Maintaining the Pace of Melanoma Innovation in the Era of an Evolving Standard of Care

There is no doubt that treatments for metastatic melanoma have changed dramatically in the decade since MRA’s founding in 2007. Targeted therapy and immunotherapy have become mainstays of treatment and have extended patient lives. In addition, new approaches to the diagnostic workup for patients have been recently announced and multiple treatments to keep melanoma from returning after surgery are now available.

Specifically:

• Twelve treatments¹ for patients with metastatic melanoma garnered FDA approval since 2011 including: a) targeted drugs for BRAF and MEK; and, b) immunotherapy with checkpoint blockade, cytokines or oncolytic viral therapy. Over 400 melanoma interventional trials are recruiting patients on www.clinicaltrials.gov,²
• Treatment continues to evolve with the late 2017 approval of nivolumab for melanoma adjuvant therapy, the April 30, 2018, approval of adjuvant dabrafenib and trametinib, and encouraging data for other drugs,³
• New melanoma staging guidelines and recommendations on complete lymph node dissection (CLND) have recently been published, ^{4, 5}
• Companion diagnostics⁹ for both targeted and immunotherapy have gained approval and biomarker development remains a top priority.

These changes in the standard of care for melanoma bring with them the need to consider what their impact is on how even newer treatments are developed from the standpoint of academic and government researchers, biopharma scientists and regulators.

Over 50 thought leaders came together at an annual, invitation- only Industry Roundtable to identify and discuss cross-cutting issues facing melanoma treatment and diagnostic development. Participants included representatives from academia, FDA, industry, NCI and MRA. The session was moderated by Dr. Antoni (Toni) Ribas and MRA Chief Science Officer, Dr. Louise Perkins. Among the topics discussed were a) clinical trials; b) endpoints; and, c) biomarkers.

Ribas asked a provocative question to kick off discussion, “Are there too many clinical trials being conducted in melanoma?” Given the need for improved outcomes and the rationale supporting most trials, the overwhelming majority of participants felt that the answer was a resounding “No, there are not too many trials.” What followed was a nuanced discussion that explored both efficiency improvements and mobilizing the precious resource of patients who are able and willing to participate in such trials. MRA, along with external partners, recently launched Melanoma > Exchange to bolster education about clinical trials and an online platform that makes it easier for patients to find a trial.

One way to improve the efficiency of melanoma clinical trials would be the development of endpoints to more accurately predict whether treatments are working as compared to those in common use today. For example, tumor shrinkage, progression after treatment and overall survival are common endpoints. But what if a blood test, an imaging endpoint or a pathology measurement could accurately shed light on whether your treatment is working or is failing earlier than current technologies can determine? There is great interest in this area and its potential to more rapidly and accurately inform drug development.

Biomarker development is a related subject that attempts to measure things like proteins or cell types to help identify which patients will bene t from which treatment. A great deal of effort in research is being invested to develop these biomarkers for melanoma and to use them to identify which patients need more aggressive or earlier therapy compared to those who will do ne with standard surgery or existing drugs.

Another topic that was discussed related to bringing potentially life-saving treatments to patients more quickly by including patients in trials who are typically excluded. For example, patients with brain metastases have historically been excluded from clinical trials even though around 15% of newly diagnosed melanoma patients have existing brain mets. Recent work by a multi-stakeholder group made the case for modernizing clinical trial eligibility, including treating certain patients with brain mets,⁶ to achieve several objectives including understanding the safety and efficacy in real- world populations and also to potentially enroll more patients on trials more quickly.

In conclusion, the rapidity of change in melanoma since the first wave of new treatments came to market in 2011 has been astounding. Through dialogue among experts such as at this Industry Roundtable, problems and solutions can emerge that address problems that now exist due to the relative success in the field.