PracticeUpdate: Haematology & Oncology

ESMO 2016

15

EXPERT OPINION TANYA DORFF Prostate cancer updates Interview by Sumanta Kumar Pal MD

BKM120 + trastuzumab demonstrates acceptable safety and encouraging activity in heavily pretreated trastuzumab- resistant, HER2-positive metastatic breast cancer BKM120 + trastuzumab has demonstrated an acceptable safety profile, and encouraging preliminary activity in patients with heavily pretreated HER2-positive metastatic breast cancer and trastuzumab resistance, including those with brain metastasis. T his outcome of a phase 1B/2 study of BKM120 + tras- tuzumab in patients with trastuzumab-resistant HER2- positive advanced breast cancer was reported at ESMO. B. Pistilli, MD, of Macerata Hospital, Macerata, Italy, explained that PI3K/AKT/mTOR pathway upregulation has been implicated in trastuzumab resistance. The impact of pathway inhibition on restoration of therapeutic sensitivity to trastuzumab is therefore being investigated. The recommended phase 2 dose of BKM120, an oral pan-class I PI3K inhibitor, + trastuzumab is 100 mg daily. Dr Pistilli reported phase 2 results of BKM120 + trastuzumab in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Patients with HER2-positive, locally advanced/ metastatic breast cancer resistant to trastuzumab (progressed while on trastuzumab, or within 4 weeks [metastatic], or within 12 months [adjuvant] of their last dose of trastuzumab) received daily BKM120 (100 mg) and the standard weekly dose of tras- tuzumab. Phase 2 eligibility criteria were: • At least one measurable lesion • At least one but four or fewer prior anti-HER2 regimens (including trastuzumab [required], lapatinib, and/or trastu- zumab emtansine) • Three or fewer lines of prior chemotherapy for metastatic disease. Phase 1B patients treated at the recommended phase 2 dose who met phase 2 eligibility criteria were included in the analysis. As of March 2012, 53 patients were included in the phase 2 analysis (the safety set, which included eight patients from phase 1IB). Forty-nine patients were evaluable for full analysis of response. Median patient age was 52 (28–75) years. They received a median of four (1–10) prior antineoplastic regimens. Five patients harboured a baseline CNS lesion (three measur- able target; two nontarget). At data cutoff, nine patients were still in the study. Most patients discontinued treatment due to disease progression (55%). Eight patients (16%) withdrew due to adverse events. The mean duration of BKM120 exposure was 11 (0.1–41) weeks. The most common suspected study drug -related grade 3/4 adverse events were:

Dr Pal and Tanya Dorff, MD, review updates from major prostate cancer trials and their clinical implications.

Dr Pal: I’m here with Dr Tanya Dorff. She also specialises in GU prostate oncology, and I’m going to ask her some of her insights related to some data we’ve seen here today at the meeting. So, Tanya, big meeting here in renal cell carcinoma and bladder, but also in prostate, and I wanted to get your take on some of the data that Dr Sweeney presented today, the update from the CHAARTED trial. Can you tell us a little bit about what he presented? Dr Dorff: Yeah, so if you remember, in the original CHAARTED presentation, there was a huge survival benefit for upfront docetaxel, but when you looked at the prespecified subset analysis, the low-risk, the low volume patients didn’t seem to benefit as much. People thought that with more time and more events the data would mature and those curves would separate, but what we saw today is that in fact they have not. So really, the bulk of the benefit of upfront docetaxel seems to be in high-volume disease. Dr Pal: That’s an interesting point, and for the practicing medical oncologist, can you give us a sense of how to appro- priately characterise a patient as having low volume or low-risk disease? Dr Dorff: The definition that was used in CHAARTEDat least was for high volume, four or more bone metastases with one outside the axial skeleton. So you could have three in your spine and pelvis and one in a rib and that got you to high- volume, or visceral metastatic disease. Dr Pal: It sounds like a pretty easy defini- tion to apply. I guess one question that I have in this domain is we’ve seen some different datasets from GETUG, from STAMPEDE, from the CHAARTED trial. Putting all these together, do you think the amalgam of data still supports perhaps treating low-risk and high-risk patients differently?

Dr Dorff: I do think so. I think there is overall a sense that you get less marginal advantage using docetaxel in those ear- lier patients. I thought the discussion today did a really good job, however, of pointing out that there might be some patients for whom it’s still appropriate because there are those other trials, even as early as some of the STAM- PEDE patients, some of whom were not even metastatic, and the CHAARTED trial was positive as a whole. So, if you don’t look at the subset analy- sis, you could make an argument that there is still room to treat low volume patients, but I think you’d select them very carefully to make sure that the benefit, which might be much smaller, is not outweighed by the risk. Dr Pal: And I think it’s a very pragmatic approach to this question. Now, I’m going to shift gears a little bit and ask you about something that’s really been burning in my mind, which is the role of AR-V7. We’ve heard about it for a long time now. You know, what really struck me is that at this meeting there are some datasets that might potentially calm the question AR-V7 as a biomarker. What’s your perspective on this issue? Dr Dorff: This was a huge meeting for AR-V7, and I’m already having patients come up to me and ask for an AR-V7 test as a way to help me choose their next therapy. And based on the Hopkins data you might have thought that it was a really good predictive test, but what we saw today were three different groups presenting data. The Memorial Sloan Kettering abstract used the Epic platform, and so they’re able to look at nuclear localisation of androgen receptor, so not just is the AR-V7 variant there, is it present or absent, but now, where in the cell is it? And that functioned better as a

predictor for benefit from taxane. Then the Spanish Oncology Group, which used a PCR based test, actually found that some of the patients who were categorized as AR-V7 positive did respond to enzalutamide, so there were only eight patients, but four of those eight patients with AR-V7 responded. So these are still all very early experi- ences, very small numbers, but I think the take-home message is we don’t yet know which assay is right and we don’t know what kind of cutoffs. So in the Spanish Group, it looked like they had a lower ratio of splice variant AR-V7 compared to AR full-length, and so it may matter how much AR-V7 is around essentially. So until these assays can be validated, I don’t think we can actually say this patient will or will not benefit from enzalutamide or abirater- one and should necessarily go to taxane therapy. I will say that, overall, the presence of AR-V7 does portend as shorter progression-free survival, so it may just be a poor prognostic marker in and of itself, but in talking to some colleagues around the meeting, with some assays you get a hundred percent detection. So I do think that we need to refine the methodology and look at things like nuclear localisation or ratio compared to full-length.

Dr Dorff is Assistant Professor of Clinical Medicine, USC Norris Cancer Center in Los Angeles.

Watch the full interview at PracticeUpdate.com

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Partial responses according to Response Evaluation Criteria in Solid Tumors were seen in four patients (8%). Stable disease was noted in 20 patients (41%). The disease control rate (com- plete response, partial response, or stable disease) was 49%. Preliminary results indicate that, of the five patients with baseline brain metastases, two had stable disease in the CNS without evidence of progression at study withdrawal. Two had overall stable disease (one for 90 days and one for 106 days) before progression in the CNS and one patient was not evaluated in the CNS after study entry. Dr Pistilli concluded that BKM120 + trastuzumab has demonstrated an acceptable safety profile, and has shown encouraging preliminary activity in heavily pretreated patients with HER2-positive metastatic breast cancer and trastuzumab resistance, including in patients with brain metastasis. © ESMO 2016

VOL. 1 • No. 5 • 2016