Melanoma and the Problem of Drug Resistance

In 2002, researchers discovered a link between mutated BRAF genes and nearly half of all melanoma tumors. Since then, BRAF inhibitors—drugs that target mutated BRAF—have become a leading go-to weapon in the battle against melanoma. Their job is to cut off signals sent by altered BRAF that promote the rapid growth and division of cancer cells.

BRAF Inhibitors and Drug Resistance

Studies show that BRAF inhibitors shrink melanoma tumors faster and better than chemotherapy. Unfortunately, the treatment’s success is short lived. It only takes about six months for cancer cells to figure out how to use alternate pathways to grow and divide once again.

Eventually, melanoma tumors become resistant to the drug’s effects, rendering the treatment essentially useless. This is similar to how skin, ear and respiratory infections can build up resistance to certain overused antibiotics.

Another problem with BRAF inhibitors is that 20 percent of users go on to develop a different type of skin cancer called squamous cell carcinomas. Although this form of skin cancer isn’t as serious as melanoma, they still require removal and treatment.

Combination Treatments for Melanoma: BRAF and MEK Inhibitors

Studies show that combining BRAF inhibitors with another targeted drug, MEK inhibitors, leads to better results.

You might be most familiar with the success of combination therapies to treat AIDS. Over the past two decades, the introduction of a triple cocktail—a combination of three gene-inhibiting drugs—has changed AIDS from being a deadly disease to making it more of a chronic, manageable condition. One goal with melanoma research is to come up with a combination drug therapy that works as well on melanoma.

How are Researchers Combating Drug Resistance?

The Melanoma Research Alliance is helping to fund many of these research projects in the hopes of finding better treatment options with improved outcomes.

  • Several ongoing clinical trials are exploring new drugs and drug combinations.
  • Other studies are looking into whether taking medications intermittently instead of daily might lower the risk of drug resistance.
  • Laboratory tests and clinical trials explore whether drug treatment should continue once cancer progresses to a certain point. Some studies suggest there may be benefits of continuing drug therapy, while other findings suggest otherwise.

Another innovative therapy now available for melanoma is immunotherapy. With this treatment, medications called immune checkpoint inhibitors stimulate the immune system to recognize and destroy cancer cells more effectively.

Studies are currently looking at the effectiveness of combining immunotherapy with other treatments, such as targeted therapies. Researchers also are exploring whether it’s best to start immunotherapy early in the treatment process or after the disease progresses.

Read more about research funded by the Melanoma Research Alliance.Some of this information was presented as part of our 7th Annual Scientific Retreat, which was held in February 2015. You can read about MRA’s Scientific Retreat.

Expanded Access Programs: A Time of Amazement in Melanoma

Immunotherapy Science Mag CoverFor those of you keeping a close eye on the field of melanoma treatments, you know that we find ourselves living in a simply amazing period of opportunity and innovation—even though there is still a long way to go.

The creation of new cancer drugs is pharmaceutical alchemy, transmuting a base idea into a life-prolonging new treatment that is both safe and effective.  While not magic, drug development is an expensive, incredibly complex and time-consuming process.  And when it works well—when there are exceptionally promising treatments near at hand—the wait for full availability to those agents can be frustrating beyond measure.

Such is the case right now with certain immunotherapy drugs that stimulate the patient’s immune system to recognize and attack cancer.  The data with these immunotherapies targeting the PD-1/PD-L1 axis (anti-PD-1 drugs) is so encouraging that three have earned U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation* which aims to speed FDA approval of the most promising drugs.

This is fantastic, but how are promising drugs made available to patients in the pre-approval period?

To accelerate the accessibility of new drugs to patients, drug developers may open so-called Expanded Access Programs (EAP).  EAPs are compassionate use programs whereby drugs are made available to patients before they are fully approved for sale by the FDA.  EAPs consume resources from treatment centers and drug companies alike, but EAPs endeavor to do the right thing to help patients before drug approval and sale. MRA is proud to have been part of the conversation with companies, clinicians and the FDA that encouraged and facilitated the opening of the anti-PD-1 drug EAPs.

So, why talk about EAPs and anti-PD-1 drugs right now?

Because melanoma is once again a case study for the cutting edge. Presently, three EAPs for melanoma are open with similarly targeted agents (the anti-PD-1 antibodies). Merck’s pembrolizumab was the first EAP to open for melanoma in March 2014, followed by BMS’ nivolumab EAP in May.  Most recently, in July, BMS launched an EAP for the combination of nivolumab with its anti-CTLA4 drug, ipilimumab.  This may not sound like much, but to have three EAPs at the same time for the same cancer is unprecedented.  To have this happen with the same type of drug is nothing short of amazing!

While anti-PD-1 treatments don’t work for everyone and do have certain side-effects, MRA and others are funding research to overcome these limitations.  Nevertheless, the demonstrated progress against melanoma fuels the hope that we’ll look back to 2014 and say, “That was the year everything changed.”

About the Author

Louise Perkins HeadshotLouise M. Perkins, Ph.D., joined the Melanoma Research Alliance (MRA) as Chief Science Officer in 2013 where she is responsible for the development and implementation of MRA’s scientific strategy.  Her interests center on translational research with specific concentration on genomics, drug discovery and the advancement of novel therapeutic approaches. Prior to joining MRA, she was Chief Scientific Officer at the Multiple Myeloma Research Foundation (MMRF) for five years following a research career of 16 years at two major pharmaceutical companies.

*Note: Merck’s anti-PD-1 pembrolizumab received Breakthrough Therapy designation for melanoma in May 2013; BMS’ anti-PD-1 nivolumab received Breakthrough Therapy designation for Hodgkin Lymphoma in May 2014; Genentech/Roche’s anti-PD-L1 MPDL-3280A received Breakthrough Therapy designation for bladder cancer in June 2014.

MRA Talks Innovative Collaborations at Partnering For Cures Meeting

MRA was honored to be chosen to deliver an Innovator Presentation at FasterCures’ 2013 Partnering For Cures meeting, held last week in New York City. The event brings together leaders from all sectors of medical research to foster collaborations critical to speeding the development of new therapies.  MRA staff and leadership also attended panel sessions and networking events, and held partnering meetings with other attendees.

Wendy Selig, MRA’s President & CEO, presented our Academic-Industry partnership model as an example of successful collaboration in the drug development space.  She was joined by Julia Perkins, Medical Director of Oncology at Pfizer, as they discussed the collaboration between MRA and Pfizer that was launched earlier this year.

You can read more about the genesis of MRA’s Academic-Industry partnership with Pfizer here.

We had a fabulous meeting and look forward to attending the Society for Melanoma Research (SMR) Melanoma Congress meeting next week in Philly!

Video: MRA Board Member and Melanoma Survivor Shares His Story at Forbes Event

Earlier this month, MRA Board Member and melanoma survivor Jeff Rowbottom spoke at the Forbes Healthcare Summit.  Jeff discussed how his diagnosis with melanoma brought him to the MRA and inspired the Leveraged Finance community to take action against the disease. This year’s summit, titled, “Empowering The Patient Revolution,” was attended by executive leadership and thought-leaders representing industry, government, academia, and advocacy.  Check out his speech and hear his perspective on how patients are impacting drug development!

Wendy Selig Explains MRA’s Focus on Collaboration

Listen to Wendy explain MRA’s singular focus on collaboration and its transformative effect on awareness building and the drug development process!

This in an excerpt from a longer interview with m/Oppenheim Associates, an executive search firm that specializes in recruiting non-profit leaders.  You can watch the full interview here.

Want to learn more about MRA’s collaborations and corporate and non-profit allies?  Check them out on our website!