Data further support role for pembrolizumab plus chemotherapy in breast cancer subset
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Pembrolizumab improved response rates regardless of chemotherapy partner among patients with metastatic triple-negative breast cancer, according to KEYNOTE-355 trial results presented at the virtual San Antonio Breast Cancer Symposium.
Based on the overall findings of the trial, the FDA granted pembrolizumab (Keytruda, Merck) plus chemotherapy accelerated approval in November for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 with a combined positive score (CPS) of 10 or higher.
“Pembrolizumab monotherapy has shown durable antitumor activity and a manageable safety profile in patients with metastatic triple-negative breast cancer. After initial efficacy was shown in the phase 1b KEYNOTE-012 trial, the phase 2 KEYNOTE-086 trial showed promising antitumor activity with pembrolizumab alone in patients with untreated PD-L1-positive metastatic triple-negative breast cancer,” Hope S. Rugo, MD, professor of medicine and director of breast oncology and clinical trials education at University of California, San Francisco, said during a presentation.
“In the phase 3 KEYNOTE-119 trial, pembrolizumab monotherapy did not result in a significant survival benefit compared with single-agent chemotherapy in patients with metastatic triple-negative breast cancer in the second- or third-line setting. However, a trend toward improved efficacy with PD-L1 enrichment was observed. In addition, responses to pembrolizumab were more durable compared with chemotherapy,” she added.
In KEYNOTE-355, investigators assessed chemotherapy with or without pembrolizumab among 847 patients with previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer. The researchers randomly assigned patients to pembrolizumab plus nab-paclitaxel (Abraxane, Celgene), paclitaxel or gemcitabine/carboplatin (n = 566), or placebo plus chemotherapy (n = 281).
Treatment continued for up to 35 cycles of pembrolizumab or placebo, or until disease progression or unacceptable toxicity.
The definitive assessment of PFS was presented at ASCO20 Virtual Scientific Symposium.
As Healio previously reported, after median follow-up of 17.5 months in the pembrolizumab group and 15.5 months in the placebo group, the addition of pembrolizumab to chemotherapy significantly improved PFS among patients with a PD-L1 CPS of 10 or higher (median, 9.7 months vs. 5.6 months; HR = 0.65; 95% CI, 0.49-0.86). However, the PFS difference between the two groups did not reach statistical significance among patients with a PD-L1 CPS of 1 or higher (median, 7.6 months vs. 5.6 months; HR = 0.74; 95% CI, 0.61-0.9).
“The HR for PFS favored pembrolizumab plus chemotherapy regardless of chemotherapy choice or CPS population,” Rugo said. “Although subgroup analyses by on-study chemotherapy were prespecified, the trial was not powered to compare efficacy among treatment groups by different chemotherapy regimens.”
During the symposium, Rugo presented findings on key secondary endpoints of objective response rate, disease control rate and duration of response.
Median follow-up was 25.9 months in the pembrolizumab group and 26.3 months in the placebo group.
Results showed the pembrolizumab regimen conferred higher ORRs among patients with a PD-L1 CPS of 10 or higher (53.2% vs. 39.8%) and 1 or higher (45.2% vs. 37.9%), as well as higher disease control rates (CPS 10, 65% vs. 54.4%; CPS 1, 58.6% vs. 53.6%) and longer median duration of response (CPS 10, 19.3 months vs. 7.3 months; CPS 1, 10.1 months vs. 6.5 months).
“Interestingly, pembrolizumab treatment effects increased with PD-L1 enrichment,” Rugo said. “These data further support the role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer.”
Perspective
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Yuan Yuan, MD, PhD
Along with the recent FDA approval of pembrolizumab for PD-L1-positive metastatic triple-negative breast cancer, we now have two randomized phase 3 trials confirming the PFS benefit of immune checkpoint inhibitors, including atezolizumab (Tecentriq, Genentech) and pembrolizumab. It is important to use relevant compendium diagnostics to the therapeutic agent of choice.
For atezolizumab, an SP142 immune cell stain should be used (41% patients in Impassion130 had immune cell staining ≥ 1%). For pembrolizumab, a 22C3 CPS score (combining tumor and immune cell stain) should be used (38% of patients in KEYNOTE-355 had CPS ≥ 10). It is noted that among patients with a CPS of 10 or higher, modest
PFS benefit was seen with atezolizumab. Current FDA approval for pembrolizumab applies only to patients with a CPS of 10 or higher.
There are a few remaining questions for practicing oncologists. First, is there any difference among chemotherapy backbones? KEYNOTE-355 was not powered to address this question. The numerical differences of HR observed in this study may reflect patient selection and tumor biology. The difference of nab-paclitaxel vs. solvent paclitaxel was seen in IMpassion130; in contrast, IMpassion131 remains intriguing, which could be due to tumor heterogeneity, unbalanced treated arms and steroid premedication use.
Second, what is the OS impact? OS data with atezolizumab showed a 7.5-month improvement in the IMpassion130 trial, presented at this year’s European Society for Medical Oncology Virtual Congress. We are eagerly awaiting OS data with pembrolizumab for KEYNOTE-355. For patients who qualify for both pembrolizumab and atezolizumab in the metastatic setting, nab-paclitaxel plus atezolizumab may be preferred due to OS benefit.
Finally, for patients who progressed through immune checkpoint inhibitor-chemotherapy combination therapy, the question is, should the immune checkpoint inhibitor be continued while only changing the chemotherapy backbone? Currently, there are no data available to test the sequencing of immune checkpoint inhibitor combination therapy. Single-agent pembrolizumab efficacy appears to be reduced in heavily pretreated patients, as seen in the KEYNOTE-086 trial. The sequencing issue remains unanswered, and future clinical trials are needed to address these questions.
References:
Adams S, et al. Ann Oncol. 2019; doi:10.1093/annonc/mdy517.
Miles D, et al. Abstract LBA15. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
Schmid P, et al. N Engl J Med. 2018; doi:10.1056/NEJMoa1809615.
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Rugo H, et al. Abstract GS3-01. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 8-11, 2020.
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