BRAF-MEK Inhibitor Combo Extends Survival n BRAF-Mutant Melanoma

Excerpt:

“The combination of encorafenib and binimetinib resulted in longer overall survival (OS) compared with vemurafenib in patients with BRAF V600–mutant melanoma, according to results of the COLUMBUS trial. Combined with an earlier report showing improved progression-free survival (PFS), this suggests the regimen should become an important option in this setting.

“Small-molecule BRAF inhibitors, originally introduced as monotherapy, offered improvements in outcomes for these melanoma patients. ‘However, response durations were short and BRAF inhibitor treatment was associated with the development of squamous cell skin cancer and other skin toxicities related to paradoxical MAPK pathway activation,’ wrote study authors led by Reinhard Dummer, MD, of University Hospital Zurich in Switzerland. Combinations of BRAF and MEK inhibition have improved the situation further, but better treatment options are still needed.”

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Overall Survival Improved With Encorafenib/Binimetinib Combination in BRAF-Mutant Melanoma

Excerpt:

In patients with advanced BRAF V600–mutant melanoma, combining the BRAF inhibitor encorafenib (Braftovi) with the MEK inhibitor binimetinib (Mektovi) improved overall survival compared to vemurafenib (Zelboraf) or encorafenib as monotherapy, with a favorable toxicity profile, according to updated results from the phase III COLUMBUS trial.

“Combined BRAF/MEK inhibitor therapy is standard of care in advanced BRAF V600–mutant melanoma, but approved combinations have unique toxicities that may impact the ability to deliver optimal treatment (ie, vemurafenib/cobimetinib [Cotellic] is associated with photosensitivity).”

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Adjuvant Dabrafenib/Trametinib Granted FDA Approval for BRAF+ Melanoma

Excerpt:

“Based on data from the phase III COMBI-AD study, the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) has been granted FDA approval for the adjuvant treatment of patients with BRAF V600E– or V600K–positive stage III melanoma following complete resection.

“In results from the trial, adjuvant treatment with dabrafenib and trametinib reduced the risk of relapse or death by 53% compared with placebo for patients with BRAF-mutant stage III melanoma.1,2 After a median follow-up of 2.8 years, the 3-year relapse-free survival (RFS) rate with dabrafenib and trametinib was 58% compared with 39% for placebo (HR, 0.47; 95% CI, 0.39-0.58; P <.001).”

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Drug Combination Targeting HSP90 and BRAF Is Safe and Effective in Advanced Melanoma

Excerpt:

“Patients with advanced or metastatic melanoma have been able to live longer cancer-free lives because of several new therapies approved over the last decade, such as BRAF and MEK inhibitors. However, despite the success of these targeted agents, most patients eventually develop drug resistance and their cancer regrows. A team of researchers at Moffitt Cancer Center have been working to learn more about how melanoma becomes resistant to BRAF inhibitors in order to develop new treatment strategies. They tested whether a drug targeting heat shock protein 90 (HSP90) combined with the BRAF inhibitor vemurafenib could be a safe and potentially effective strategy to treat patients with melanoma. Their study was published online ahead of print in Clinical Cancer Research.”

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New Developments in Melanoma Treatment


Neoadjuvant (before-surgery) treatments for resectable melanoma

Neoadjuvant treatments are the mainstay in the care of patients with breast, colon, and other cancers, but have not traditionally been used in melanoma. This has changed now, with the publication of a report showing that patients with resectable stage III or IV BRAF-mutant melanoma benefit from treatment with the BRAF/MEK inhibitor drugs dabrafenib and trametinib prior to (and continued after) surgery. The randomized clinical trial that produced these findings was small, but the benefits were so obvious that the researchers had to close the control group—those patients who received a placebo instead of neoadjuvant treatment. 71% of the 14 patients in the trial who received BRAF/MEK inhibitors prior to surgery were disease-free after 18 months, whereas all seven patients in the control group experienced a recurrence. The trial is continuing without the control group: all patients will receive treatment prior to surgery

Adjuvant (after-surgery) treatments

Melanoma patients whose tumors are surgically removed experience a very high rate of recurrence. Until recently, adjuvant treatments to prevent recurrences were limited to the drug interferon alpha-2B and, more recently, ipilimumab (brand name Yervoy), an anti-CTLA-4 immune checkpoint drug approved by the U.S. Food and Drug Administration (FAD) for adjuvant treatment in 2015. Interferon treatment is extremely harsh, with many adverse effects, and is not often used anymore. Yervoy is often associated with autoimmune side effects, which are sometimes quite serious.

Enter nivolumab (Opdivo) the anti-PD-1 checkpoint drug approved by the FDA to treat metastatic melanoma and other cancers. A clinical trial showed that the recurrence-free survival (RFS) rate at 18 months with nivolumab was 66.4% compared to 52.7% for ipilimumab (Yervoy) in patients with resected stage IIIB/C or IV melanoma. This amounts to a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor. Not the least important factor is the much lower rate of side effects seen with nivolumab compared to ipilimumab. Nivolumab is now approved by the FDA as an adjuvant treatment after surgical resection of melanoma.

Pembrolizumab, a competing anti-PD-1 drug, also showed encouraging results in a randomized trial for stage III melanoma. The stakes in this trial were lower, since the control arm received a placebo (not ipilimumab!). Risk reduction was 43%, according to preliminary results of the trial.

For patients with BRAF-mutant stage III melanoma, adjuvant treatment with the BRAF/MEK inhibitors dabrafenib and trametinib was just recently granted a priority review by the FDA, signaling a likely approval soon. Recurrence-free 3-year survival was 58% for the combination versus 39% for placebo.

New treatments for metastatic melanoma

A Knowledge Blog post from last summer described new combination treatments for metastatic melanoma. There have been significant developments since then.

Several trials combined PD-1 blockers (pembrolizumab or nivolumab) with small molecules known as IDO inhibitors. The latter help shut down the activity of immune system cells known as regulatory T cells (T regs), which dampen the immune response triggered by anti-PD-1 drugs. Combination of pembrolizumab with the IDO inhibitor epacadostat increased the rate of responses to pembrolizumab from 32% to 56%. This is very comparable to the response rate seen with the FDA-approved combination of nivolumab and ipilimumab. However, the significant toxicities seen with addition of ipilimumab are not observed when IDO inhibitors are added. Several other competing IDO inhibitors are currently in trials with both pembrolizumab and nivolumab. Importantly, there is also hope that these drug combinations may abolish resistance to PD-1 blockers in previously treated melanoma patients.

Another promising combination has been tested in a small clinical trial of nivolumab with NKTR-214, a specifically modified form of the protein IL-2, which is a strong activator of the immune system. High-dose IL-2 is a drug that has long been approved for metastatic melanoma but is rarely used because of the extremely serious adverse effects. NKTR-214 is a modified (PEGylated) IL-2 that has much reduced side effects, and does not activate inhibitory T regs. Clinical trial results have been released for 11 melanoma patients treated with the combination. Of the patients enrolled, 73% have experienced objective responses, which is obviously much higher than what is seen with nivolumab alone. This trial is now enrolling patients who have or have not already been treated with immune drugs.

Patients who were treated with anti-PD-1 drugs and experience progression may consider enrolling in trials that add relatlimab (an anti-LAG3 immune drug) to nivolumab. In a trial that enrolled heavily pretreated patients who failed on previous treatment with anti-PD-1 drugs, the rate of response was 11.5%, but many more patients (38%) have achieved stable disease. The presence of LAG3 protein (but not PD-L1 protein) in the tumors was predictive of response.

There are other new drugs to watch. TLR9 agonists (activators) have shown early promising results in melanoma. TLR is a group of receptors that are strongly involved in innate immunity. A recent publication showed that intratumoral injection of a TLR9 activator with an antibody to OX40 (a protein on T cells) has extraordinary activity in a mouse cancer model. Trials that combine anti-OX40 and TLR9 agonists are forthcoming. However, two TLR9 agonists, SD-101 and IMO-2125, have shown very promising results in combination with anti-PD-1 or anti-CTLA4 drugs.

The other drug with early promise is ImmunoPulse IL-12 (pIL-12). In combination with pembrolizumab, it induced responses in 43% of patients who had not been previously treated with immune drugs. The important point is that patients in this trial were specifically selected to have a tumor profile that is associated with lack of response to pembrolizumab. pIL-12 is injected into tumors, so this intervention is appropriate for patients who have injectable tumors.

New BRAF/MEK inhibitors for melanoma have emerged: encorafenib and binimetinib produced a 3-year overall survival rate that is twice as high as seen with vemurafenib, a BRAF inhibitor. The comparison is not exactly meaningful because vemurafenib is not used as a single drug in BRAF-mutant melanoma these days, but this phase III trial was initiated back in 2013, prior to the approval of other BRAF/MEK combinations. The new combination may be approved mid-2018.

The triplet combinations for BRAF-mutant melanoma should be mentioned (immune plus targeted drugs). A trial that combined dabrafenib and trametinib with pembrolizumab reported early success, with a confirmed response rate of 67% in 15 patients who received the combination.


Research Is Changing the Game for Melanoma Treatment

Excerpt:

“Wilmot Cancer Institute patients with advanced melanoma (stage III) now have more options for treatment, thanks to research co-authored by a University of Rochester Medical Center surgical oncologist and published in The Lancet Oncology.

“The study involved comparing two treatment approaches for high-risk melanoma patients with a BRAF gene mutation in their cancer: standard care, which calls for upfront surgery, or giving a two-drug, targeted therapy regimen before surgery and again afterward. Patients in the latter group had longer disease-free survival in the Phase 2 trial, and after seven months researchers halted the study earlier than expected due to the positive results.”

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Targetable Mutations in NSCLC: More Testing Needed!


Diagnosis of adenocarcinoma of the lung, a major subtype of non-small lung cancer (NSCLC), nowadays triggers mandatory testing of tumor tissue for alterations in four genes: EGFR, ALK, ROS1, and more recently, BRAF. If present, these alterations predict sensitivity to specific targeted drugs approved by the U.S. Food and Drug Administration (FDA) that work better and often longer than standard chemotherapy, and are better tolerated.

However, there are many more targetable/actionable genomic alterations (also known as “drivers”) in NSCLC. This blog post will briefly discuss most of them, with the goal of promoting molecular testing for more than the four “usual suspects” mentioned above. Some patients with these alterations may benefit from FDA-approved drugs or from enrollment in clinical trials that are testing additional drugs and drug combinations. Continue reading…


Three-Drug Regimen Active in BRAF-Mutant Melanoma

Excerpt:

“Triplet therapy for advanced, BRAF V600-mutant melanoma led to objective responses in 73% of a small group of patients enrolled in a phase I trial, according to updated results reported at the 2017 ESMO Annual Congress in Madrid.

“Ongoing follow-up in the trial showed that 11 of 15 patients responded to the combination of pembrolizumab (Keytruda), dabrafenib (Tafinlar), and trametinib (Mekinist). Seven of the 11 responding patients had not progressed after a median follow-up of 20 months. ‘Updated results of the phase I portion of the KEYNOTE-022 trial confirmed previously reported efficacy of this triplet combination,’ said Antoni Ribas, MD, PhD, a professor of medicine, surgery, and molecular and medical pharmacology at the University of California at Los Angeles. ‘The results demonstrated durability of responses. No late or unexpected toxicities occurred with longer follow-up. The randomized phase II portion of KEYNOTE-022 is ongoing.’ ”

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Array BioPharma Announces FDA Acceptance For Review Of Binimetinib And Encorafenib New Drug Applications For Patients With Advanced BRAF-mutant Melanoma

Excerpt:

“Array BioPharma (ARRY) today announced that the U.S. Food and Drug Administration (FDA) has accepted for review its New Drug Applications (NDAs) to support use of the combination of binimetinib 45 mg twice daily and encorafenib 450 mg once daily (COMBO450) for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. In addition, the FDA informed Array that based on their preliminary review of the applications they have not identified any potential review issues, and that they are not currently planning to hold an advisory committee meeting to discuss these NDAs.  Array completed its NDA submissions at the end of June 2017based on findings from the pivotal Phase 3 COLUMBUS trial.”

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