Earlier in the year, Javier Cortes, MD, PhD, presented progression-free survival results from the phase 3 KEYNOTE-355 clinical trial, which showed the importance of the addition of taxanes to a platinum-based regimen in the triple-negative breast cancer space.
In November, the FDA granted accelerated approval to pembrolizumab (Keytruda) in combination with chemotherapy as treatment for patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors have demonstrated PD-L1 expression with a combined positive score (CPS) of 10 or greater.1
In conjunction with the designation, the PD-L1 IHC 22C3 pharmDx was also approved as a companion diagnostic to aid in identifying patients with locally recurrent unresectable or metastatic TNBC who are likely to derive benefit from pembrolizumab plus chemotherapy.
The approval was based on results of f the phase 3 KEYNOTE-355 trial (NCT02819518), which examined chemotherapy plus either the PD-1 inhibitor or matched placebo. Earlier in the year, Javier Cortes, MD, PhD, presented progression-free survival (PFS) results from the trial at the American Society of Clinical Oncology 2020 Virtual Scientific Program.2
“Pembrolizumab in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS as compared with chemotherapy alone for a first-line treatment of patients with metastatic TNBC with a PD-L1 CPS of 10 or higher,” said Cortes, the head of breast cancer and gynecological cancers at Hospital Universitario Ramón y Cajal in Madrid, Spain, during a presentation of the data. “A trend toward improved efficacy with PD-L1 enrichment was observed,” he noted.
The initial feasibility of pembrolizumab monotherapy in TNBC was shown in the phase 1b KEYNOTE-012 trial (NCT01848834)3 and was later supported by results from the phase 2 KEYNOTE-086 trial (NCT02447003), which demonstrated a trend toward favorable efficacy in patients with PD-L1 expression.4
Although pembrolizumab monotherapy failed to establish greater survival versus chemotherapy in TNBC, there are multiple clinical trials to support its use in combination with chemotherapy as neoadjuvant treatment; these trials provide a rationale for exploring the combination in metastatic stages of the disease.
“The immunomodulatory properties of chemotherapy suggest that combining pembrolizumab with chemotherapy might enhance antitumor activity,” said Cortes, who is also a clinical investigator in the breast cancer research program at Vall d’Hebron Institute of Oncology in Barcelona, Spain. “Several clinical studies in patients with breast cancer show that combination regimens with pembrolizumab plus chemotherapy as neoadjuvant treatment offer promising antitumor activity.
These include the phase 1b KEYNOTE-173 (NCT02622074), which demonstrated a promising safety profile as well as antitumor responses in patients with early-stage TNBC. Higher levels of both PD-L1 as well as stromal tumor–infiltrating lymphocytes were correlated with higher pathologic complete response (pCR) rates.5
In another cohort of patients with earlystage breast cancer who were treated as part of the adaptively randomized I-SPY 2 trial (NCT01042379), including those with hormone receptor–positive and triple-negative disease, pCR rates were more than double with pembrolizumab and chemotherapy versus chemotherapy alone as neoadjuvant treatment. As a result, the investigators concluded that the success of the combination in phase 3 trials is highly likely.6
In the phase 3 KEYNOTE-522 trial (NCT03036488), patients with previously untreated stage II or III TNBC received neoadjuvant chemotherapy with or without pembrolizumab, revealing a significantly higher pCR rate with PD-1 inhibition.7
This approval marks the second for a PD-1/L1 agent in the treatment of this tumor type. In March 2019, atezolizumab (Tecentriq) became the first immunotherapy to be approved to treat patients with PD-L1–positive TNBC, based on results of the phase 3 IMpassion130 trial (NCT02425891).8
At the European Society for Medical Oncology Virtual Congress 2020, final overall survival (OS) data were reported for the trial and showed a clinical meaningful OS benefit with atezolizumab plus nab-paclitaxel (Abraxane) versus placebo plus nab-paclitaxel (HR, 0.67; 95% CI, 0.53-0.86). Additional follow-up showed that the combination remained safe and tolerable in these patients.9
Patients who were treated as part of the KEYNOTE-355 trial were those with treatment-naïve, recurrent inoperable or metastatic TNBC who did not have active central nervous system or autoimmune disease. Investigators analyzed PFS, which accounted for 1 of the trial’s primary end points, using a hierarchal strategy, in as much as PFS was to be determined in patients with a CPS of 10 or greater. They followed by analyzing PFS in those with a CPS of 1 or greater and, finally, in the intention-to-treat (ITT) population. Patient baseline characteristics were balanced between the 2 arms.2
In patients with a CPS of 10 or greater, the median PFS was 9.7 months versus 5.6 months (HR, 0.65; 95% CI, 0.49-0.86; P = .0012). The benefit of the combination was consistent across patient subgroups, including those stratified by ECOG performance status, geographic region, chemotherapy regimen, and prior therapy.
In patients with a CPS of at least 1, a prespecified statistical criterion indicated that differences in PFS were not significant, with corresponding medians of 7.6 months and 5.6 months (HR, 0.74; 95% CI, 0.61-0.90; P = .0014). Similarly, investigators observed no statistically significant improvements in the ITT population (HR, 0.82; 95% CI, 0.69-0.97.
Immune-mediated adverse events (imAEs) were more prominent in the pembrolizumab arm (25.6%) versus the chemotherapy-alone arm (6.0%). Hypothyroidism (15.5% with pembrolizumab vs 3.2% with placebo), hyperthyroidism (4.8% vs 1.1%), pneumonitis (2.5% vs 0%), colitis (1.8% vs 0.4%), and severe skin reaction (1.8% vs 0.4%) were the most common all-grade imAEs. No grade 3 or greater imAEs were observed with placebo versus 5.2% with pembrolizumab.
“The inclusion of taxanes and a known platinum-based regimen permits assessment of the clinical benefit of pembrolizumab in combination with several routinely used chemotherapy partners,” Cortes said. “These findings suggest overall [benefit with the] addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic TNBC. OS follow-up is ongoing.”
1. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. FDA. November 13, 2020. Accessed November 19, 2020. https://bit.ly/32VvoqP
2. Cortes 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. Nanda R, Chow LQM, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460-2467. doi:10.1200/JCO.2015.64.8931
4. Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30(3):397-404. doi:10.1093/annonc/mdy517
5. 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(5):569-581. doi:10.1016/j. annonc.2020.01.072
6. Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6(5):676-684. doi:10.1001/ jamaoncol.2019.6650