Targeted Therapies Continue to Shape Future Breast Cancer Paradigm

Kevin Kalinsky, MD, MS

With the identification of numerous molecular abnormalities that can affect treatment and the course of disease in patients with breast cancer, it’s become understood that genetic profiling can define clinical trial eligibility, the presence or absence of aberrations help to drive treatment decisions, and variants can be predictive for response or resistance.

However, research efforts to further evolve precision oncology in breast cancer is anything but slowing down.

“There are multiple genomic alterations in breast cancer for which there are standard-of-care therapies,” said Kevin Kalinsky, MD, MS, director of the Glenn Family Breast Center and associate professor of medicine at Winship Cancer Institute of Emory University. “Germline and somatic testing results have clinical implications for our patients. From a research perspective, we can also think of the fact that we are discovering new targets, [and,] importantly, also trying to identify potential resistance mechanisms. This may help identify and get an understanding of why that is and what we can do to improve responses to particular said therapy.”

Kalinsky hosted the virtual roundtable discussion “Coffee Talk” during the 38th Annual Miami Breast Cancer Conference to help oncologists understand the real-world applications of targeted therapy. He was joined by Jennifer Litton, MD, vice president of clinical research of The University of Texas MD Anderson Cancer Center; Komal Jhaveri, MD, clinical director of early drug development at Memorial Sloan Kettering Cancer Center; and Aditya Bardia, MD, MPH, director of the breast cancer research program at Massachusetts General Hospital and Harvard Medical School.

In the discussion, the breast oncology leaders homed in on the intriguing research targeting PIK3CA, BRCA1/2, AKT1, ERRBB2, ERRB3, and other actionable and/or explorative drivers in breast cancer.

Harnessing the Power of PARP and Immunotherapy

When discussing the integration of PARP inhibitors into the landscape of metastatic triple-negative breast cancer (TNBC), clinical trials of immunotherapy must be examined closely, explained Litton.

The phase 3 KEYNOTE-355 trial, for example, was the basis for the FDA’s November 2020 accelerated approval for pembrolizumab (Keytruda) in combination with chemotherapy for use in patients with PD­-L1–positive, locally recurrent, unresectable, or metastatic TNBC. Along with the combination of Tecentriq (atezolizumab) and nab-paclitaxel (Abraxane) approved in March 2019, which was based on data from the phase 3 IMpassion130 study, there are now 2 immunotherapy options available for patients with TNBC. Litton examined how PARP inhibitors can synergistically work with immunotherapies, as seen in the phase 2 MEDIOLA trial, results of which were presented at the 2019 ESMO Congress.

In MEDIOLA, investigators assigned 34 patients with germline BRCA-mutated, metastatic breast cancer to receive 300 mg of oral olaparib (Lynparza) twice daily for 4 weeks and thereafter a combination of olaparib at 300 mg twice daily and 1.5 g of intravenous durvalumab (Imfinzi) every 4 weeks until disease progression.

Thirty patients were evaluable for efficacy. The median progression-free survival (PFS) was 8.2 months with an overall response rate (ORR) of 63.3% (95% CI, 43.9%-80.1%). The 12-week disease control rate (DCR) was 80%, exceeding the target of 75%. The ORR in patients with TNBC was 58.8% (95% CI, 32.9%-81.6%) and 69.2% (95% CI, 38.6%-90.9%) in those with hormone receptor–positive disease.¹

Therefore, when determining whether to start a patient on a PARP inhibitor or immunotherapy, “Because I often get, ‘Well you have a BRCA-positive patient, and a PD-L1–positive patient, which one do I do?’ I don't think there's an absolute right answer here.”

Litton concluded that considerations of the landscape, and of other available treatments, are needed when making sequencing decisions for this patient population.

Alpelisib Is Active Without CDK4/6 Inhibitors

Jhaveri explored the lessons learned from the SOLAR-1 trial (NCT02437318), along with cohorts A and B of the BYLieve trial (NCT03056755). SOLAR-1 and cohort A compared alpelisib (Piqray) plus fulvestrant (Faslodex) versus placebo/fulvestrant in patients with PIK3CA-positive, hormone receptor–positive/HER2-negative advanced breast cancer. Patients in SOLAR-1 also previously received endocrine therapy. In cohort B of BYLieve, patients were assigned to alpelisib plus letrozole (Femara).

In SOLAR-1, the median PFS was 11.0 months among patients with PIK3CA mutations assigned to the alpelisib combination vs 5.7 months in patients who received placebo plus fulvestrant (HR, 0.65; 95% CI, 0.50-0.85; P <.00065).² In patients who had a prior CDK4/6 inhibitor (n = 20), the median PFS was 5.5 months vs 1.8 months (HR, 0.48; 95% CI, 0.17-1.36) favoring the experimental arm. Here, a total 44.4% of patients were alive without disease progression at 6 months.

In cohort A of BYLieve, 50.4% (95% CI, 41.2%-59.6%) of patients were alive and progression-free at 6 months.³ The median PFS was 7.3 months (95% CI, 5.6-8.3).

In cohort B, alpelisib/letrozole induced a median PFS of 5.7 months (95% CI, 4.5-7.2). A total of 46.1% (95% CI, 36.8%-55.6%), of patients were alive without disease progression at 6 months per local investigator assessment, meeting the primary end point of the study.⁴

“What have [we] learned is not meant for cross-trial comparisons by any means. But, I think we can tell ourselves that there is activity for alpelisib with or without prior CDK4/6 inhibitors,” Jhaveri said. “While this activity was higher in the SOLAR-1 setting, which was predominantly CDK4/6–naïve patients, when we look at real-world data and the data that we have, it is reassuring to see the activity of alpelisib post-CDK4/6 inhibitor.”

Jhaveri concluded that unanswered questions involve being able to improve outcomes with alpha-specific PI3K inhibitors, if there is an optimal sequence with everolimus (Afinitor), and whether there is activity with Akt inhibitors in all-comers following CDK4/6 inhibition. Lastly, activity could be seen with oral selective estrogen receptor modulators combined with PI3K/Akt/mTOR inhibitors, she added.

HER3 Emerges as a Therapeutic Target

HER2 has been a treatment target in breast cancer for years, but Bardia emphasized that investigators are now researching HER3. Unlike other human epidermal growth factor receptors, HER3 has minimal intrinsic kinase activity. Overexpression increases metastatic potential and acts as a major cause of treatment failure in several cancers, including those of the breast, ovaries, and prostate.⁵

“There is emerging interest in targeting other subsets including HER2-low and HER3-positive metastatic breast cancer with novel antibody-drug conjugates [ADCs],” Bardia added.

Bardia said that patritumab deruxtecan (U3-1402), an ADC with a mechanism of action similar to that of fam-trastuzumab deruxtecan-nxki (Enhertu), could be the first agent approved to target HER3 in breast cancer. Patritumab deruxtecan has a high drug-to-antibody ratio and the stable linker is selectively cleaved by lysosomal enzymes upregulated in tumor cells. Bardia added that the agent’s high cell membrane cross-penetration allows for potential payload activity against neighboring tumor cells with antigen heterogeneity.

Patritumab deruxtecan showed promising activity in data presented at the 2019 ESMO Breast Cancer Conference. Forty-two patients with metastatic breast cancer and HER3 expression, were assigned to 1.6 mg/kg to 8.0 mg/kg patritumab deruxtecan in an ongoing phase 1/2 trial (NCT02980341). At a median follow-up of 10.5 months, the ORR was 43% and the DCR rate was 91%.⁶ The median PFS was 8.3 months.

In touching on targeted advances in HER2-positive breast cancer, Bardia pointed to the multiple new therapies in the third-line and beyond setting: trastuzumab deruxtecan, tucatinib (Tukysa) with capecitabine and trastuzumab (Herceptin), neratinib (Nerlynx) with capecitabine, and margetuximab-cmkb (Margenza) plus chemotherapy. Choosing these therapies should be dictated by safety profile, site of metastatic disease, prior therapy, and patient preference, he noted.

Overall, some of these clinical trials “may be changing how we think about treating patients with said alterations in these various pathways,” Kalinsky concluded.

References

1. Domchek S, Postel-Vinay, Im S, et al. Phase II study of olaparib (O) and durvalumab (D) (MEDIOLA): updated results in patients (pts) with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Ann Oncol. 2019;30(suppl_5):v475-v532. doi:10.1093/annonc/mdz253

2. Andre F, Ciruelos E, Rubovsky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi: 10.1056/NEJMoa1813904

3. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2—) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. J Clin Oncol. 2020;38(suppl; abstr 1006). doi:10.1200/JCO.2020.38.15_suppl.1006.

4. Rugo H, Lerebours F, Juric D, et al. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Poster PD2-07. https://bit.ly/3oFqdn9

5. Liu X, Liu S, Lyu H, Riker AI, Zhang Y, Liu B. Development of effective therapeutics targeting HER3 for cancer treatment. Biol Proced Online. 2019;21:5. doi:10.1186/s12575-019-0093-1

6. Yonemori K, Masuda N, Takahasi S, et al. Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results from a phase I/II trial. Ann Oncol. 2019;30(suppl_3):iii47-iii64. doi:10.1093/annonc/mdz100