Efficacy Analysis for Frontline Combination Therapy With Pembrolizumab Indicates Benefit in TNBC, Regardless of Chemotherapy Choice

Hope S. Rugo, MD

Frontline pembrolizumab (Keytruda) plus chemotherapy for advanced triple-negative breast cancer (TNBC) demonstrated efficacy across key patient subgroups, including those with PD-L1 expression by combined positive score (CPS), in subgroup analyses of a randomized phase 3 trial.

“Pembrolizumab and chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS [progression-free survival] versus chemotherapy alone in the first-line treatment of patients with metastatic TNBC with a tumor PD-L1 CPS of 10 or more,” Hope S. Rugo, MD, said in a presentation at the 2020 San Antonio Breast Cancer Symposium.¹ “In subgroup analyses, the improvement in PFS with pembrolizumab plus chemotherapy was observed regardless of chemotherapy partner.”

For the double-blind KEYNOTE-355 trial (NCT02819518), patients in the locally recurrent, inoperable, or metastatic setting who had not received prior chemotherapy and were at least 6 months out following curative-intent treatment (N = 847) were randomized 2:1 to receive either pembrolizumab plus chemotherapy (n = 566) or chemotherapy alone (n = 281) until disease progression, unacceptable toxicity, withdrawal of consent, or patient decision. Stratification factors included the type of on-study chemotherapy, tumor PD-L1 expression at baseline (CPS ≥1 vs <1), and prior treatment with the same class of chemotherapy in the (neo)adjuvant setting. Patients with active central nervous system metastasis, autoimmune disease, or systemic steroid use were not eligible for participation in the study.

The dual primary end points of the trial were PFS and overall survival (OS) in patients with PD-L1–positive tumors (CPS ≥10 and CPS ≥1) and in the intention-to-treat (ITT) population. Secondary end points included objective response rate (ORR), duration of response (DOR), and disease control rate (DCR). Treatment effect in both the PD-L1–positive and ITT populations according to on-study chemotherapy partner was an exploratory end point.

At the American Society of Clinical Oncology 2020 Virtual Scientific Program, PFS results were presented and showed a statistically significant improvement with the addition of pembrolizumab in patients with PD-L1 expression by CPS of 10 or more (HR, 0.65; 95% CI, 0.49-0.86; P = .0012).²

In the current analysis of PFS results, outcomes were presented for each chemotherapy partner as well as key secondary efficacy measures with results consistently favoring pembrolizumab.

Chemotherapy partners included intravenous (IV) nab-paclitaxel (Abraxane) 100 mg/m2 on days 1, 8, and 15 of every 28-day cycle; IV paclitaxel 90 mg/m2 on days 1, 8, and 15 of every 28-day cycle; or gemcitabine 1000 mg/m2 plus carboplatin area under the curve 2 on days 1 and 8 of every 21-day cycle. IV pembrolizumab 200 mg was administered every 3 weeks for up to 35 cycles.

The hazard ratios for PFS favored pembrolizumab plus chemotherapy regardless of the choice of chemotherapy partner or patient population by PD-L1 CPS. Anecdotally, the analysis of pembrolizumab plus paclitaxel versus paclitaxel alone resulted in the greatest PFS benefit in the CPS 10 or greater group (HR, 0.33; 95% CI, 0.14-0.76), the CPS 1 or greater group (HR, 0.46; 95% CI, 0.26-0.82), and the ITT population (HR, 0.57; 95% CI, 0.35-0.93) when compared with the hazard ratios of the same comparisons with other chemotherapy partners. However, Rugo said no conclusions could be drawn that indicate which chemotherapy regimen was favored in combination with pembrolizumab administration.

“Although subgroup analyses by on-study chemotherapy were prespecified, the trial was not powered to compare efficacy across treatment groups by different chemotherapy regimens,” said Rugo, who is a professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

Response rate improvement with pembrolizumab increased with CPS. Patients with a score of 10 or greater derived the most benefit with pembrolizumab with an ORR of 53.2% versus 39.8% with chemotherapy alone. Corresponding ORRs in patients with a CPS of 1 or greater were 45.2% and 37.9%. In the ITT population, the ORR was 41.0% with pembrolizumab versus 35.9% with chemotherapy alone. Regardless of chemotherapy partner, the correlation of CPS with tumor response to pembrolizumab was observed.

Similarly, the difference in DCR between the pembrolizumab and chemotherapy-alone arms increased in step with CPS. In patients with a CPS of 10 or greater, the DCR was 65.0% versus 54.4% with pembrolizumab and chemotherapy alone, respectively. Corresponding DCRs in the CPS of 1 or greater and the ITT populations were 58.6% versus 53.6% and 56.0% versus 51.6%, respectively.

PD-L1 enrichment was also correlated with greater differences in median DOR between the experimental and control arms. The median DOR was 19.3 months with pembrolizumab versus 7.3 months with chemotherapy in the population with a CPS of 10 or more, was 10.1 months versus 6.5 months in those with a CPS of 1 or more, and was 10.1 months versus 6.4 months, respectively, in the ITT population.

Patient baseline characteristics were well balanced between the 2 trial arms. The median age for both groups was 53 years and about 40% of patients had an ECOG performance status of 1. PD-L1 expression by CPS was greater than 1 in roughly three-quarters of patients and greater than 10 in close to 40%. Gemcitabine/carboplatin was the most frequently used chemotherapy use in close to 55% of patients followed by nab-paclitaxel in roughly a third; the rest received paclitaxel. Most patients had no prior experience with the same class of chemotherapy agent chosen for therapy.

Prior data regarding pembrolizumab as monotherapy and in combination with chemotherapy have established the agent’s effect on tumor response in patients with TNBC across various clinical settings, with improved clinical efficacy presenting in patients with higher PD-L1 expression. In the phase 3 KEYNOTE-119 trial (NCT02555657), pembrolizumab as monotherapy induced deeper and more durable responses versus chemotherapy—especially in the PD-L1–enriched population—yet this failed to translate into a survival benefit.³ Data in the early-stage TNBC setting offer rationale for the use of pembrolizumab plus chemotherapy, evidenced first by the phase 1b KEYNOTE-173 trial (NCT02622074), in which the combination showed promise in patients with high-risk disease with a pathologic complete response (pCR) rate of 60%.⁴ Randomized data from the phase 3 KEYNOTE-522 trial (NCT03036488) further supported its use in the early-stage setting with a statistically significant pCR improvement seen with the use of pembrolizumab plus chemotherapy versus chemotherapy alone.⁵

In November, pembrolizumab in combination with chemotherapy was granted accelerated approval by the FDA for use in patients with locally recurrent, unresectable, or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an approved test, based on findings from KEYNOTE-355.⁶

Regarding the availability of OS data, Rugo said these results would likely be ready for presentation next year.

References

1. Rugo HS, Schmid P, Cescon DW, et al. Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract GS3-01.
2. Cortés J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(suppl 15):1000. doi: 10.1200/JCO.2020.38.15_suppl.1000
3. Cortés J, Lipatov O, Im S, et al. KEYNOTE-119: phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2019;30(suppl 5):v859-v860. Abstract LBA21. doi:10.1093/annonc/mdz394
4. Schmid P, Salgado R, Park YH, et al. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol. 2020;31(suppl 5):p569-p581. doi:10.1016/j.annonc.2020.01.072
5. Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549
6. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. FDA. November 13, 2020. Accessed December 10, 2020. https://bit.ly/2VYAT4d