Biomarkers Allow for Tailoring TNBC Treatments

Kevin Kalinsky, MD, MS

Several factors aid treatment selection for patients with newly diagnosed metastatic triple-negative breast cancer (TNBC), with upfront PD-L1 and BRCA testing being the most critical biomarkers to examine, according to Kevin Kalinsky, MD, MS.

“Newer agents are now available for patients with metastatic TNBC, and we have to figure out how to best sequence these agents,” said Kalinsky, in a presentation at the 39th Annual Miami Breast Cancer Conference®.¹ “It is critical to do PD-L1 testing. If positive, I would propose they’re appropriate [candidates] to receive chemotherapy plus checkpoint inhibition.”

“There are also other indications for giving immunotherapy here, such as tumor mutation burden or MSI [microsatellite instability]-high, where you can use single-agent immunotherapy,” added Kalinsky, who is the director of the Glenn Family Breast Center and Breast Medical Oncology at Winship Cancer Institute in Atlanta, Georgia. “[PARP inhibitors are] additional agents [available] for patients with BRCA mutations, especially for those who have PD-L1–negative disease.”

Frontline Immunotherapy

Initial results from the phase 3 IMpassion130 trial (NCT02425891) earned the combination of the PD-L1 inhibitor atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) an accelerated approval as a treatment for patients with unresectable locally advanced or metastatic PD-L1–positive TNBC.² However, contradictory findings from the phase 3 IMpassion131 (NCT03125902) subsequently prompted the drug's developer, Roche, to voluntarily withdraw this indication in August 2021.³

In the final analysis from IMpassion130,⁴ the combination elicited a median overall survival (OS) of 25.4 months compared with 17.9 months for placebo and nab-paclitaxel (HR, 0.67; 95% CI, 0.53-0.86). The 3-year OS rates were 36% vs 22%, respectively. In data from the IMpassion131 trial,⁵ the median OS for patients with PD-L1–positive TNBC was 22.1 months with atezolizumab plus paclitaxel vs 28.3 months with placebo and paclitaxel (HR, 1.11; 95% CI, 0.76-1.64).

“Patients who received paclitaxel alone in IMpassion131 did quite well; what I would consider relatively well,” Kalinsky said. “There was a difference in the control arm between these studies [and] some differences in the PD-L1 testing. In IMpassion130, approximately 40% of PD-L1 determination was based on the primary tissue. Where you do the biopsy is also notable. If it is in the liver, PD-L1–positivity is much lower, for instance.”

In November 2020, the PD-1 inhibitor pembrolizumab (Keytruda) gained accelerated approval in combination with chemotherapy as a treatment for patients with locally recurrent unresectable or metastatic PD-L1–positive TNBC, based on findings from the phase 3 KEYNOTE-355 (NCT02819518).⁶ This was converted to a regular approval in July 2021.⁷ Contrary to the IMpassion130 and 131 studies, the chemotherapy administered in the KEYNOTE-355 study was variable, with options being nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin.

In updated data from KEYNOTE-355 presented in 2021,⁸ the median OS with pembrolizumab plus chemotherapy in patients with PD-L1–positive TNBC (combined positive score [CPS] ≥ 10) was 23.0 months compared with 16.1 months for chemotherapy and placebo (HR, 0.73; 95% CI, 0.55-0.95). The 2-year OS rates were 48.2% and 34.0%, respectively.

Outside of the chemotherapy used in each study, there were also a few differences in the patient characteristics between the KEYNOTE-355 study and the IMpassion130 and 131 studies. In the KEYNOTE-355 study, Kalinsky pointed out, patients had received neoadjuvant/adjuvant therapy at least 6 months before entering the study. For the IMpassion130 and 131 studies, this was at least 12 months. Additionally, PD-L1 was assessed in the KEYNOTE-355 study using CPS, with various cutoffs compared with testing methodologies used in the IMpassion trials.

PARP Inhibition

If immunotherapy is not indicated and a germline BRCA mutation is present, PARP inhibition offers a viable option for patients, Kalinsky said. There are currently 2 FDA-approved PARP inhibitors for patients with germline BRCA-mutated, HER2-negative metastatic breast cancer. The first, olaparib (Lynparza), was approved based on phase 3 data from the OlympiAD study (NCT02000622)⁹ and the second, talazoparib (Talzenna), was approved based on findings from the phase 3 EMBRACA trial (NCT01945775).¹⁰

In the OlympiAD study,¹¹ the median progression-free survival (PFS) with olaparib was 7.0 months vs 4.2 months with chemotherapy (HR, 0.58; 95% CI, 0.43-0.80; P < .001). In data from the EMBRACA study,¹² the median PFS for patients in the talazoparib arm was 8.6 months compared with 5.6 months for patients treated with chemotherapy (HR, 0.54; 95% CI, 0.41-0.71; P < .001).

At this point, single-agent PARP inhibition remains the standard of care in this population, although several studies have explored the combination of a PARP inhibitor with other agents, specifically immunotherapy or chemotherapy. “There is a preclinical rationale for putting these 2 agents together,” Kalinsky said.

The phase 3 BROCADE 3 study (NCT02163694) also assessed the PARP inhibitor veliparib in combinatio=n with carboplatin and paclitaxel for patients with BRCA-mutated advanced breast cancer; however, a statistically significant advantage was not observed for the triplet compared with chemotherapy alone.¹³ The median PFS in the veliparib arm was 14.5 months compared with 12.6 months for chemotherapy alone (HR, 0.71; 95% CI, 0.57-0.88; P = .0016).

In addition to this combination, PARP inhibitors have been combined with checkpoint therapies; however, these combinations did not improve response rates, Kalinsky said. The MEDIOLA study (NCT02734004) explored olaparib plus the PD-L1 inhibitor durvalumab (Imfinzi) and the TOPACIO study ((NCT02657889) examined the PARP inhibitor niraparib (Zejula) plus pembrolizumab.

“For PARP inhibition plus immunotherapy, it might not be just about response but also the durability of response. We’ll need to wait to see what those long-term extensions of the curves look like,” Kalinsky said.

Second Line and Beyond

For patients who are both PD-L1–positive and BRCA-positive, Kalinsky recommended starting with a combination of immunotherapy and chemotherapy and then utilizing PARP inhibition in the second-line setting. If one biomarker is negative, this limits options to either PARP inhibition or chemoimmunotherapy. If both are negative, a taxane or platinum chemotherapy is the preferred frontline therapy, he said.

Beyond these therapies, in the second-line or beyond, the Trop-2–directed antibody-drug conjugate (ADC) sacituzumab govitecan-hziy (Trodelvy) is the ideal choice, he said. Sacituzumab govitecan received full FDA approval in April 2021 as a treatment for patients with unresectable locally advanced or metastatic TNBC following 2 or more prior systemic therapies, based on findings from the phase 3 ASCENT trial (NCT02574455).¹⁴

In data from the ASCENT trial,15 sacituzumab govitecan elicited a median PFS of 5.6 months compared with 1.7 months for treatment of physician’s choice (HR, 0.41; 95% CI, 0.32-0.52;
P < .0001). The median OS was 12.1 months with sacituzumab govitecan compared with 6.7 months for the control arm (HR, 0.48; 95% CI, 0.38-0.59; P < .0001).

Other ADCs are also beginning to emerge as potential treatments for patients with TNBC, Kalinsky said. Data from the phase 1 TROPION-PanTumor01 study (NCT03401385) demonstrated early promise for the Trop-2–targeted ADC datopotamab deruxtecan in patients with TNBC.16 The objective response rate in this study was 34% (n = 15/44). Daiichi Sankyo and AstraZeneca, the companies codeveloping the agent, are beginning to plan a phase 3 registration trial for the agent.17

In addition to these agents, the HER2-targeted ADC fam-trastuzumab deruxtecan-nxki (Enhertu) has shown efficacy in patients with HER2-low metastatic breast cancer, making it a potential candidate in the future for patients with TNBC. This agent significantly improved PFS and OS compared with physicians’ choice of therapy for patients with HER2-low metastatic or unresectable breast cancer, regardless of hormone receptor status in the phase 3 DESTINY-Breast04 study (NCT03734029).18 Results from this trial have not yet been released but are anticipated at a future medical meeting.

References

1. Kalinsky K. Sequencing therapy for mTNBC: immunotherapy, ADC, and PARP inhibitors. Presented at: 39th Annual Miami Breast Cancer Conference®. March 3-6, 2022; Miami Beach, FL.
2. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA. Updated March 18, 2019. Accessed March 5, 2022. bit.ly/3vHvv8n
3. Roche provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer. News release. August 27, 2021. Accessed March 5, 2022. bit.ly/3zvwism
4. Iwata H, Emens L, Adams S, et al. IMpassion130: final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Ann Oncol. 2020;31(suppl 6):S1261-S1262. doi:10.1016/j.annonc.2020.10.069
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13. Diéras V, Han HS, Kaufman B, et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(10):1269-1282. doi:10.1016/S1470-2045(20)30447-2
14. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. Updated April 8, 2021. Accessed March 5, 2022. bit.ly/3sMeYgn
15. Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485
16. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan (Dato-DXd) in advanced/metastatic HER2 negative breast cancer: triple negative breast cancer results from the phase 1 TROPION-PanTumor01 study. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-05. Accessed March 5, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/2164
17. Datopotamab deruxtecan continues to show promising durable response and disease control in patients with metastatic triple negative breast cancer. News release. Daiichi Sankyo; December 7, 2021. Accessed March 5, 2022. bit.ly/35PpD28
18. Enhertu significantly improved both progression-free and overall survival in DESTINY-Breast04 trial in patients with HER2 low metastatic breast cancer. News release. Daiichi Sankyo; February 21, 2022. Accessed March 5, 2022. bit.ly/3JHGFhd