ODAC Votes to Wait on Neoadjuvant Pembrolizumab Approval in High-Risk TNBC

In a 10 to 0 vote, the FDA’s Oncology Drug Advisory Committee (ODAC) did not support the approval of pembrolizumab (Keytruda) in combination with chemotherapy as neoadjuvant therapy for high-risk, early-stage triple-negative breast cancer (TNBC). The unanimous vote was to defer regulatory action on the Biologics License Application (BLA).1

The ODAC group determined that the survival findings were immature and required longer follow-up.

The Committee also noted that pCR has not been established as an end point that is reflective of clinical benefit due to uncertainty revolving around its relationship to EFS and overall survival.

“I think we had a very thorough and thoughtful discussion of the issues surrounding this potential additional indication for pembrolizumab.The sponsor’s presentation and many of the public comments accurately portrayed the serious nature of TNBC and the unmet needs in its treatment,” Philip C. Hoffmann, MD, professor of medicine at University of Chicago and the chairperson for ODAC, told Targeted Oncology. “While there is reason to be optimistic that the addition of pembrolizumab to neoadjuvant chemotherapy for TNBC will lead to an improvement in event-free survival and overall survival, the improvement in those end points has not yet been demonstrated. Along with the fact that some of the immune-related adverse events associated with pembrolizumab are serious and chronic, the Committee felt unanimously that more follow-up time and later analyses were needed before this indication could be confidently added.”

The BLA for pembrolizumab under this indication was based on data from the KEYNOTE-522 (NCT03036488) clinical trial.

KEYNOTE-522 is a phase 3 clinical trial that evaluated the benefit of adding the immune checkpoint inhibitor pembrolizumab (Keytruda) to neoadjuvant chemotherapy treatment in patients with early TNBC. The study enrolled 1174 patients who were assessed for the coprimary end points of pathologic complete response (pCR) and event-free survival (EFS).

According to results from KEYNOTE-522 published in the New England Journal of Medicine, the addition of pembrolizumab to chemotherapy achieved a pCR of 64.8% (95% CI, 59.9%-69.5%) compared with chemotherapy alone, which achieved a pCR of 51.2% (95% CI, 44.1%-58.3%). The results were considered to be significantly higher according to the study investigators.

At 18 months, 91.3% (95% CI, 88.8%-93.3%) of patients who received neoadjuvant pembrolizumab were alive without disease progression, local or distant recurrence, and without a second primary tumor compared with 85.3% (95% CI, 80.3%-89.1%) in the chemotherapy alone arm (HR, 0.63; 95% CI, 0.43-0.93).

The addition of pembrolizumab to chemotherapy also appeared tolerable in patients with the incidence of treatment-related adverse events of grade 3 or higher being only 5% higher at 78% than in the chemotherapy-alone arm (73%).2

At the time results were first presented, several experts expressed excitement for the indication in interviews with Targeted Oncology. Peter Schmid, MD, PhD, lead at the Centre for Experimental Cancer Medicine, Barts Cancer Institute previously stated: “For TNBC, there is an established pathway by the FDA and European authorities looking at changes in the differences of pCR rates of disappearance before surgery because there is a plethora of data showing that patients who have a pCR have a better outcome. If we increase the pCR rates in clinical trials, it is very likely to translate into a benefit in terms of reducing recurrences and in terms of overall survival. For that reason, the regulatory authorities have established a pathway of what we call an accelerated approval based on this end point. One can’t predict what is going to happen, but that is 1 way we hope the authorities will look at these data.”

Schmid’s excitement around the KEYNOTE-522 results was shared by Hope S. Rugo, MD, director of Breast Oncology Clinical Trials Investigation at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center who said: “Immunotherapy is very exciting. We saw this marked improvement in pathological complete response rate in KEYNOTE-522 by adding pembrolizumab to standard neoadjuvant chemotherapy in TNBC. The interesting thing about the trial is that it’s powered for pCR as well as EFS and what they showed was a significant improvement in pCR.”

In the study, patients randomized 2:1 to received either the pembrolizumab plus chemotherapy arm or the chemotherapy alone. In pembrolizumab/chemotherapy arm, patients received the immune checkpoint inhibitor every 3 weeks in combination with weekly paclitaxel and carboplatin, given either weekly or every 3 weeks, for 4 cycles. Then, patients received pembrolizumab, cyclophosphamide, and doxorubicin or epirubicin every 3 weeks for 4 cycles before surgery. Following surgery, patients received 9 cycles of pembrolizumab every 3 weeks as adjuvant therapy.

Patients treated in the chemotherapy arm received placebo every 3 weeks in combination with weekly paclitaxel and carboplatin, given either weekly or every 3 weeks, for 4 cycles; followed by placebo, cyclophosphamide, and doxorubicin or epirubicin every 3 weeks for 4 cycles before surgery. Adjuvant therapy placebo was given for 9 cycles, every 3 weeks.

Individuals were eligible to enroll if they had newly diagnosed, locally advanced, non-metastatic TNBC, adequate organ function, and an ECOG performance status of 0 or 1. Patients with an invasive malignancy diagnosed within the last 5 years, active autoimmune disease, HIV, or hepatitis B or C virus were excluded from the trial.

_References:

_{Pembrolizumab Oncologic Drugs Advisory Committee Briefing Document. FDA. February 9, 2021. Accessed February 10, 2021. https://www.fda.gov/media/145654/download}

_{Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. doi:10.1056/NEJMoa1910549}