Friday, June 13, 2014

Pretty Darn Impressive....a chat between Ribas and Weber categorizes PD1 as such and touches on other ASCO reports

This morning I received this link in my inbox....TWICE!!!  Thanks, Bentie and Steven! The quotes that caught my interest are noted.  The discussion ranged over anti-PD1, comparing the various results, addressed combining ipi and nivo, targeted therapies, the COMBI-D trial, and intralesional can check out the whole video/transcript yourself with the link below.

"Pretty Darn Impressive" PD1 data in Melanoma....a chat between Ribas and Weber

Ongoing Breakthroughs in Immunotherapy.  Antoni Ribas, MD, PhD and Jeffrey Weber, MD, PhD
June 12, 2014

Weber:  The melanoma... session included 4 very impressive abstracts on PD-1...antibodies... It opened with the first new PD-1 antibody that we have heard from a relatively small study of about 100 patients...had a fairly good 1-year survival rate of 64%.  However, it only had about a 5%-6% response rate. That was pidilizumab (CT-011). ..10 years ago that might have cut it in the melanoma field for further development...[currently] I would be hard pressed to have enthusiasm for it.  This was a very well done study...but I am hard pressed to want to take pidilizumab further, given the current landscape. [see abstract referenced in June 5, 2014 post]

WeberIn both the nivolumab [BMS anti-PD1] and pembrolizumab [MK3475, Merck's anti-PD1] abstracts (from your own [Ribas] abstract on pembrolizumab with 411 patients), we are looking at an average of about a 40% response rate across a number of different cohorts....and a lesser response rate (28%) in those who failed ipilimumab.  This is consistent with my experience in PD-1 trials, in which the response rate of those who failed [ipi] was 25%-26%....but in those who were ipi-naive, most of whom were previously untreated, we are getting close to a 40% response rate, with 1-year survivals in the range of 67%-69% and an 18 month survival of 62%...we are talking about at least a 24-month median survival, and that's pretty darn impressive from pembrolizumab.  We have high expectations that the drug will receive approval from the [FDA] before the end of the year. [see abstract in June 1, 2014 post]

There was an update by Hodi on the data...presented last year by Sznol...a 107 patient, phase 1/2 trial of nivolumab...This time, survival is in the realm of 17.5 months, across a 100-fold cohort in terms of dose.  Many patients were previously treated with 2-4 regimens, so... pretty beat-up patients...compared to the pembrolizumab patients, but the response rate was still 32%.  [see abstract in June 5, 2014 post at bottom]

...I presented...a 33% response rate in the ipi-naive group; I showed a 26% response rate in the ipi-refractory group. The median survival is excellent, but it's still less than 24 months...albeit in a group of patients who were treated at suboptimal nivo doses and who had already been through multiple regimens.  Nonetheless, were impressive, showing very good survival.  Clearly, any drug with more than a 30% response rate in patients who have been through a median of 3 previous regimens in melanoma is looking very good. That drug [nivo], we assume, is going to come up for registration sometime this year.

Ipi-Nivo Combo
...highlight was ...the abstract...presented by update of the concurrent ipi/nivo study. [see abstract in June 1, 2013 post]...response rate about 45% in an updated expanded cohort of those with nivo at 1mg/kg and ipi at 3mg/kg...for as long as 96 weeks.  The response rate was in the mid-40% range, but of greater importance, the 2-year survival was in the high-70% important landmark in melanoma. ....must be balanced against a 62% rate of grade 3/4 immune-related adverse events, many of which were easily reversible...only about half required an interruption of treatment....Whenever the rate of side effects at grade 3/4 exceeds the response rate, you have to sit up and take notice.  Nonetheless, a 70% plus survival rate at 2 years is outstanding in melanoma.

Ipi as adjuvant 
...Then...heard an ipi abstract from Eggermont on the first large, randomized adjuvant ipilimumab trial ever presented...patients with stage IIIA, IIIB, or IIIC were randomly allocated to ipi at 10mg/kg for a 12 week induction, followed by up to 3 years of treatment every 12 weeks vs placebo.  ...endpoint was progression free survival, and there was a definite difference:  about 26 months vs 17 months..... The rate of grade 3/4 immune related adverse events was 40% or higher.  Many patients had to stop treatment.  Most of these...occurred in the first 12 weeks.  There were a modest number of deaths: 6 deaths in 425 patients who received ipi.  The dose of 10mg/kg is not standard in the US or Europe.  It raises issues of whether this will be taken forward.

Ribas:  Is the rate of toxicity higher than what is seen in the metastatic setting?

Weber:  It was very similar to the metastatic setting....In the big picture, the rate of deaths was low.  The therapy was well tolerated. Most of the patients were stage IIIB and IIIC resected patients, and those are very high-risk patients.

Targeted therapies
Weber:  I was very impressed with Sosman's presentation of the CDK-4 inhibitor combined with the MEK inhibitor 162...a 33% response rate, ...phase 1 study with only 22 patients....Nonetheless, the NRAS-mutated population - which are BRAF wild-type because the 2 mutations are mutually exclusive - was a relatively hopeless cohort in terms of targeted therapy, and now it looks like there will be a useful and efficacious targeted therapy for at least 15% of melanoma patients who are NRAS-mutated BRAF wild-type. 

We heard Flaherty, who gave us an update on the BRF-113220 trial. [see abstract in June 4, 2014 post] ...randomized study with 162 patients, of whom 54 received dabrafenib alone (the BRAF inhibitor), 54 received dabrafenib with a lower dose of the MEK inhibitor trametinib, and 54 received dabrafenib and what we hoped was the optimal dose of the MEK inhibitor.  The updated data showed a clear superior rate of response: 76% vs the mid-50% range for either of the other arms.....there was a 25-month median survival...our institution was the biggest accruer to that trial.  About 20% of our patients at 3-4 years are still on treatment and doing well, with many complete responses over time.  It is a very impressive treatment.  It makes you wonder:  Maybe a BRAF mutated patient who starts on this combination should not receive immunotherapy first.  I would like to know what happened to the patients who failed the combination and then went on to immunotherapy. A debate is raging in our field about whether we should give immunotherapy or targeted therapy first, but I can't argue with a 25 month median survival - the best in any phase 2 trial of a significant size that I have ever seen.

Injectable therapies
Ribas:  ...a randomized trial of an injectable virus called T-VEC compared with granulocyte-macrophage colony stimulating factor (GM-CSF).

Weber:  ...the responses were 16% vs 2%.  Obviously you don't expect any responses with GM-CSF, so 2% would be essentially zero.  A 16% response rate overall in a patient with injectable local-regional disease plus systemic disease is pretty modest....that is close to being able to show the satisfaction of the oncologic community that there are benefits to giving this injectable therapy....Injectable therapies are making a comeback.....eons ago we were injecting BCG, interferon, and IL-2 into local-regional melanoma there are some interesting drugs, and T-VEC is one of them.  I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipi, or a combination of those....that's where I see intralesional therapy going.  [see abstract and history of intralesional therapy in February 2, 2014 post]

So, there's my best synopsis...all their words...not mine.  Have to say, proud of the selection Brent and I made while looking through hundreds of ASCO abstracts. Only missed a couple that were discussed here.  Also pleased that two experts seem to view the data as I that:
1. CT-011 (pidilizumab) is not worth pursuing.
2. Pembrolizumab and Nivo, the other two anti-PD1 drugs, are serving patients very well, and will probably be FDA approved this year.
3. The ipi/nivo combo offers good results, but somewhat concerning adverse events.
4. The ipi as adjuvant trial (this one was news to me) is certainly interesting, though the 10mg/kg dose is larger than what is routinely given here.  Would those patients still have had good outcomes with fewer adverse events at 3mg/kg?  I hope someone will do THAT adjuvant study!!
5. CDK-4 with MEK looks like it can really help NRAS patients who have had very limited options.  Hopefully, the data will hold up.
6. BRAF combo therapy seems pretty awesome.  What to do first?  Immunotherapy vs BRAFi???  Hopefully that answer will become more clear in the coming year.
7. Intralesional therapy made the "greatest hits" list!  Love it. Combining it with other therapies seems like a win-win to me!

That's a 2014 ASCO wrap-up!  Wishing all of you, especially the very best. -c

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