients? How can doctors select which patients should be treated with different types of drugs (targeted versus immune checkpoint versus intralesional)? And how can doctors identify patients who may benefit from a combination of different drugs?

BRAF-mutant melanoma: targeted drugs 

Getting a positive test for the BRAF V600 tumor mutation is certainly good news for a newly diagnosed melanoma patient. This is because some targeted drugs work very well against such tumors, which account for about 50% of melanomas.

The drugs vemurafenib or dabrafenib, which attack tumors by inhibiting mutant BRAF proteins, are no longer used on their own because combining them with MEK inhibitors (cobimetinib and trametinib, respectively) works so much better. The percentage of patients who respond to combined BRAF/MEK inhibition is about 70% or higher, and durable complete responses were observed in about 19% patients with stage IV or unresectable stage III melanoma in three large clinical trials that tested these combinations. The results of treatment with dabrafenib and trametinib in patients with resectable stage III melanoma were particularly impressive. One hundred percent of these patients had no relapse within the first six months after treatment, compared to just 28% of those treated with standard chemotherapy. All patients had fewer than three metastatic sites.

That last point brings us to an important question: Which stage IV patients with BRAF-mutant (BRAF+) melanoma may need a combined treatment with targeted and immunotherapy (immune checkpoint) drugs?

It is becoming clear that stage IV patients who have fewer, less bulky metastases (lower tumor burden) do much better on BRAF/MEK-targeting drugs. High blood levels of a protein called LDH has long been recognized as a poor prognostic factor in melanoma, and it has not lost its grim significance in the era of targeted and immunotherapy drugs. Patients with high LDH and many metastatic tumors may need a combined treatment with BRAF/MEK inhibitors and immune checkpoint drugs.

So far, combination treatments have proven to be efficacious in patients with high tumor burden. The problem is that combining BRAF/MEK inhibitors with immune checkpoint drugs of the type known as anti-PD-1 increases side effects (toxicity) in quite a dramatic way. The Keynote 022 clinical trial—which combined the anti-PD-1 drug pembrolizumab with dabrafenib and trametinib in a small group of patients—reported that 40% experienced serious side effects (grade 3–4), and close to 30% discontinued treatment. A response rate of 60% was observed but remains to be confirmed.

A very similar rate of side effects was observed in a trial that combined atezolizumab (another immune checkpoint drug of the type known as anti-PD-L1) with vemurafenib and cobimetinib. On a highly positive note, 83% of the patients in this trial responded to the treatment, with 10% going into complete remission. An earlier study of durvalumab (also anti-PD-L1) with dabrafenib and trametinib saw responses in 69% of patients.

Several trials have also addressed the possibility of sequential treatment with two different types of drugs in order to address the problem of toxicity.

Immune checkpoint drugs across the molecular subtypes

Immune checkpoint drugs may also be effective in tumors with mutations other than BRAF, including a mutation in the NRAS gene (NRAS+). Data are being accumulated for patients receiving the FDA-approved immunotherapy drugs nivolumab or pembrolizumab (both anti-PD-1 drugs). It appears that 47% of patients receiving nivolumab survive for three years, and 48–49% of those receiving pembrolizumab survive for 2 years (pembrolizumab data have not yet reached the 3-year point). Combination of nivolumab and ipilimumab (a type of immune checkpoint drug known as an anti-CTLA4 antibody) could eventually produce better results, but at the cost of a much higher toxicity. It is a bit difficult to say if these data are similar for BRAF+ and BRAF-/NRAS+ melanoma patients receiving immune checkpoint drugs, because most patients with BRAF+ cancers receive targeted drugs.

NRAS-mutant melanoma

Patients whose tumors test positive for an NRAS mutation (NRAS+) but not for a BRAF mutation (BRAF-) certainly have fewer treatment options than those whose tumors are BRAF-positive. NRAS mutations are encountered in about 20% of melanomas, and there are no effective targeted drugs for this subgroup. The only targeted drug that has shown promise in NRAS+ melanoma is binimetinib, a MEK inhibitor. In a trial for patients who were either untreated or had not responded to immune checkpoint drugs, binimetinib produced responses in 45% of patients; of those receiving only dacarbazine, a standard chemotherapy, just 9% responded. However, binimetinib prolonged overall survival by just 1.3 months compared to dacarbazine—not exactly an impressive improvement, which is apparently why the manufacturer of binimetinib withdrew its application for FDA approval of the drug.

Other trials are testing immune checkpoint drugs combined with MEK inhibitors for patients whose melanomas have no BRAF mutations (of which a substantial proportion have mutated NRAS). No results of these trials have yet been reported. Meanwhile, a very small study reported a response rate of 45% to combination of atezolizumab (anti-PD-L1) and cobimetinib in BRAF- melanoma patients. Additional trials testing durvalumab or pembrolizumab with trametinib have not posted results yet.

Regardless of specific tumor mutations, much hope lies in the clinical exploration of combinations of drugs that activate the immune system in different ways. Numerous immune checkpoint drugs work by activating the immune system. However, unlike the anti-PD-1 and anti-CTLA4 drugs discussed above, which remove inhibitory signals from the immune system’s T cells so they can attack cancer cells, newer drugs actually activate T cells by binding to positive regulatory proteins on these cells. Other new drugs aim to eliminate inhibitory signals created in the tumor microenvironment, such as those produced by different types of inflammatory cells or regulatory T cells. I would refer the interested reader to this excellent overview of these new drugs, which are now being tested against metastatic melanoma in numerous phase I trials.


Innovative Immunotherapy Combo Tests IDO Inhibitor in Melanoma Trial

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“Investigators are looking into a novel immunotherapy combination that pairs the first-in-class IDO1 inhibitor epacadostat (INCB024360) with the checkpoint blockade agent pembrolizumab (Keytruda) in patients with unresectable or metastatic melanoma.

“The phase III KEYNOTE-252/ECHO-301 trial, which is enrolling at more than 120 locations, will randomize 600 patients in a 1:1 ratio to either epacadostat combined with pembrolizumab or pembrolizumab plus placebo (NCT02752074).”

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Binimetinib Delayed Progression of NRAS-Mutant Melanoma

Excerpt:

“The MEK inhibitor binimetinib improved progression-free survival compared with dacarbazine in patients with NRAS-mutant melanoma, according to the phase III results of the NEMO trial published in Lancet Oncology.

“In addition, improved progression-free survival was seen in patients who had previously failed immunotherapy, the current guideline-recommended first-line treatment.

” ‘Future treatment algorithms for metastatic melanoma might incorporate binimetinib therapy in patients with advanced NRAS-mutant melanoma, including after the failure of immunotherapy,’ wrote Reinhard Dummer, MD, of the department of dermatology at the University Hospital Zurich Skin Cancer Center in Switzerland, and colleagues.”

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Super Patient: Peter Fortenbaugh Faces the Uncertainty of Pioneering Melanoma Treatment


In spring of 2014, Peter Fortenbaugh noticed what appeared to be a tick that had bitten his lower calf. “It turned out not to be a tick, but it didn’t really go away,” he says.

The spot began to grow and bulge, and in October, Peter showed it to his primary care doctor, who referred him to a dermatologist to remove it. At the time, Peter recalls, it did not occur to him that the growth could be serious.

“I was actually very concerned about skin cancer because I spent a lot of time out in the sun sailing,” Peter says. “I put on a tremendous amount of sunscreen and protection, but never on my legs…I never connected the dots.”

However, a biopsy of the growth came back positive for melanoma. Peter, who lives in Palo Alto, California, with his wife and three children, immediately reached out to several doctors in the San Francisco Bay Area, and all had the same advice: “Take it out, take a biopsy.” Continue reading…


COLUMBUS Trial: Binimetinib plus Encorafenib Improves PFS in BRAF–Mutant Melanoma

Excerpt:

“The phase 3 COLUMBUS trial, designed to evaluate binimetinib plus encorafenib for the treatment of BRAF–mutant melanoma, met its primary endpoint of improving PFS over vemurafenib, according to the drug’s manufacturer.

“These results also were presented at the Society for Melanoma Research Congress in Boston.

“In part 1 of the trial, researchers randomly assigned 577 patients with locally advanced, unresectable or metastatic melanoma with BRAF V600mutations to receive 45 mg binimetinib (MEK162, Array BioPharma) plus 450 mg of encorafenib (LGX818, Array BioPharma), 300 mg encorafenib monotherapy or 960 mg vemurafenib (Zelboraf, Genentech) monotherapy.”

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Atezolizumab Combos Highly Effective for Advanced Melanoma

Excerpt:

“The addition of the PD-L1 inhibitor atezolizumab (Tecentriq) to the MEK inhibitor cobimetinib (Cotellic) and the BRAF inhibitor vemurafenib (Zelboraf) induced a high response rate for patients with BRAF-mutant unresectable melanoma, according to findings from a phase Ib study presented at the 2016 Society for Melanoma Research Annual Meeting.

“At the data cutoff of June 15, 2016, 30 patients had received ≥1 dose of atezolizumab. The response rate with the triplet was 83%, which included 3 complete responses (10%) and 21 partial responses. Overall, 29 of the 30 patients were evaluable for response, with just 1 patient experiencing primary progressive disease. At the time of the analysis, median duration of response and progression-free survival were not yet reached.”

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Investigational Immunotherapy Was Safe, Tolerable, and Showed Some Activity Against Melanoma

Excerpt:

“The investigational immunotherapeutic IMC-20D7S was safe, well tolerated, and showed signs of modest clinical activity for patients with advanced melanoma, according to results from a first-in-human phase I clinical trial published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

” ‘Even though immunotherapy has significantly improved outcomes for some patients with advanced melanoma, many patients have tumors that do not respond to currently available treatments or have tumors that initially respond but then become resistant to them,’ said Jedd D. Wolchok, MD, PhD, the Lloyd J. Old/Virginia and Daniel K. Ludwig Chair in Clinical Investigation and chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center (MSK) in New York. ‘In this study, we evaluated the safety and early clinical activity of a new antimelanoma immunotherapy.’ ”

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High Response Rates Observed with Ipilimumab Plus Nivolumab in Advanced Melanoma

Excerpt:

“Combined ipilimumab and nivolumab administered pre- and post-surgery reduced the tumor burden in patients with Stage III B/C melanoma, according to first results from the OpACIN trial reported at the ESMO 2016 Annual Congress.

“Tumor load was reduced after 6 weeks of ipilimumab plus nivolumab immunotherapy in 8 of 10 patients. Pathologic complete response (pCR) was achieved by 3 patients; and 5 patients showed minimal remaining micro metastases, including one partial response (PR) with remaining metastasis of 0.5 mm. One patient showed stable disease and 1 patient experienced progressive disease.”

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