|Richard W. Joseph, MD|
Assis. Prof., Oncology
Melanoma Int'l Foundation
NOT Just Skin Cancer
Richard Joseph, MD, is an assistant professor of medicine/oncology at Mayo Clinic. His Hematology/Oncology fellowship was completed at MD Anderson Cancer Center. He is a voting member of the NCCN (National Comprehensive Cancer Network. He belongs to Melanoma International’s Scientific Advisory Board and received MIF’s Doctor of the Year award for 2015.
The following is an interview between myself and Dr. Richard Joseph to provide a better understanding of the broader implications of the exciting data that was presented at the American Society of Clinical Oncology (ASCO). Many of the questions are from the inquiring (brilliant) minds of MIF’s forum participants.
» PD1/IPI Combination Trial Checkpoint 067 Results, Wolchok et al.
Question 1: Will the combination of Pd1/IPI be approved for first line treatment only?
Dr. Joseph: “The approval will likely only occur in the front line given that is where it was studied in clinical trial. With that being said, it does seem like a proper rationale to try the combination of nivolumab and ipilimumab in patients who have progressed on these as single agents and I believe this concept will be tested in future clinical trials. “
Question 2: Will prescribing this combination be based on BRAF status or the PDL 1 biomarker?
Dr. Joseph: “At this point, we do not have a reliable marker for who should receive the combination. The combination had efficacy in BRAF mutant and wild-type as well as PDL1 positive and negative patients. There was a signal that PDL1+ patients may not need the combination, but this data is still not mature and the study wasn’t designed to answer this question. I think future studies of PDL1+ patients are warranted, testing the combination versus single agent anti-PD1.”
Question 3: Will patients who failed to respond to IPI and/or PD1 as single agents be refused the combination of the two?
Dr. Joseph: “This will be on a case-by-case basis and depend on the patient’s insurance. My guess is that Medicare will not approve the combination in this setting since they always stick to the official label, but some private insurers might allow it.”
Question 4: Will doctors still prescribe IPI(Yervoy) in the front line therapy setting?
Dr. Joseph: “Given that both Keytruda and Opdivo had significantly improved outcomes with less toxicity than Yervoy, it is my opinion that single agent ipilimumab will be phased out in the front line setting.“
Question 5: Stage III: Will PD1 be used as an adjuvant therapy for stage III or resected stage IV. Or would the combination be used there too?
Dr. Joseph: “Several studies are assessing the efficacy of adjuvant anti-PD1. To my knowledge, there are no studies planned for the combination in the adjuvant setting.”
Question 6: Are there any studies coming up where the combination is tested on people who have failed anti PD1 and possibly Ipi instead of treatment naïve?
Dr. Joseph: “I believe these studies are in the pipeline, but it might be a while.”
The PDL-1 expression remains controversial. The CheckMate 067 trial mentioned above, showed patient with less than 5% PDL benefited from the combinations treatment. What are your thoughts?
Dr. Joseph: “I think there is a huge need to first standardize the PDL1 assay. In most Merck studies, 75% of the population is PDL1 positive. In the BMS studies, 30% of the population is PDL1 positive. In my mind, the only way to explain this discrepancy in PDL1+ patients is the assay. I think once we standardize the assay, we can then test the assay in a variety of clinical scenarios and then make conclusions about the clinical utility of the assay. I agree, at this point, PDL1 expression is not ready to be used in the clinic, but I think this is an assay issue and not a marker issue. Don’t get me wrong, PDL1 will never be a perfect marker due to its variation in expression, but I wouldn’t call it terrible either.”
Opdivo vs. Keytruda:
Do you think convenience may be the differentiator to using Keytruda, since it is given less often and shorter infusions. ( i.e. Opdivo is given every 2 weeks for 60 minute infusions, vs. Keytruda is given every 3 weeks 30 minute infusion.) Or could cost cutting do it?
Dr. Joseph: “I agree most patients and physicians would prefer to give a drug less frequently, if the efficacy appears equal and for this reason, I prescribe more Ketyruda than Opdivo. “
WHEN ALL NEW THERAPIES FAIL
Question 1: Do you have any suggestions for those patients who do not respond (or have progressed) on Ipi and PD1 i.e. the 60% of patients who don’t respond and are BRAF negative…try the combo if and when approved?
Dr. Joseph: “Trying the combination in patients who have progressed is very reasonable. My hunch is that the combination will not have the same efficacy as in treatment naïve patients, but I do think some patients will benefit. Obviously, this question will be best be answered by a clinical trial.”
Question 2: Should a patient try the TVEC if it is approved this year? Or try to get into a trial with a PDL1? Briefly, which new therapies are coming and are there promising ones like PD1 was?
Dr. Joseph: “I think TVEC is a promising agent, when used in combination with PD1. It does have some activity as a single agent, but I don’t think its activity is good enough to use instead of anti-PD1 or the combination.
“Trying an anti-PDL1 after progression on anti-PD1 is a possible option, but my hunch is that this strategy will not be effective. In terms of the melanoma pipeline, there are no agents that I’m aware of that are generating the same excitement as anti-PD1, but there are several promising agents.”
» BRAF/MEK Combinations Update: COMBI-d Study, Long, GV, et al
Question1: Standard BRAF therapy has been vemurafenib and dabrafenib combined with mekinist (MEK) – Is there any reason to believe that there are big differences (i.e. in drug tolerance/disease progression) between a dabrafenib, for example and an investigational med called cobimetinib (also a MEK)?
Dr. Joseph: “I do not believe there will be clinically significant differences between the combination of dabrafenib/trametinib and vemurafenib/cobimetinib. Both the efficacy and toxicity appear very similar. While there maybe some small differences, I view these agents as mostly equivalent.”
Miscellaneous Questions About Braf/MEK
Question 1: BRAF inhibitors: how many complete response and at what period? Is the response connected somehow with what organs were affected originally?
Dr. Joseph: “Complete remissions are rare, but do occur with BRAF inhibitors and combinations. The time period to response is very quick, but variable. To my knowledge, there is no data linking complete remissions and what organs were involved at baseline.”
Question 2: In cases of complete response – is there any chance to stop inhibitors treatment after 1 to 2 years of being NED or life-long therapy recommended?
Dr. Joseph: “Great question. If I had a patient in a complete response with a BRAF/MEK, I would be hesitant to stop and do nothing. I would favor stopping and starting with anti-PD1. Obviously, a data free zone at this point.”
Question 3: Are side effects decreasing/increasing/stay the same with time?
Dr. Joseph: “Side effects seem fairly consistent to me.”
Question 4: Intermittent BRAF therapy – any results on it?
Dr. Joseph: “There is a trial looking at this. To my knowledge, there are no results yet. It does seem like a promising strategy.”