It took a while, but there are some scientific insights I gained at the Melanoma Research Alliance's Scientific Retreat a month ago and the American Association of Cancer Research's Tumor Immunology and Immunotherapy Conference in December. Most things I still don't understand so, I'm hoping the ones I kinda-sorta do, will give the rest of the world some understanding on both the chemistry of the science and the "chemistry" of how treatments are being teamed together.
I recently heard one oncologist compare the current melanoma medical landscape as an "alphabet soup" of treatments. Let's follow that analogy with what was presented at both conferences:
What is the "Alphabet Soup"?
This is an eye-blurring on. CTLA-4 (aka Ipilimumab or Yervoy) and PD-1 (pembrolizumab/Keytruda, nivolumab/Opdivo) is the more-well-known tip of the acronym iceberg. Among the research presented were (hold your breath) hypotheses and findings on PKC (Protein Kinase C), JAK1/RNF125, CDK4 + MEK inhibitors, BRAF/CRAF, PI3K/AKT pathway, and quite a few others I couldn't write down (or make sense of) fast enough (exhale). The alphabet soup even rained down in broader presentations – "genetically modified CD25 to express IL2 (in TIL: allows lower doses of IL2 without lymphdepletion)"; "targeting co-stimulator pathways ICOS (B16 IVAX vaccine) and 4-1BB increases survival with mICOS & CTLA4". It was non-stop, "would-you-like-to-buy-a-vowel?" hieroglyphics.
The first morning at the MRA Retreat was an hour old and I was already lost – a CDK 4/6 inhibitors presentation left me staring at the screen wondering if I had learned anything in a year. It obviously meant something to most people in the room; there was a line of doctors during Q&A asking targeted questions (pun intended). If there were such a thing as medical research speed dating, it would look a lot like this. The takeaways are these therapies are REALLY intricate and the "bowl of soup" has a LOT of letters in it. That plethora of letters leads to…
Finding the right letters to form a word
Melanomas can have over 200 mutations, and has the highest mutation rate of all cancers. The first goal, partially achieved, is to understand molecular and immune effects of therapies by themselves, before combinations are considered. The myriad of mutations and medicines could not ALL be put through individualized clinical trials, so comprehension and a little medical intuition fill in gaps until personalized medicine arrives.
Follow-up work is still needed to figure out how to best identify the patients who will respond to targeted or immunotherapies, and to which ones. For example, NRAS-mutant melanoma responds better to immunotherapies than melanomas without an NRAS mutation. A follow-up study of 5,000 initial clinical-trial ipilimumab patients (i.e. the ones who have had the drug the longest) showed a long-term survival rate of 20-22% across a 10 year period. Even a study showing no long term survivors on a pancreatic cancer study utilizing CD40 (from Katelyn Byrne at UPenn's Abramson Cancer Center) becomes valuable; listening to the minutia of CD40 and the incremental increase in lifespan is a reminder that PD-1, CTLA-4, and the other alphabet soup words likely had similar beginnings.
Putting the right words together
"Do we begin with targeted and switch to immunotherapy, or vice versa?"
Targeted therapy is associated with more favorable tumor microenvironment, BUT with a concurrent increase in PD-1/L1. That, apparently, is bad (and the reason dummy bloggers like me shouldn't lazily abbreviate its true name, anti-PD-1). How one influences the other, though, is still TBD.
"Are we able to identify subsets of patients who would better respond to targeted therapies?"
For example: How to identify patients who would respond to a PX-866 and vemurafenib (Zelboraf) combination, and take them out of BRAF/MEK pool to use this combination instead?
"Can we match the right treatments in the right sequence?"
Patients without significant levels of CD8 T-cells in their tumors that did PD-1 did not have a response to the PD-1 treatments. Ipilimumab (Yervoy) drives t-cells into the tumor, potentially unlocking a brake on the PD-1 therapy. One or the other may not work, but their combination, and the order the drugs were administered, can turn progressive disease into a clinical response.
"Do we do target and immunotherapies concurrently?"
Researchers are still trying to understand the varying responses to combination trials – but they are proving effective, with recent combo studies giving one year survival rates ranging from 30% to 80%. Old combinations pushed the survival curve out, but patients were still dying. Yervoy, then Keytruda/Opdivo, pushed the overall survival level up. The initial findings are the latest combination trials are pushing that level WAY up.
What do the words actually say?
They are telling the oncology world it is no longer OK to do a biopsy and just say "this is melanoma". Getting pre-treatments, setting up targeted/immunotherapy sequences, laying out options and determining combinations… these are all important steps when addressing a cancer diagnosis – and not just Stage IV melanoma. Immunotherapy and target therapy combinations are in clinical trial for most major cancer types. Earlier melanoma stages should be getting immunotherapies soon; studies are up for pediatrics, solid cancers with brain metastases, and in neoadjuvant settings (to shrink a tumor before surgery or another treatment).
The words are speaking the medical language too. They are challenging doctors to investigate and determine variables in treatment, such as continuous vs. intermittent dosing, or giving treatment beyond initial progression. Researchers are now asking a question I've wondered for some time: When do we get to stop comparing to chemotherapy? (The quick answer: for melanoma, it should be yesterday, and for some other metastatic cancers, hopefully not far on the horizon). Hopefully, the answers to many of the questions posed above lie in the letter combinations of the alphabet soup of therapies. Campbell's certainly got it right, though – the tomato base is a much more appropriate metaphor for the murky world of cancer research than any clear broth could be.