Pick your poison: Weber and Agarwala discuss combination therapy for melanoma

Combining immunotherapy and targeted drugs for melanoma: Weber and Agarwala
(Late note:  since publication of this post, the link above has been taken down.  However, the points below are my transcription of their commentary. - c, 2018)

The link above connects to a video discussion and slides by Dr. Jeffrey Weber and Dr. Sanjiv Agarwala regarding combination therapies and other treatment information as it relates to melanoma.  Much like the prior link I discussed, material is presented in an understandable manner in the form of a continuing education program for general oncologists and others in the field...from the horse's mouth.

Points I noted:

• BRAF is the only predictive marker for the use of BRAF inhibitors.
• 40-50% of melanoma is BRAF positive.
• The RAS-RAF-MEK-ERK MAP kinase pathway is a critical signaling path in melanoma.
• MELANOMA SUB-TYPES via landscape as origin:  
• Skin with sun damage = 50% BRAF, 20% NRAS, 0 KIT
• Skin without chronic sundamage = 22% BRAF, 0 NRAS, 19% KIT
• Mucosal = 9% BRAF, 12% NRAS, 25% KIT
• Acral = 22% BRAF, 16% NRAS, 24% KIT
• BRAF resistance develops due to reactivation of the MEK pathway.  This is why the addition of MEKi to BRAFi prevents that resistance, thereby increasing effectiveness and decreasing side effects.
•  The COMBI-d trial (dabrafenib plus trametinib vs dabrafenib alone), the Combi-V trial (dabrafenib and trametinib vs vemurafenib alone) and the CoBRIM trial (vemurafenib with cobimetinib vs vemurafenib and placebo) all demonstrate the effectiveness of combination therapy when compared to one targeted therapy alone.

Here's a link addressing BRAFi info out this year as well as earlier articles about BRAFi combo's:   BRAFi : What predicts resistance.
Here's a link regarding an article this year that addressed CoBRIM as well as PDL1 in immunotherapy combinations (which the docs address later in the video as well.):  Combos looking good but if PDL1 positive - just do nivo!

 IMMUNOTHERAPY:

• CTLA4 and PD1 put brakes on the immune system (in 2 different areas, in different ways), but ultimately prevent T cells from eradicating melanoma and other cancers.  When you turn CTLA4 and PD1 "off" with ANTI-CTLA4 (ipilimumab) and ANTI-PD1 (Nivolumab/Opdivo or Pembrolizumab/Keytruda) you allow T cells to engage and do their job.
• Studies with ipi show a plateau in overall survival of 22% at 3 years.
• When ipi is combined with GM-CSF, 1 year OS is 68% vs 52% in ipi alone.
• When ipi is combined with T-VEC (an intralesional therapy) you get a better response rate...about 55% combined complete and partial responses....than with either drug alone. NOTE: You can find more info on GM-CSF using the search bubble on my blog.  Here's a link to some of the latest on intralesional therapies out of ASCO 2015:  Intralesional therapy for melanoma: ASCO 2015
• Some questions remain with ipi: What is the optimal dose?  3mg/kg vs 10mg/kg? The 169 trial is a randomized Phase 3 trial, ongoing, looking at differences in dosage.  Trials are looking at whether ipi should be administered in the current 4 dose - then stop, protocol...or are maintenance doses helpful?  Weber feels 4 doses are sufficient, but trial results are still pending.
• Ipi as adjuvant?  The 1609 trial is looking at this question and the 10mg/kg dose is showing promise, results to be out in about a year or 2.
• Overall, ipi is showing a 10-15% response rate, BUT...there are significant numbers of those demonstrating 10 YEAR survival.
• Anti-PD1 (both products) give clearly greater responses than traditional chemo and better than ipi as well...with an overall response rate of about 40-45%.
• Folks with tumors that are positive for PD-L1 respond better to anti-PD1 products.   However, many problems remain with the clarity of the test, availability of the test, consistency of results, etc.  Therefore, it is a useful...though not a predictive...marker.
• Because CTLA4 and PD-1 work differently...combining the two antibodies....can provide even better responses.  Additionally, ipi failures can respond to anti-PD1 and anti-PD1 failures can respond to ipi.
• In an early combo study of nivo and ipi, patients experienced an ORR of 53% and 40% had significant tumor reduction.
• In another nivo/ipi combo study, there was a 61% response rate and 22% rate of complete response on the combo vs 11% and none with ipi alone.
• In PD-L1 positive patients: those in the combo had a 58% overall response vs 18% ORR to ipi alone.  PD-L1 negative patients: had an ORR of 55% to the combo vs 4% ORR to ipi alone.
• Responses were durable.  Almost all responders continued to maintain their response at a rate of 82%.  Even of patients who had to stop treatment due to side effects, 2/3 of them continued to respond.
• Grade 3/4 toxicities increase almost as much as the response in the combo with a rate of 55%, though almost all are reversible.
• In the CA209-067 study, the ipi/nivo combo was compared to ipi alone and nivo alone.  ORR were 57.6% for the combo, 19% for ipi alone and 43.7% for nivo alone.
• However, when looking at PD-L1 staining:  When positive, the difference between PFS with the ipi/nivo combo vs nivo alone is negligible. So the argument may be made to go with nivo alone...since the difference in response is minimal, but side effects are much less.  However, more definitive studies are needed.
• The ipi/nivo combo overall is providing increased response rates and increased progression free survival.  
• Survival may even be better with the combo than with sequential nivo or ipi.
• However, for PD-L1 positive patients (40% of the population) concurrent therapy may be no better than nivo alone, followed by ipi if there is progression.
• For PD-L1 negative patients, the majority of patients, the ipi/nivo combo is better than a single agent, though you have to keep in mind that fewer than 1/2 of responding patients are able to tolerate the combo longer than 24 weeks.
• A study is underway looking at planned sequential therapy giving patients ipi followed by nivo, OR nivo followed by ipi....with nivo maintenance....preliminary results to be out within a week at meeting in Vienna.
• HOW TO DECIDE, in the BRAF positive patient....between immunotherapy single vs combo vs BRAF inhibitors.  These docs report that they tend to treat indolent patients with anti-PD1 alone.  However, in patients with increased LDH and a heavy disease burden, they would lean toward using BRAFi or the ipi/nivo combo.  Or to put it another way:  BRAF positive and negative patients do equally well on anti-PD1, so BRAF positive patients with indolent disease and low tumor burden, would probably be wise to place on immunotherapy.  In fast growing disease, with a high disease burden...and BRAF positive...use a BRAF/MEK combo first.  If BRAF negative - use the ipi/nivo combo.
• Question with no current answer:  With a patient who initially responded to nivo, but then progresses...should you switch to ipi or ADD ipi?  Docs feel that a trial looking at survival with these two options should be done...though it is NOT underway currently.
• Final thought, ipi is no longer these doc's first line drug choice when used alone.  They feel that anti-PD1, even as a single agent, is going to prove to have durable responses. While ipi combo's are going to be very important.

Long, I know.  Hope it helps. - c