Melanoma is leading the way on the crest of the immunotherapy treatments. I couldn't get an active number of melanoma clinical trials involving immunotherapies, but it's in the double digits (unfortunately, many – like mine – are already closed to new participants). Counting targeted therapies and combination trials pushes that number higher. These researchers really are at the cutting edge of oncology.
It's not just melanoma that benefits, either. Last week, Bristol-Myers Squibb's anti-PD-1 Opdivo gained expanded approval to treat Non-Small Cell Lung Cancer (NSCLC). In the last year, Opdivo received breakthrough designation for Hodgkin lymphoma, and Merck's Keytruda got the same for NSCLC. Related, Genetech's PD-L1 drug MPDL3280A, which operates similarly to PD-1, was given breakthrough status for NSCLC after already being granting it for bladder cancer.
The very first presentation opened up with the question, "When do we get to stop comparing to chemotherapy?" With six approved targeted immunotherapies in the last four years (plus one combination), the question probably should be "Why are we even using chemotherapy anymore?" Between the existing approvals and the pipeline of clinical trials using combinations and/or new drugs, chemotherapy should be a thing of the past for nearly all melanoma patients by the MRA's 10th Scientific Retreat in 2018.
The entire conference – heck, most of the HOTEL – was focused on sharing trial data and its implications. The 250 attendees were made up of about 70 percent researchers, and side conversations were rarely about anything BUT melanoma. I got in a word about German Shepherds to one oncologist, whose wife breeds them and gave one to a college friend. Otherwise, this was all about rustling the coats out of the labs and into a room to share, converse and question. There was even a little spirited ad-hoc "discussion" over BRAF during one of the Q&A sessions – it was somewhat humorous to hear biochemistry being hotly debated (even if you don't understand either side). This is how treatments, and cures, get accelerated.
Among its multiple references at the retreat, this was brought up in discussions connecting skin cancer prevention, earlier skin cancer detection, and treatments addressing melanomas before they reach the critical metastatic phase. There was an entire panel devoted to prevention and early detection, which may not have the scientific splash of "curing cancer" but is by far the most effective treatment.
Yervoy, the first immunotherapy to make a big splash, is now being considered by the FDA as an adjuvant treatment of Stage 3 melanomas that have been surgically removed. (An adjuvant is given after an initial treatment, such as surgery or radiation, has removed detectable cancer.) This is great news, as stage 3 patients are at a high risk for recurrence but have limited treatment options until they are reclassified as Stage 4.
There was a common theme of "not being satisfied with good enough", speaking in terms of both science and regulation. It isn't enough that new drugs show improvement; work will continue until melanoma is eradicated. Nor are the headlines generated by recent breakthroughs sufficient, when there are still patients worldwide with limited knowledge or access to the best treatments. As an example of urgency meeting progress, Keytruda is now available in the UK in their Early Access to Medicines Scheme (EAMS), allowing British patients to access the medicine even before U.K. regulatory approval.
There is the targeting of co-stimulator pathways like ICOS, 41BB, CTLA-4; LAG3, BTLA checkpoint inhibitors; and PI3K mechanisms, JAK1 and RNF125 binds were all discussed. Complex enough, or do you want examples? These guys are S-M-A-R-T.
Targeted combinations were presented, including potential additions to the toolbox of BRAF and MEK inhibitor drugs. UCLA researchers recently uncovered how melanoma eventually resists these targeted therapies, by developing genetic changes in certain cancer genes. Reversing these changes or shutting them off completely with a new drug/new combination would delay or even eliminate the resistance that occurs in most targeted therapy patients.
Priority review has also recently been granted for the combination of Genetech BRAF drugs cobimetinib and vemurafenib (Zelboraf). Combinations have been a hot topic since last year's ASCO "Melanoma Monday" campaign presented initial data on several studies that showed extremely strong responses to multiple therapies.
Getting a new cancer drug to market isn't just dropping a bunch of tumor cells inside a lab rat and seeing which compounds work best (there was one discussion that even concluded with "So now we should see what happens in human patients…"). This takes hours and hours per day, days and days per month, then months and months over years just to get a chance to utter that line. Finding the molecular needle in the haystack is more than divide and conquer, too. There is a special kind of dedication that goes into the extended search for a cure – one that spans entire careers building knowledge and experience looking for that breakthrough moment.
All the acronyms, molecular-this and pathway-that process into one conclusion: There are a significant number of irons in the melanoma fire, many having startling efficacy. These forward-looking presentations provide the one thing all cancer patients cling to – the hope of being one of the "lucky" ones whose biology happens to respond to available treatments. Research is finding long-term survival plateaus around year 3 for Yervoy patients, and this rate holds steady going out many years.
Jim Allison closed the retreat down with the observation that those long-term survivors are dying of something other than melanoma. The momentum of current progress, the urgency of collaboration, and the brilliant combinations of the complex treatment ecosystems has given me hope and determination to prove Dr. Allison right. Dying of old age would be a happy ending to this blog, wouldn't it?