Komal Jhaveri, MD, discusses the 3 major classes of drugs showing potential in the TNBC pipeline.
Komal Jhaveri, MD
Encouraging findings with checkpoint inhibition, PARP inhibitors, and antibody-drug conjugates are steps forward in changing the outlook for patients with metastatic triple-negative breast cancer (TNBC), according to Komal Jhaveri, MD.
Beyond the promising progression-free survival (PFS) data with atezolizumab (Tecentriq) combined with nab-paclitaxel (Abraxane) seen in the IMpassion130 trial,1 and the 2 FDA-approved PARP inhibitors olaparib (Lynparza) and talazoparib (Talzenna), 2 antibody-drug conjugates are also moving through the pipeline.
The FDA granted a priority review designation to sacituzumab govitecan in July 2018 as a treatment for patients with metastatic TNBC who have received ≥2 prior therapies, based on phase II data demonstrating that the antibody-drug conjugate elicited an objective response rate (ORR) of 34% in patients with heavily pretreated metastatic TNBC.2 However, in January 2019, the FDA issued a complete response letter to Immunomedics, the manufacturer of the drug, regarding its biologics license application, identifying issues related to chemistry, manufacturing, and control matters.
Ladiratuzumab vedotin, a second antibody-drug conjugate, demonstrated encouraging phase I findings in a study presented at the 2018 San Antonio Breast Cancer Symposium. In patients with heavily pretreated TNBC treated with a 2.5-mg/kg dose of ladiratuzumab vedotin, the estimated median progression-free survival (PFS) was 11.6 weeks.3 The estimated 3-, 6-, and 9-month PFS rates were 49%, 24%, and 10%, respectively.
Some of the next steps in the TNBC treatment paradigm, Jhaveri said, include determining better predictive markers of benefit, exploring combinations with PARP inhibitors, and conducting larger trials of antibody-drug conjugates.
In an interview during the 2019 OncLive® State of the Science Summit™ on Breast Cancer Jhaveri, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the 3 major classes of drugs showing potential in the TNBC pipeline.Jhaveri: TNBC, unlike melanoma, lung cancer, or renal cell carcinoma if you will, is certainly lagging behind when it comes to getting approvals for immunotherapy. But finally, we have some exciting data we heard at the 2018 ESMO Congress, which has now been published in the New England Journal of Medicine by Peter Schmid and colleagues from the phase III randomized IMpassion130 trial. This evaluated the role of first-line therapy for patients with metastatic disease who did not have any other treatment, and they either received standard of care nab-paclitaxel or atezolizumab in combination with nab-paclitaxel.
The primary endpoint for this was PFS in both the intent-to-treat (ITT) and the PD-L1—positive subgroups. OS was also planned with hierarchal testing for OS for ITT and the PD-L1–positive groups. What we saw was exciting hazard ratios of 0.8, supporting the role of atezolizumab and [overall] the combination of atezolizumab and nab-paclitaxel in both the ITT and PD-L1–positive subgroups.
While we saw a clinically meaningful improvement in OS in the PD-L1—positive subgroup, statistically significance could not be claimed due to the hierarchal testing for that group. Having said that, a 25-month median OS in the first-line setting is rather unprecedented and not trivial for this difficult and rather aggressive subtype of breast cancer. We are excited about these data. These data are very exciting and the very first step forward for the role of immunotherapy for our patients with metastatic TNBC, but we have ways to go and millions of other things that we need to understand better. While in this trial, we saw that the benefit was more so in the PD-L1—positive group, but PD-L1 positivity itself is not really a very robust [marker], nor is it the only solution to a puzzle. It’s just a piece of the big puzzle of how to harness the immune system and unleash the immune system against tumors.
We really need to do a lot more work to identify better predictive biomarkers of benefit. In the IMpassion130 trial, only 41% of tumors were PD-L1—positive; the duration of response was about 8.5 months and the PFS data was a 2.5% absolute benefit. Longer follow-up will give us better OS data, but we do need to understand what patient population would definitely benefit, and [we need to] expand that patient population so we can extend the benefit that we have with immunotherapy to more patients. 2018 gave us approvals for the PARP inhibitors olaparib and talazoparib. These are based on phase III trials—OlympiAD and EMBRACA—both of which consistently showed a statistically significant improvement in PFS of about 3 months— favoring the PARP inhibitors compared with physician’s choice of chemotherapy. These trials were in platinum-sensitive patients, so they were allowed to have a platinum-based therapy in the metastatic setting but not allowed to progress in that setting to be eligible. Or, if they received a platinum-based therapy in the neoadjuvant nor adjuvant setting, the treatment-free interval had to be at least 12 months.
We do need a head-to-head trial, similar to the TNT trial that evaluated the role of carboplatin and showed doubling of response rates in the germline BRCA-mutant patients compared with docetaxel. What we don’t have currently is a head-to-head trial of a platinum-based therapy with a PARP inhibitor.
Our focus right now has also been to understand resistance mechanisms to PARP inhibitors. One thing that we are trying to understand better is by accumulation of the DNA damage occurring due to PARP inhibition. There might be upregulation of PD-L1 activity and/or activation of the STING pathway, which has led to multiple trials evaluating combinations of PARP inhibitors with immune therapies, specifically checkpoint blockade. We have the MEDIOLA trial looking at durvalumab (Imfinzi) and olaparib, the TOPACIO trial of niraparib (Zejula) and pembrolizumab (Keytruda), and an ongoing trial of avelumab (Bavencio) with talazoparib.
Early data from these trials are suggesting that perhaps there might be an increased durability and potentially improved PFS with the combination. The response rates remain identical to what we have seen with monotherapy. We need more data, more understanding, and better biomarkers to better understand this. Sacituzumab govitecan is [targeted against] TROP-2, which can be expressed in about 80% of TNBCs. We saw some exciting data in a phase II trial of 110 patients who received the antibody-drug conjugate; the payload was SM-38. What we saw in this heavily pretreated population was an ORR of 34%. It is a tough population that received 2 lines of therapy in the metastatic setting already. Nine patients remained progression free at 1 year; four of these 9 patients were progression free at 2 years. This was an encouraging data set that led to the application that they put out for priority review. The phase III ASCENT trial is enrolling 488 patients and randomizing them to receive sacituzumab govitecan to physician’s choice of chemotherapy; the results of that trial are eagerly awaited.
Another antibody-drug conjugate is ladiratuzumab vedotin. That antibody-drug conjugate is against a target called LIV-1, which is also commonly expressed and seen in about 68% of patients with TNBC. We saw an exciting ORR in the range of about 25%, also in a heavily pretreated TNBC population. The payload here, unlike sacituzumab govitecan, which was SM-38, is a microtubule inhibiting agent, monomethyl auristatin E. It is very well tolerated, in a heavily pretreated population, with a very decent ORR in the later-line setting. We eagerly await larger trials of these novel drugs to see if they can improve the treatment landscape for our patients. We are definitely trying to make a dent in the data set we had historically. Historically, we think about a median OS of about 12 months, which is rather tough with this patient population. The encouraging data from the IMpassion130 trial showed us a numerical gain of 10 months. Hitting 25 months in the first-line setting with the combination gives me hope that we are headed in the right path and we will be able to further improve the outcome of these patients.