番茄社区

At the , over 100 sessions and thousands of abstracts on the latest emerging topics in cancer treatment were presented in an all-virtual format. 番茄社区 brought together three expert leaders in their fields: , a breast oncologist at Dana-Farber Cancer Institute in Boston; , a thoracic oncology specialist at City of Hope in Duarte, California; and , a genitourinary oncologist at the Cleveland Clinic in Ohio. They were joined by moderator , of the University of California San Francisco Comprehensive Cancer Center, for a virtual roundtable discussion on the new and potentially practice-changing data from the meeting.

In this third of four exclusive 番茄社区 episodes, the discussion returns to advancements in the treatment of breast cancer.

Episode 1: Advances in Breast Cancer

Episode 2: Lung Cancer Highlights

Following is a transcript of their remarks:

Hope Rugo, MD: Hello. Welcome to this virtual roundtable, where we will be discussing some of the key data that emerged from this year's ASCO meeting. I'm Hope Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center.

Today I'm joined by three expert leaders in their fields: Dr. Sara Tolaney, a breast oncologist at Dana-Farber Cancer Institute; Dr. Jack West, a thoracic oncology specialist from City of Hope; and Dr. Shilpa Gupta, a genitourinary oncologist from the Cleveland Clinic. Welcome and thanks for joining me.

Sara, there are some other topics that were presented at ASCO that I think were important to us in clinical practice. There, of course, was a huge amount of data, but let's just talk about three different areas. One was through our own consortium that we both belong to, which was really, I think, interesting data looking at olaparib in patients who had other germline DNA-damaging mutations or acquired somatic mutations. It's really interesting in the metastatic setting. Tell us a little bit about that trial we call by Nadine Tung.

Sara Tolaney, MD: I know. I think this was actually a very exciting trial that was presented. This was a phase II study that took patients with metastatic breast cancer who had had up to two lines of chemotherapy for their metastatic disease. They had to have either a germline mutation in a DNA damage response pathway or have a somatic mutation in BRCA1 or 2, or in other genes that are in the DNA damage pathway.

What they found was that amongst those patients who had germline PALB2 mutations -- and I will say these datasets are very small, so there's only 11 patients in the germline PALB2 cohort. But nine of them had objective responses, and, in fact, the other two had stable disease. It was really like an 82% objective response rate, which is something we really never see, so I think very impressive.

Then in the somatic patients, the somatic BRCA patients, we also saw that half the patients, or 50% of patients, achieved a response, so not that far off from what we see with germline BRCA patients with PARP inhibition.

Given these very exciting and promising data, Nadine is working to expand these cohorts, to add more patients to the germline PALB2 and to the somatic BRCA to have larger numbers of patients.

I will be truthful saying that these data, if I had a patient and there wasn't a slot on a clinical trial, I would consider honestly prescribing olaparib to a germline PALB2 patient. I realize it's based on very small numbers, but it's just such a startling response rate, and biologically makes sense. It seems like it's a really promising treatment for these patients.

Dr. Rugo: I agree and I think that maybe we could add the PARP inhibitors even earlier too. One of my patients on this trial who had a fabulous response with PALB2 rapidly progressed in brain and maybe there will be something that we can do by treating earlier to prevent that rapid resistance and these protected slots.

We learned also about CDK4/6 inhibitors. We've been questioning what the right partner is for CDK4/6 inhibitors in the first-line metastatic setting, based on the prior FALCON data that suggested that fulvestrant in patients who never had been exposed to any endocrine therapy in any setting might be better than an aromatase inhibitor [AI] if you only had bone and soft disease. It was a subset of a subset. But the addressed this. What did that tell us?

Dr. Tolaney: I think we've been interested to see these data because of, as you alluded to, prior data suggesting fulvestrant may be superior to an AI, but PARSIFAL really looked to randomize patients in the first-line setting to get fulvestrant with palbociclib or an AI with palbociclib, and looked at progression-free survival.

In fact, there was no difference between the two arms, so the progression-free survival numerically was a little bit greater for the AI-plus-palbociclib arm relative to the fulvestrant arm, but not statistically significant. They were not only not able to show superiority for fulvestrant-palbo over AI-palbo, but they also were not able to show non-inferiority.

I think, to me, what this shows is that while there is data to suggest that when fulvestrant is given alone, it may be superior to an AI. That when given with a CDK4/6 inhibitor, the choice of endocrine therapy didn't really matter here.

In truth, it doesn't really change the way I've been practicing to date, in the sense that if I have a patient who comes in with de novo disease, or maybe a couple years out from their adjuvant AI, then I think about using an AI and CDK4/6 inhibition. Whereas if I have someone who progressed on an AI in the adjuvant setting, then in the first-line setting, I'm going to fulvestrant and CDK.

I think it does, in essence, confirm our clinical practice patterns that we're not going to change those. But it's certainly interesting because it does suggest that there's something different when you combine endocrine therapy with CDK4/6.

I think we also saw some really interesting biomarker data that came out from other trials to suggest that maybe CDK4/6 inhibitors also suppress the ESR1 mutations, and I wonder if perhaps that mechanism may be playing a role in the PARSIFAL results.

Dr. Rugo: I thought that was really interesting because even people who'd been exposed to prior AIs -- they had to have been at least a year out -- didn't have any worse outcome, which we would have predicted if they had all these ESR1 mutations. But I think it's really interesting.

It also suggests that, as we know already, if you're not actually progressing on an AI, the rate of ESR1 mutations is relatively low. We'll see more data on that from PARSIFAL in the future, I'm guessing, when they look at the tumor tissue. But it's interesting.

One of the reasons why we like to use AIs is because it's an all-oral regimen, of course, which is really important to patients, but also because then we can "save" fulvestrant for other partners. The partner that has been approved in combination with fulvestrant, other than CDK4/6 inhibitors, is the alpha-specific PI3-kinase inhibitor, alpelisib, which was approved in combination with fulvestrant based on almost doubling of the progression-free survival in patients who'd progressed on an aromatase inhibitor and had a known PIK3CA mutation in their tumor.

What's interesting about that trial, , is that it had almost completely accrued before CDK4/6 inhibitors became approved to treat metastatic breast cancer, so patients had not received CDK4/6 inhibitors. Only a tiny number had. In that tiny number of patients, it looked like alpelisib benefited patients, but it's hard to say.

We designed the trial, which I presented at ASCO this year, and I'm interested in your thoughts on that. We presented cohort A, which were patients who had progressed on a CDK4/6 inhibitor and an AI as their last therapy, had a known PIK3CA mutation, and then were treated on study with fulvestrant and alpelisib.

Our primary endpoint was looking at patients who were alive and without progression at 6 months out. There were other cohorts that either haven't reached the 6-month endpoint or are still accruing. The chemotherapy cohort is accruing.

Of course, we also looked at progression-free survival overall, as well as the safety, and as you know, what we showed was that slightly over 50% of patients were progression free and well, without a major event at 6 months, which compared very favorably to SOLAR-1.

We also showed that progression-free survival compared favorably and that safety was a little better, if you just look across trials, comparing to SOLAR-1, perhaps, we hope, due to experience, and knowing how to treat and prevent rash, for example, and treat hyperglycemia. Then in a real-world comparison analysis using the Flatiron database, we showed that the PFS [progression-free survival] in was better than what we would have seen with standard therapy in a patient cohort previously treated with CDK4/6 inhibitors and with PIK3CA mutations.

All of that was quite interesting. How would you look back on this data and take it into practice?

Dr. Tolaney: I think it was really important data to see, because, as you allude to, I think there were only like 20 patients in SOLAR-1 who were post-CDK4/6, so it's very nice to actually have real data for the way we're currently utilizing alpelisib, which is really in a post-CDK4/6 space.

I think what we're seeing is having a PFS over 7 months, to me, is really pretty significant because we know fulvestrant -- when used as monotherapy in a patient with a PIK3CA mutation -- actually has a very short PFS, with many studies reporting PFS of just about 2 months in some patients.

Seeing it being over 7 months clearly suggests that alpelisib is adding activity to this patient population. It's 40% of our patients with ER-positive disease, so it's a really substantial portion of patients that can derive benefit from alpelisib.

I do think, as you alluded to, we are getting better with dealing with the toxicities. I think the data that you showed looking at antihistamine prophylaxis is really very important because it really did decrease rates of grade 3/4 rash by about half. That makes a huge difference in being able to keep people on drug, and that's why I think we're seeing lower discontinuation rates.

I think oncologists have never been the best at managing diabetes, but I think we've learned how to now check, screening hemoglobin A1c's, check fasting glucose, and initiate metformin early. I think all these learnings are allowing us to better keep patients on treatment and allow them to see the benefit.

Dr. Rugo: Great. Thanks very much. I appreciate that. Your thoughtful responses and reviews are great. Thanks very much. We have so much more to talk about, but we'll talk about it at another time. Thanks.

Dr. Tolaney: Thanks for having me.

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