Rugo Highlights Latest Advances in TNBC Treatment

Hope Rugo, MD

At the 2019 Lynn Sage Breast Cancer Symposium, experts addressed the latest advancements for the treatment of patients with triple-negative breast cancer (TNBC). Clinical trials are now investigating a number of different avenues for patients with TNBC, including immunotherapy, checkpoint inhibition, antibody—drug conjugates (ADCs), and other novel agents.

"Immunotherapy is very exciting," said Hope S. Rugo, MD. "We saw this marked improvement in pathological complete response [pCR] in KEYNOTE-522 by adding pembrolizumab [Keytruda] to standard neoadjuvant chemotherapy for TNBC."

The phase III KEYNOTE-522 trial randomized over 1100 patients to receive chemotherapy in combination with either pembrolizumab or placebo. The data, which were presented at the 2019 ESMO Congress, demonstrated that neoadjuvant pembrolizumab in combination with chemotherapy extended pCR rates in patients with early TNBC.

Evidence was also presented that suggest there is a role for ADCs in this space, as well as other agents. PARP inhibitors, in particular, are being explored as a treatment for patients with TNBC, including agents such as olaparib (Lynparza) and talazoparib (Talzenna). Both agents have already been approved by the FDA for the treatment of patients with breast cancer in different subtypes and are now under investigation for triple-negative disease. Veliparib (ABT-888) is also being evaluated.

In an interview with OncLive, Rugo, director of Breast Oncology Clinical Trials Investigation at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed the latest advancements in the treatment landscape for patients with TNBC. She also highlighted some data from clinical trials presented at the 2019 ESMO Congress that are particularly encouraging in this field.

OncLive: Could you discuss the latest advancements and ongoing research for treatments for patients with TNBC?

Rugo: At Lynn Sage this year, I was invited to talk about new treatment options for TNBC, and I think immunotherapies are a critical component of this. With PARP inhibitors now approved, there’s a lot of interest in expanding the reach of PARP inhibitors outside of patients with germline BRCA mutations and also improving the response in patients with BRCA mutations. The OLYMPIA adjuvant trial completed accrual this year, so we will be looking for that. There’s really intriguing data in the neoadjuvant setting with single-agent talazoparib in patients with germline BRCA mutations, and a phase II trial is now going on with high pCR rates with talazoparib alone. OLYMPIA, of course, is looking at adjuvant olaparib in patients with germline BRCA mutations, which is a much larger trial. It is really exciting to see that complete accrual now.

Combining PARP inhibitors with chemotherapy was presented at ESMO this year, showing improvement in PFS in the second progression after randomization with the addition of the fairly less potent PARP inhibitor veliparib to carboplatin and paclitaxel. I think the reason they could add it was because it doesn’t cause as much bone marrow toxicity. There was a marked increase in the rate of grade 3 thrombocytopenia with the addition of veliparib, but otherwise, the toxicities were relatively similar. What happens in terms of long-term data will really determine how we use that combination, but what’s intriguing to me is the concept of getting an induction with chemotherapy plus or minus a checkpoint inhibitor, then maybe using the PARP inhibitor combined with immunotherapy as maintenance. This is actually similar to what’s being done in ovarian cancer, and there are very interesting data from the laboratory suggesting that the combination of PARP inhibitors and checkpoint inhibitors will enhance the efficacy of checkpoint inhibitors. PARP inhibitors increase the immune responsiveness of the tumor microenvironment by a variety of mechanisms, so there are actually a number of studies going on looking at those combinations as well with some early encouraging data.

The other areas of discussion are about using platinum or not. Now that there [are data from the] KEYNOTE-522 trial showing a marked improvement in pCR with the addition of pembrolizumab to standard neoadjuvant chemotherapy, the question is, what is standard? They chose a standard regimen that included platinum in the paclitaxel part of the treatment. We’ve seen increased pCR with the platinum, but no convincing data have proven an event-free survival (EFS) or disease-free survival (DFS). The KEYNOTE-522 trial is powered to look at that but didn’t randomize to platinum or not. The trial that I really think is going to help us with that is the BrighTNess trial that randomized patients to either receive paclitaxel AUC6; paclitaxel-carboplatin AUC6; or paclitaxel, carboplatin, plus veliparib. The addition of veliparib did not improve pCR rates, but carboplatin did. That’s a trial that is powered to look at EFS or DFS. Obviously, we have to take into account what treatment people might get after surgery that might impact that evaluation.

There are some other trials also looking at the role of platinum as post-neoadjuvant therapy. The ECOG trial is looking at platinum versus capecitabine as opposed to neoadjuvant therapy, and then there is an NRG adjuvant trial, which is a simple AC taxane with or without carboplatin. It will be interesting to see 2 things. One is if the KEYNOTE-522 trial influences the use of platinum, not just pembrolizumab, which I’m guessing it will even though that was just a choice of a regimen. Also, [we will see] how this impacts the trials that are ongoing where we are looking to have more data about the use of platinum.

What data have we seen for ADCs in this space?

There are a number now that are being studied. These are antibodies targeting a novel antigen on the tumor. The Trop-2 ADC sacituzumab govitecan uses a novel toxin, a metabolite of irinotecan called SN-38, and has shown very nice response rates of about 33% in heavily pretreated patients with TNBC. It has also shown some responses in some hormone receptor (HR)—positive disease.

The phase III ASCEND trial in heavily pretreated patients with TNBC, which randomized [patients to either] sacituzumab govitecan or chemotherapy of physician’s choice, has just completed accrual, and we are hoping for results next year. We are also hoping to potentially see at least an accelerated approval of sacituzumab govitecan early next year. Another ADC is ladiratuzumab vedotin (SGN-LIV1A), which is against LIV-1, and that trial is earlier in its developmental life cycle. There’s some interesting and intriguing data in combination with immunotherapy as well, so we will see where that goes. That’s against LIV-1, and it has monomethyl auristatin E (MMAE), an auristatin analogue that is the toxin.

There are 2 other ADCs, and 1 of them is a HER2-targeted drug, [fam-] trastuzumab deruxtecan (DS-8201). That agent actually appears to have a bystander effect where the tumors nearby get killed. They saw efficacy in patients with HER2-low and HER2-positive disease. That is now being tested in a randomized phase III DESTINY trial, so the HER2 ADC and HER2-low disease (IHC 1+ or 2+). No amplification by FISH versus chemotherapy of physician’s choice, this anti-HER2 ADC appears to be highly effective, and its major toxicity has been interstitial lung disease that appears to be able to be caught early and controlled without progression to life-threatening toxicity with the current dose and current monitoring.

There’s also a HER3 ADC. These HER3 ADCs utilize a biosimilar to trastuzumab (Herceptin). The toxin is an exatecan derivative that has metabolized in the cancer cell. The HER3 antibodies are intriguing because they use an antibody to HER3 and the same toxin. They’ve also seen some very good activity in patients who have HER3-expressing breast cancer, which appears to be quite common actually. There are plans for the next generation of trials with that HER3 ADC also.

Are there any other agents in development for the treatment of patients with TNBC?

Small molecules are being tested, both small molecules that target AKT, ipatasertib and pimasertib, as well as a MEK inhibitor, cobimetinib (Cotellic), as well as others. Mostly, I think we are moving towards testing patients who have a defect in the pathway that is being targeted, so for AKT, the PI3K pathway. However, there are some small data that showed that when you combine an AKT inhibitor with paclitaxel and add in a checkpoint inhibitor, atezolizumab (Tecentriq) in this case, you would see responses regardless of whether or not there were alterations in PTEN/PI3K/AKT. That’s quite intriguing and will be studied in the next phase III study with ipatasertib and atezolizumab, as well as paclitaxel.

There’s a number of trials we will be seeing with AKT inhibitors, particularly phase III studies of patients with alterations in the pathway or not and randomizing them to paclitaxel with placebo or the AKT inhibitor. Now the next generation is adding in a checkpoint inhibitor. The same is being done with the MEK inhibitor. Although the trials are earlier, there’s a little bit of interesting data in combination with the checkpoint inhibitor, and that will be pursued further. I think these may enhance the effect of checkpoint inhibitors.

Do you have any final comments on the evolving treatment landscape for TNBC?

Immunotherapy is very exciting. We saw this marked improvement in pCR in KEYNOTE-522 by adding pembrolizumab to standard neoadjuvant chemotherapy for TNBC. The unique aspect of this trial is that it’s powered for pCR as well as EFS in 1200 patients. What they showed was a significant improvement in pCR going up to ranges higher than what we’ve seen with the addition of platinum. That’s actually really encouraging in the 64% to 65% range. The toxicity was quite manageable, so that’s good as well. There’s a suggestion of fewer events in the pembrolizumab-treated arm in the EFS, but it’s way too early to say.

There is also another trial that was presented at ESMO that looked at pembrolizumab versus chemotherapy of physician’s choice. We already had a press release saying it wasn’t superior, which is what it was powered on, but it was equivalent in toxicity; it was less with the checkpoint inhibitor than with chemotherapy, so that is interesting. They looked at PFS in patients who had different combined positive scores (CPS), which is a measure of the PD-L1 expression using a scoring system that is much more positive than the scoring system used for atezolizumab. It’s called PD-L1 IHC 22C3 pharmDx, and it scores several different kinds of cell types, adds them together and divides them by 100, divides them by the number of tumor cells, and then multiples by 100. They said their endpoints were looking at 0 and a CPS of between 1 and 10, but then they looked at the subset who had a CPS of 20, which wasn’t a predetermined endpoint, so it’s exploratory and it was a much smaller number of patients. They saw a big separation in the curves favoring pembrolizumab, so this will be pursued further. I think it’s really intriguing.

There’s also a lot interest in PARP inhibitors, as I mentioned, looking at homologous recombination defect type testing to see whether or not that can help determine the benefit of combining a PARP with immunotherapy, but these are all approaches for the future.

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