ONCAlert | Upfront Therapy for mRCC

Case 4: Treating Platinum-Resistant Recurrent Disease

Targeted Oncology
Published Online:1:02 PM, Wed June 12, 2019


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Robert L. Coleman, MD: Shannon, what’s your take on how we’ve got to move the I/O [immuno-oncology] space forward?

Shannon N. Westin, MD: I think the combinations are what are very exciting, and I think that my colleagues here mentioned a few of the studies that are of interest. Certainly, the combination of a PARP [poly (ADP ribose) polymerase] with immunotherapy, and whether it’s the immune agent that sensitizes to the PARP or the PARP that sensitizes to the immune, or both. Those data are certainly intriguing. Because of that, we’re moving that type of thing up front. The question will be: Can you go back, in a patient like this who has become platinum resistant, if you use those things up front? That is a question that we need answered. I think that anti-angiogenics in combination with immunotherapy are very exciting and certainly seem to be tolerable, which is good, because you worry about the different overlapping toxicities. I do think that that’s really where this space is going. I think that the single-agent I/O [immuno-oncology] is just not a home run in ovarian cancer. We’re trying to find out the best way to maximize. I do think it’s worth mentioning potentially using chemotherapy and I/O. It’s something that we were pretty excited about. Our excitement is certainly tempered by these data that we’re discussing today. But you do wonder if there’s a particular combination that may be more successful than what has really been reported.

David O’Malley, MD: The JAVELIN Ovarian 200 curves, or the progression-free survival curves on the PD-L1 [programmed death-ligand 1] population, the positive population, excuse me, clearly are separated between those 3 arms.

Robert L. Coleman, MD: Yeah. Greg brought up the point about the tumor mutational burden. I feel like, in general, ovarian cancer, all comers, just doesn’t have a high load. Obviously, we see it with our BRCA patients. It’s higher. We see it with MSI [microsatellite instability]. But at least there seems to be some relationship between tumor mutational burden and the potential for response. Certainly, in other tumor types we’ve seen this, but whether or not it’s going to pan out in ovarian cancer, I don’t know. We always start this story in the recurrent and resistant space, which may be the most T-cell exhausted space to start, right? And then we try to move it forward. As you mentioned, we’ve looked at this in the frontline setting, and it looks [as if] that’s probably not going to work in the platinum-sensitive untreated patients. It’s tricky.

David O’Malley, MD: It makes intuitive sense to me, and thus I have no intuition. High-volume disease wouldn’t benefit as much. When you look at the subgroup analysis in JAVELIN Ovarian 200, the high-volume disease patients are the ones who benefit. The low-volume disease patients didn’t seem to benefit at all. Again, this is a subgroup analysis. There may be something for that tumor infiltration in the larger-volume disease combined with the immunogenicity of the cytotoxic that could potentially help. Again, we’re identifying these patients and why it’s so important to get them on a clinical trial, and we need to get biopsies of these patients, so you can figure out what to do.

Robert L. Coleman, MD: Let’s say the patient got gemcitabine-carboplatin, and she goes about 4 months this time, is disease-free, and ultimately progresses? You get tumor tissue back, and she’s BRCA-positive. Do you treat her? She’s somatic BRCA-positive.

Susana M. Campos, MD, MPH: Oh, she’s somatic. She’s had 2 prior lines of therapy now. She’s had the platinum, the taxane. Based on ARIEL2, I would absolutely start her on rucaparib if she’s somatic.

Robert L. Coleman, MD: But she’s platinum resistant. Does that temper your excitement?

Susana M. Campos, MD, MPH: It does, somewhat, but she’s still a somatic carrier. At this point in time, even extrapolating—this is with a little bit of thought process—if you look at the QUADRA study, yes, patients who were platinum sensitive, HRD [homologous recombination deficiency] positive, actually benefited the most. But there were patients who were resistant who still benefited.

Robert L. Coleman, MD: Yeah, you see it with all 3 drugs.

Susana M. Campos, MD, MPH: And so you ask yourself the question as you’re treating this individual: Are you never going to give this young woman a PARP inhibitor at all? Either define it as yes or no. I’m a big fan of the fact that it’s going to speak to you because she’s either going to respond or not.

Robert L. Coleman, MD: Yeah, they’re going to define themselves, right. Shannon, what if you had done an HRD test? Let’s say she’s wild type but she’s HRD positive. Would that have changed your thoughts about it?

Shannon N. Westin, MD: We don’t know yet, right? Susana just referenced the QUADRA data, which are some of the only data we have in this kind of more, further-line therapy. We certainly have the maintenance data to indicate that there’s a sequential difference and benefit based on BRCA positivity, and HRD positivity, and they’re completely wild type. I think it intrigues you. It depends if you can get it. I have a hard time getting the PARP inhibitors.

Robert L. Coleman, MD: Oh, for that reason?

Shannon N. Westin, MD: For the HRD, from the insurance companies. I think it’s worse getting kind of closely monitored prescriptions for that case. But I think that looking at combinations in these patients is very exciting for trials.

David O’Malley, MD: In the true wild type, I think that’s why I don’t love the HRD test, or the LOH [loss of heterozygosity] test, or whatever test it is. That’s why I want to know what the mutations are. We know RAD51C and RAD51D behave just like PARP, or very similar. The Fanconi anemia pathway does not. PALB2 may not. Maybe RET doesn’t.

Robert L. Coleman, MD: You had a very interesting subanalysis that looked at some of the individual gene mutations and their outcomes. I thought it was pretty compelling. Hopefully we’ll see that in print soon. It basically suggested that maybe there are certain mutations that we ought to go after, and since we’re getting a whole bunch of them on our sequencing, maybe we can use that for future...

David O’Malley, MD: When we look at identifying the patients who are more apt to benefit, if it is in later lines or earlier lines, we need to move in that direction.

Robert L. Coleman, MD: Excellent. Well, this was a great discussion. Thank you so much. I’d like to thank my colleagues here—Dr Susana Campos, Dr Dave O’Malley, Dr Shannon Westin, and Dr Greg Riedlinger—for this and for all your comments. This has been a wonderful discussion. To our viewing audience, thank you for joining us for this Targeted OncologyTM Virtual Tumor Board® presentation. We hope today’s discussion was a valuable use of your time and that you acquired some practical knowledge that you can take back to your clinic. Thank you.

Transcript edited for clarity.


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Robert L. Coleman, MD: Shannon, what’s your take on how we’ve got to move the I/O [immuno-oncology] space forward?

Shannon N. Westin, MD: I think the combinations are what are very exciting, and I think that my colleagues here mentioned a few of the studies that are of interest. Certainly, the combination of a PARP [poly (ADP ribose) polymerase] with immunotherapy, and whether it’s the immune agent that sensitizes to the PARP or the PARP that sensitizes to the immune, or both. Those data are certainly intriguing. Because of that, we’re moving that type of thing up front. The question will be: Can you go back, in a patient like this who has become platinum resistant, if you use those things up front? That is a question that we need answered. I think that anti-angiogenics in combination with immunotherapy are very exciting and certainly seem to be tolerable, which is good, because you worry about the different overlapping toxicities. I do think that that’s really where this space is going. I think that the single-agent I/O [immuno-oncology] is just not a home run in ovarian cancer. We’re trying to find out the best way to maximize. I do think it’s worth mentioning potentially using chemotherapy and I/O. It’s something that we were pretty excited about. Our excitement is certainly tempered by these data that we’re discussing today. But you do wonder if there’s a particular combination that may be more successful than what has really been reported.

David O’Malley, MD: The JAVELIN Ovarian 200 curves, or the progression-free survival curves on the PD-L1 [programmed death-ligand 1] population, the positive population, excuse me, clearly are separated between those 3 arms.

Robert L. Coleman, MD: Yeah. Greg brought up the point about the tumor mutational burden. I feel like, in general, ovarian cancer, all comers, just doesn’t have a high load. Obviously, we see it with our BRCA patients. It’s higher. We see it with MSI [microsatellite instability]. But at least there seems to be some relationship between tumor mutational burden and the potential for response. Certainly, in other tumor types we’ve seen this, but whether or not it’s going to pan out in ovarian cancer, I don’t know. We always start this story in the recurrent and resistant space, which may be the most T-cell exhausted space to start, right? And then we try to move it forward. As you mentioned, we’ve looked at this in the frontline setting, and it looks [as if] that’s probably not going to work in the platinum-sensitive untreated patients. It’s tricky.

David O’Malley, MD: It makes intuitive sense to me, and thus I have no intuition. High-volume disease wouldn’t benefit as much. When you look at the subgroup analysis in JAVELIN Ovarian 200, the high-volume disease patients are the ones who benefit. The low-volume disease patients didn’t seem to benefit at all. Again, this is a subgroup analysis. There may be something for that tumor infiltration in the larger-volume disease combined with the immunogenicity of the cytotoxic that could potentially help. Again, we’re identifying these patients and why it’s so important to get them on a clinical trial, and we need to get biopsies of these patients, so you can figure out what to do.

Robert L. Coleman, MD: Let’s say the patient got gemcitabine-carboplatin, and she goes about 4 months this time, is disease-free, and ultimately progresses? You get tumor tissue back, and she’s BRCA-positive. Do you treat her? She’s somatic BRCA-positive.

Susana M. Campos, MD, MPH: Oh, she’s somatic. She’s had 2 prior lines of therapy now. She’s had the platinum, the taxane. Based on ARIEL2, I would absolutely start her on rucaparib if she’s somatic.

Robert L. Coleman, MD: But she’s platinum resistant. Does that temper your excitement?

Susana M. Campos, MD, MPH: It does, somewhat, but she’s still a somatic carrier. At this point in time, even extrapolating—this is with a little bit of thought process—if you look at the QUADRA study, yes, patients who were platinum sensitive, HRD [homologous recombination deficiency] positive, actually benefited the most. But there were patients who were resistant who still benefited.

Robert L. Coleman, MD: Yeah, you see it with all 3 drugs.

Susana M. Campos, MD, MPH: And so you ask yourself the question as you’re treating this individual: Are you never going to give this young woman a PARP inhibitor at all? Either define it as yes or no. I’m a big fan of the fact that it’s going to speak to you because she’s either going to respond or not.

Robert L. Coleman, MD: Yeah, they’re going to define themselves, right. Shannon, what if you had done an HRD test? Let’s say she’s wild type but she’s HRD positive. Would that have changed your thoughts about it?

Shannon N. Westin, MD: We don’t know yet, right? Susana just referenced the QUADRA data, which are some of the only data we have in this kind of more, further-line therapy. We certainly have the maintenance data to indicate that there’s a sequential difference and benefit based on BRCA positivity, and HRD positivity, and they’re completely wild type. I think it intrigues you. It depends if you can get it. I have a hard time getting the PARP inhibitors.

Robert L. Coleman, MD: Oh, for that reason?

Shannon N. Westin, MD: For the HRD, from the insurance companies. I think it’s worse getting kind of closely monitored prescriptions for that case. But I think that looking at combinations in these patients is very exciting for trials.

David O’Malley, MD: In the true wild type, I think that’s why I don’t love the HRD test, or the LOH [loss of heterozygosity] test, or whatever test it is. That’s why I want to know what the mutations are. We know RAD51C and RAD51D behave just like PARP, or very similar. The Fanconi anemia pathway does not. PALB2 may not. Maybe RET doesn’t.

Robert L. Coleman, MD: You had a very interesting subanalysis that looked at some of the individual gene mutations and their outcomes. I thought it was pretty compelling. Hopefully we’ll see that in print soon. It basically suggested that maybe there are certain mutations that we ought to go after, and since we’re getting a whole bunch of them on our sequencing, maybe we can use that for future...

David O’Malley, MD: When we look at identifying the patients who are more apt to benefit, if it is in later lines or earlier lines, we need to move in that direction.

Robert L. Coleman, MD: Excellent. Well, this was a great discussion. Thank you so much. I’d like to thank my colleagues here—Dr Susana Campos, Dr Dave O’Malley, Dr Shannon Westin, and Dr Greg Riedlinger—for this and for all your comments. This has been a wonderful discussion. To our viewing audience, thank you for joining us for this Targeted OncologyTM Virtual Tumor Board® presentation. We hope today’s discussion was a valuable use of your time and that you acquired some practical knowledge that you can take back to your clinic. Thank you.

Transcript edited for clarity.
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