Checkpoint and PARP Inhibition Remain the Focus of Ongoing Research in TNBC

Yuan Yuan, MD, PhD

The field of triple-negative breast cancer (TNBC) is pushing to improve treatment by answering questions regarding biomarkers of response, defining the utility of neoadjuvant approaches, and exploring potential combinations with checkpoint inhibitors and PARP inhibitors, according to Yuan Yuan, MD, PhD.

“In triple-negative breast cancer, we have seen a lot of excitement. We usually say [that these patients] have a very dismal prognosis, but we now see [signals] of hope,” explained Yuan, an associate professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, in a presentation during a 2020 Institutional Perspectives in Cancer webinar on breast cancer.

Checkpoint Inhibitor Approvals Leave Unanswered Questions in the Frontline Space

In March 2019, the FDA approved the combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) for use as frontline treatment for patients with unresectable locally advanced or metastatic PD-L1–positive TNBC.¹ The approval was based on findings from the phase 3 IMpassion130 trial (NCT02425891), which demonstrated a 38% reduction in the risk of disease progression or death with the combination vs placebo plus nab-paclitaxel in this patient population.²

Results from the final overall survival (OS) analysis of the IMpassion130 trial, which were presented during the 2020 European Society for Medical Oncology (ESMO) Virtual Congress, showed that the difference in OS was not statistically significant with the addition of atezolizumab in the intention-to-treat (ITT) patient population; however, a clinically meaningful OS benefit was observed in patients with TNBC that was PD-L1 positive, according to the VENTANA PD-L1 SP142 assay.³ The median OS in this subgroup was 25.4 months with atezolizumab vs 17.9 months with placebo (HR, 0.67; 95% CI, 0.53-0.86).

A similar trial to IMpassion130 was IMpassion131 (NCT03125902). However, the data from the phase 3 IMpassion131 study failed to demonstrate a progressionfree survival (PFS) or OS benefit with frontline atezolizumab plus paclitaxel vs placebo plus paclitaxel in the ITT population or PD-L1–positive population of patients with TNBC.⁴

“What is causing the difference between IMpassion130 and IMpassion131? A lot of discussion is ongoing [to answer that question],” Yuan said.

Pembrolizumab (Keytruda) became the second approved checkpoint inhibitor in TNBC when it received FDA approval on November 13, 2020, for use in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express a PD-L1 combined positive score (CPS) of 10 or higher as determined by an FDA-approved test.⁵

The accelerated approval was based on data from the KEYNOTE-355 trial (NCT02819518), which showed that pembrolizumab plus chemotherapy prolonged PFS compared with placebo plus chemotherapy (9.7 months vs 5.6 months, respectively; HR, 0.65; 95% CI, 0.49-0.86; 1-sided P =.0012) in patients with a PD-L1 CPS of 10 or higher.⁶

Although not deemed statistically significant, the median PFS was 7.6 months with pembrolizumab/chemotherapy vs 5.6 months with chemotherapy alone in patients whose tumors had a PD-L1 CPS of 1 or higher (HR, 0.74; 95% CI, 0.61-0.90; P = .0014).

“[The approval of pembrolizumab] was practice changing, but it also brought a lot of questions,” said Yuan. “Which agent do we pick [between pembrolizumab and atezolizumab]? Which [assay] do we use [to test for PD-L1 status]? Currently, at City of Hope, we only have in-house testing with the [VENTANA] SP142 assay.”

Pembrolizumab also demonstrated proof of concept in the neoadjuvant setting based on findings from the phase 2 I-SPY2 trial (NCT01042379), Yuan said. Then, during the 2019 ESMO Congress, data from the phase 3 KEYNOTE522 trial (NCT03036488) showed that neoadjuvant pembrolizumab plus chemotherapy extended pathologic complete response (pCR) rates by 13.6 percentage points compared with chemotherapy alone for patients with early TNBC (95% CI, 5.4-21.8; P <.001).⁷

Moreover, patients appeared to respond irrespective of PD-L1 status.

Similar findings were observed with atezolizumab in the phase 3 IMpassion031 trial (NCT03197935), in which neoadjuvant atezolizumab plus chemotherapy significantly improved pCR rates compared with placebo/chemotherapy, regardless of PD-L1 status.⁸

“[KEYNOTE-522 and IMpassion031] are teaching us that PD-L1 may not be the perfect biomarker in the early-stage setting. We will need to do a better job of teasing out who exactly responds to checkpoint inhibitors [in the neoadjuvant spaces],” Yuan explained.

A potential drawback of utilizing checkpoint inhibitors in the neoadjuvant space is the risk of long-term toxicity. This may negate the benefit of such agents in the curative setting because patients may be able to obtain pCRs through other treatment modalities with limited toxicity, Yuan added.

In addition, the question of what chemotherapy backbone is optimal to pair with checkpoint inhibitors remains largely unanswered. Data from the phase 3 NeoTRIPaPDL1 trial (NCT02620280), which were presented during the 2020 ESMO Virtual Meeting, showed that atezolizumab plus carboplatin and nab-paclitaxel did not improve pCR rates vs chemotherapy alone but increased the pCR by 10% or more in “immune-rich” groups with high-risk and locally advanced TNBC.⁹ Additionally, the atezolizumab-containing regimen turned PD-L1–negative tumors positive in most immunotherapy-treated patients.

Ongoing trials are under way to parse out some of the remaining questions, including the role of neoadjuvant checkpoint inhibitors. For example, a phase 3 trial (NCT03281954) is ongoing to evaluate neoadjuvant chemotherapy plus atezolizumab or placebo followed by adjuvant atezolizumab or placebo in patients with TNBC.¹⁰ Results from this study could shed light on whether neoadjuvant atezolizumab confers unacceptable toxicity, as well as provide additional data to determine which chemotherapy partner is optimal.

PARP Inhibitors Provide Potential Combination Strategies With Checkpoint Inhibitors

Without cross-trial comparisons, it is difficult to determine which PARP inhibitor is optimal for patients with TNBC. However, a trend appears to show that talazoparib (Talzenna) may yield the most potent efficacy, followed by niraparib (Zejula), rucaparib (Rubraca), olaparib (Lynparza), and veliparib, said Yuan.

Regarding current FDA indications, olaparib was approved by the FDA in January 2018 for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutant, HER2-negative metastatic breast cancer who have previously received chemotherapy.¹¹ In October 2018, the agency approved talazoparib for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.¹²

Notably, some synergistic activity has been demonstrated with the combination of PARP inhibitors and checkpoint inhibitors. For example, findings from the phase 2 TOPACIO trial (NCT02657889) showed efficacy with niraparib plus pembrolizumab, irrespective of BRCA mutation or PD-L1 status.¹³

Antibody-Drug Conjugates Add to the Armamentarium in Later-Line TNBC

Cellular therapies, such as antibody-drug conjugates (ADCs), have also moved into the treatment landscape of TNBC, explained Yuan.

Notably, sacituzumab govitecan-hziy (Trodelvy) was granted accelerated approval by the FDA in April 2020 for the treatment of patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.¹⁴

Other ADCs, such as fam-trastuzumab deruxtecan-nxki (Enhertu), are emerging in this space and will further signal a need for refined treatment selection to determine which patients should receive which therapies, concluded Yuan.

References

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9. Bianchini G, Huang CS, Egle D, et al. Tumour infiltrating lymphocytes (TILs), PD-L1 expression and their dynamics in the NeoTRIPaPDL1 trial. Ann Oncol. 2020;31(suppl 4):S1145-S1146. doi:10.1016/j.annonc.2020.08.2241
10. Clinical Trial of neoadjuvant chemotherapy with atezolizumab or placebo in patients with triple-negative breast cancer followed after surgery by atezolizumab or placebo. ClinicalTrials.gov. Posted September 13, 2017. Updated November 20, 2020. Accessed February 11, 2021. https://clinicaltrials.gov/ct2/show/NCT03281954.
11. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. FDA. Published January 12, 2018. Accessed February 11, 2021. http://bit.ly/2NlpYAc.
12. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. FDA. Published October 16, 2018. Accessed February 11, 2021. http://bit.ly/3aNTruI.
13. Vinayak S, Tolaney SM, Schwartzberg L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019;5(8):1132-1140. doi:10.1001/jamaoncol.2019.1029
14. FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. FDA. Published April 22, 2020. Accessed February 11, 2021. http://bit.ly/3abkqBG.