Emerging Novel Therapies, San Antonio Breast Cancer Symposium 2020

 In this exclusive virtual roundtable video from MedPage Today, three expert leaders in the field of breast cancer discuss the latest emerging and potentially practice-changing data from the virtual San Antonio Breast Cancer Symposium.

Moderator Hope S. Rugo, MD, is joined by Jennifer K. Litton, MD, and A. Jo Chien, MD, in this third of four episodes, where they discuss the studies presented at the meeting that focused on the potential of novel oral taxanes and antibody-drug conjugates in metastatic breast cancer.

Episode 1: Immunotherapy Options

Episode 2: Adjuvant Anti-CDK4/6 in Early, HR-Positive Breast Cancer

Following is a transcript of their remarks:

Hope Rugo, MD: Hello and welcome to this virtual roundtable where we will be discussing some of the key data that emerged from this year's San Antonio Breast Cancer meeting. I'm Hope Rugo, professor of medicine at the University of California San Francisco's Comprehensive Cancer Center, and I'm joined today by two expert leaders in the field of breast cancer and great colleagues, Dr. Jennifer Litton from the MD Anderson Cancer Center and Dr. Jo Chien from the University of California San Francisco's Comprehensive Cancer Center. Thanks for joining me today.

Now I think what we'll do is focus on novel therapy, some of the novel therapies that were presented at San Antonio. We can't be exhaustive, of course, but we'll talk about some of the agents that either are already being used in the clinic or are emerging agents. One area of great interest is oral taxanes. We've been trying to get oral taxanes for ages. There is a problem with absorption due to P-glycoprotein and also problems just with the formulations of these agents. But we saw data from one really interesting trial presented for the first time, the CONTESSA trial, looking at tesetaxel, a novel taxane, and capecitabine combined in hormone receptor-positive metastatic disease.

Then we also saw an update both on efficacy and safety from the oPac+E [oral paclitaxel and encequidar] study that had been first presented at San Antonio 2019. Jennifer, tell us a little bit about those two trials.

Jennifer Litton, MD: The CONTESSA trial was presented by Dr. O'Shaughnessy and looked at tesetaxel plus a dose-attenuated capecitabine versus capecitabine alone, and showed an improvement in progression-free survival with a hazard ratio of 0.716, and that was an increase in median PFS from 6.9 to 9.8 months.

When we looked at the toxicity, what was really striking was a high rate of grade 3 and 4 neutropenia of 38.3%, which was significant. There was also some... neuropathy increased and about 20% of alopecia, which brings in, too, several questions still. Is it the combination, when we're doing a combination in the metastatic setting, or was it also the dose, given that many of the patients on this trial needed dose reductions before they were able to continue on? I think further information regarding that as a combination will be forthcoming.

The oPac+E update showed still the improvement in progression-free survival. There was less neuropathy. The GI toxicity, once managed during the course of this trial, was able to be managed and better tolerated. Some of the discussion was around the comparator to a Q3-week taxol and further data is going on with a weekly taxol, another combination, so we'll have to look forward to those trials too once they present.

Rugo: That's great. I thought having an oral taxane for our patients might really be wonderful because they wouldn't need the IV access. That's such a pain for breast cancer patients so early in their course of disease. They really like taking capecitabine, even with the palmar-plantar erythrodysesthesia that bothers people, and the 8% rate of grade 2 alopecia with tesetaxel, I think. There's also less relatively with oPac+E. I think one is given once every 3 weeks. The other is given for 3 days weekly and needs fasting, so it's going to be really interesting to see what the regulatory review is and to see how we put these drugs into practice.

Having less neuropathy with oPac+E and a relatively low rate with tesetaxel is also, I think, very encouraging. Certainly even grade 2 neuropathy is bothersome and really there is a striking difference with oPac+E, so really interesting.

There were some other areas of interest in terms of novel agents, Jo. The ASCENT trial, the phase III trial which provided really, I think, impressive confirmatory data about the efficacy of sacituzumab govitecan, the novel Trop-2-directed antibody-drug conjugate that had one accelerated approval based on fairly remarkable phase II data earlier in 2020.

This data was presented at ESMO and showed improved overall survival and progression-free survival in patients receiving [sacituzumab govitecan] compared to a treatment of physician choice. Sara Hurvitz presented really interesting data on biomarkers and BRCA to try and better understand if we can identify a group who benefits.

We also saw the disappointing data with an AKT inhibitor and some additional data from a phase II trial, and then there's a fascinating new antibody-drug conjugate with data presented by Ian Krop, U3-1402, that targets HER3. Can you tell us a little bit about those different analyses?

A. Jo Chien, MD: Yeah. Sure. I'll start with maybe IPATunity, which is a trial we've been really waiting for the results of for a long time and really excited to see. The PI3K-AKT pathway is a pathway that we know is a driver in many cancers and we've been trying to target for a long time, and actually there's one drug approved in hormone receptor-positive cancer. But a phase II study, the LOTUS study, has previously reported overall survival benefit with AKT inhibitor ipatasertib in combination with paclitaxel in the first-line metastatic triple-negative setting. IPATunity is a phase III trial confirming these results and unfortunately it did not show a difference in PFS between the paclitaxel-ipatasertib versus paclitaxel alone arm. This was disappointing, but I wouldn't count this class of agents out completely. While it may not have a place with paclitaxel alone in the first-line setting in metastatic triple-negative breast cancer, I think there is some evidence now that AKT inhibitors may play an immunomodulatory role. There was actually some interesting data presented of AKT inhibitors, ipatasertib in particular, in combination with atezolizumab [Tecentriq], showing that you can increase T cell infiltrates and CD8 cells, and actually chain, or at least... not convert. But in tumors that were PD-L1-negative, they have seen tumors become PD-L1-positive after exposure to AKT inhibitors and atezolizumab. I don't think that story is completely over, but I don't think necessarily there is a role for this drug in the first-line setting in the way that it was tested in this trial.

In terms of the sacituzumab data from the ASCENT trial, so as you said, this is a phase III study that led to the approval of sacituzumab in the later-line triple-negative setting, and Sara Hurvitz presented some biomarker correlative data from this trial looking at whether Trop-2 expression impacted benefit from sacituzumab.

This was protein expression using an age score, IHC-based assay, and they defined Trop expression with high, medium, and low, and did not see association between the level of Trop-2 expression and benefits. Whether you were high or a medium, you seemed to benefit similarly.

This was, I should highlight, an exploratory analysis, though pre-planned. The numbers were smaller and there was some suggestion that the Trop-2 low may not have benefited as much and may have done worse overall. But again, this was exploratory, small numbers, and at this time I don't think we should be testing for Trop-2 in our decision making for sacituzumab.

The third study is the patritumab, U3-1402, which is a HER3 antibody, patritumab. It's an ADC, so it's linked to deruxtecan, the same chemo as in DS-8201, and this drug is really interesting. It's targeting HER3 and Dr. Krop presented phase I/II data showing an overall response rate of about 30% in hormone receptor-positive/HER2-negative breast cancer. This is a heavily pretreated population. It was a typical phase I demographic with a median of 3 to 4 lines of prior treatment, so a 30% response rate is very interesting.

They also looked at triple-negative, and in triple-negative patients there was also a decent response rate of about 16%, so I thought this was a really interesting agent. They also looked to see whether HER3 expression correlated with response and it did not seem to be associated, whether you were HER3-high or low, you seemed to benefit, so I think we'll be seeing a lot more from this agent in both triple-negative and hormone receptor-positive/HER2-negative disease.

Rugo: I think that was really a fascinating agent, patritumab, but I think that it's always... you have to be sure you get enough syllables in... but it's interesting deruxtecan causes the interstitial lung disease [ILD] and they did see a lot of bone marrow suppression, so this is something we're going to have to be aware of and try and understand. They had one death on that study from ILD and that's something we're continuously discussing in patients treated with trastuzumab deruxtecan, a very remarkable drug, now approved.

This has been really interesting and helpful, and I think gives us all a good background to evaluate the data that comes next year in additional studies, as well as potential approval of the first oral novel taxanes, and use of sacituzumab appropriately in our patients. Thanks very much.

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