Biomarkers of Response Steer Treatment Selection in Breast Cancer

Tiffany Traina, MD

CDK4/6 inhibitors, checkpoint inhibitors, and PARP inhibitors are reshaping the treatment paradigm in breast cancer, explained Tiffany Traina, MD. She added that although CDK4/6 inhibitors have become the preferred frontline approach in combination with endocrine therapy for all patients with advanced hormone receptor (HR)–positive, HER2-negative disease, the biomarkers PD-L1 and BRCA1/2 are still being used to guide eligibility for immunotherapy and PARP inhibition, respectively, in triple-negative breast cancer (TNBC).

“This has been a big year for new data in breast cancer and having an opportunity to sit with colleagues who are experts in this content area to review the data and put it into context for us was helpful. It was really a pleasure to moderate the session, which is a great resource to distill down all this exciting information and figure out how to place it into context for our patients,” Traina said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on breast cancer.

In the interview, Traina, vice chair of oncology care in the Department of Medicine, and section head of the Triple Negative Breast Cancer Clinical Research Program at Memorial Sloan Kettering Cancer Center (MSKCC), discussed the body of evidence supporting the use of CDK4/6 inhibitors in HR-positive, HER2-negative breast cancer, shifting standards of care in HER2-positive disease, as well as biomarkers of response with checkpoint inhibitors and PARP inhibitors in TNBC.

OncLive^®: Komal Jhaveri, MD, FACP, of MSKCC, discussed the treatment landscape in HR-positive, HER2-negative disease and touched on the use of ribociclib (Kisqali) in the MONALEESA-7 trial (NCT02278120). What data do we have to support this approach?

Traina: Dr Jhaveri presented [updated] data from the MONALEESA-7 trial, which was a first-line study of letrozole with or without ribociclib in which ovarian suppression was permitted. We had already seen that CDK4/6 inhibitors have a significant effect on progression-free survival [PFS], with about a 50% improvement in PFS when added to endocrine therapy.

Now, we have data on the secondary end point of overall survival [OS], with a hazard ratio of almost 0.76, translating to almost a 25% improvement in OS. The median OS was upwards of about 58 months with ribociclib vs 41 months with endocrine therapy alone. That was really exciting new data for us to see in the first-line setting with a CDK4/6 inhibitor.

Looking at palbociclib (Ibrance), which was explored in the PALOMA-3 trial (NCT01942135), what was exciting about the results?

PALOMA-3 was a study of another CDK4/6 inhibitor, palbociclib. This was a placebo-controlled trial in the second-line or later setting with an endocrine therapy backbone of fulvestrant [Faslodex] plus or minus palbociclib. In that study, again, we saw about a 50% improvement in PFS [with the addition of the CDK4/6 inhibitor], and the hazard ratio for OS [reflected] about a 20% trend toward improved OS, measuring about 35 months vs 28 months with palbociclib and placebo, respectively. These are consistent and compelling data for adding a CDK4/6 inhibitor [to endocrine therapy]. In practice, rather than this being a second-line or later option, it’s really our preferred option in the first-line setting.

Another trial, MONARCH-3 (NCT02246621), investigated abemaciclib (Verzenio)in this patient population. How did the results from this trial affect the use of CDK4/6 inhibitors as a class?

MONARCH-3 was yet another randomized CDK4/6 inhibitor study, looking at abemaciclib in combination with letrozole in the first-line setting. Consistent with what we’re seeing across the class, the addition of abemaciclib to endocrine therapy significantly improved PFS, with about a doubling from 15 months [with letrozole alone] to 28 months [with the addition of abemaciclib]. As a class, CDK4/6 inhibitors really hold the space as a preferred option in the first-line setting with endocrine therapy.

Shifting to the presentation Shanu Modi, MD, of MSKCC, gave on HER2-positive breast cancer, what study has had the greatest effect on clinical practice in this setting?

A lot of exciting data are coming out for patients with HER2-positive advanced disease. Dr Modi’s presentation was wonderful, and one of the most exciting abstracts [she shared] was DESTINY-Breast03 [NCT03529110]. This was a randomized trial of the antibody-drug conjugate [ADC] fam-trastuzumab deruxtecan-nxki [Enhertu], which was compared with T-DM1 [ado-trastuzumab emtansine (Kadcyla)] in the second- and later-line setting for patients with HER2-positive metastatic breast cancer. In the trial, trastuzumab deruxtecan had a significantly higher response rate of more than 80% compared with T-DM1 around 30%. The median PFS for trastuzumab deruxtecan has not been reached yet vs about 7 months with T-DM1, with a hazard ratio of 0.28 and a P value that had about 28 decimal points. There’s definitely an impressive PFS advantage to trastuzumab deruxtecan. It’s still [too] immature to [comment on] OS data, but we’ll be watching out for those follow-up presentations.

I would also add that having this randomized trial of trastuzumab deruxtecan against standard-of-care therapy is one of the first randomized trials we’ve seen with this ADC. Its efficacy has been incredibly compelling, and it now represents one of our standard-of-care options in the second-line setting. It was also reassuring to see that toxicity was better than what we had seen in some of the earlier phase 1 and phase 1 expansion studies. For example, we saw far less ILD [interstitial lung disease], and no grade 4 or grade 5 episodes of ILD were seen, which is really encouraging.

Joshua Drago, MD, of MSKCC, presented on the treatment landscape of TNBC, where he highlighted data from the KEYNOTE-355 trial (NCT02819518) with pembrolizumab (Keytruda). How did the regimen fare in terms of PFS and OS?

Dr Drago presented largely on immunotherapy in TNBC. The KEYNOTE-355 trial is one to spend some time on. This was a randomized, first-line study of patients with metastatic TNBC who were randomized to treatment of physician’s choice plus or minus pembrolizumab. Treatment of physician’s choice allowed for either paclitaxel, nab-paclitaxel [Abraxane], or a combination of gemcitabine and carboplatin, which are some of our most used agents in the first-line setting.

Encouragingly, the addition of the checkpoint inhibitor seemed to benefit all patients in terms of PFS, but where the data become compelling is when you look at PD-L1 as a biomarker of benefit. Patients who had a PD-L1 CPS [combined positive score] greater than or equal to 10% derived the greatest benefit from the addition of pembrolizumab. As a result, with the FDA approval of pembrolizumab in this setting, there is a companion diagnostic to test for PD-L1 by 22C3. You really want to be thinking about using pembrolizumab if your patient’s tumor shows a CPS of 10% or greater.

Finally, Elaine Walsh, MBBCh BAO, PhD, of MSKCC, spoke about PARP inhibitors in TNBC. How have we seen these agents grow in utility?

Dr Walsh presented on PARP inhibition in the setting of patients with advanced and even early-stage breast cancer. These agents have been transformative targeted therapies for a subset of patients who carry germline BRCA1/2 pathogenic mutations. She spent some time talking about the impact of olaparib [Lynparza] as well as talazoparib [Talzenna], 2 now FDA-approved PARP inhibitors for patients with advanced germline BRCA1/2 mutations.

What was really of interest and hypothesis generating is that there may be an opportunity to scale the benefits of PARP inhibition beyond just germline BRCA mutations. She presented data from a TBCRC study where patients who had somatic BRCA1/2 mutations or germline PALB2 mutations had compelling response rates with single-agent PARP inhibitors. That trial is expanding its recruitment, enriching for patients with somatic BRCA1/2 or germline PALB2 mutations.

We’ve also seen exciting data with olaparib in the adjuvant setting from the OlympiA study [NCT02032823], which is tremendously practice changing when we look at the impact of 1 year of adjuvant olaparib in patients who had high-risk breast cancer, whether they were estrogen receptor positive or triple negative and carried a germline BRCA mutation. There are a lot of exciting opportunities ahead.