Optimizing Perioperative Therapy in Triple-Negative Breast Cancer

The treatment landscape for early-stage triple-negative breast cancer (TNBC) continues to evolve with evidence from ongoing neoadjuvant and adjuvant therapy trials.

A major development was the KEYNOTE-522 trial that established pembrolizumab (Keytruda) plus neoadjuvant chemotherapy as a new standard of care for early TNBC.

“The KEYNOTE-522 trial is a pivotal trial that for the first time demonstrated that adding an anti-PD-1 antibody to the poly-chemotherapy backbone in the neoadjuvant setting significantly improved pathologic complete response rates,” said Iris Zhi, MD, PhD, of NYU Langone Health in New York. The results of KEYNOTE-522 led to the regimen’s FDA approval for high-risk early TNBC.

In May at the American Society of Clinical Oncology (ASCO) meeting, final results from the study at a median follow-up of 7.8 years showed that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab continued to show significantly improved event-free and overall survival rates compared with chemotherapy alone.

However, as with many advances in cancer care, the trial results also left certain questions unanswered, or prompted new ones, about the best way to individualize care for these patients.

Chemotherapy Backbone

“Since KEYNOTE-522 there is a big gap in knowledge, and that gap is the backbone regimen,” said Ahmed Elkhanany, MD, of Baylor College of Medicine in Houston. “Is the backbone regimen used in KEYNOTE-522 the most active regimen, or can we trim some of these agents for patients?”

The chemotherapy regimen in KEYNOTE-522 was paclitaxel plus carboplatin followed by doxorubicin plus cyclophosphamide or epirubicin plus cyclophosphamide.

“That is a lot of chemotherapy, and we have seen consequences in the clinic,” Elkhanany said. “Patients have febrile neutropenia, persistent neuropathy, treatment-related amenorrhea in young patients, and with anthracyclines, cardiac problems and delayed risk for leukemia.”

The phase II, single-arm NeoPACT trial evaluated the use of neoadjuvant pembrolizumab plus only carboplatin and docetaxel in patients with TNBC and showed an encouraging pathologic complete response (pCR) rate and 3-year event-free survival. This prompted the initiation of SWOG’s phase III SCARLET trial, which will randomly assign patients with early TNBC to anthracycline-free, taxane-platinum neoadjuvant chemotherapy with pembrolizumab or to taxane, platinum, and anthracycline neoadjuvant chemotherapy with pembrolizumab.

“Although most of us suspect that this will be a positive trial, particularly in low-volume disease…, until the data read out, we should not drop anthracyclines outside of a clinical trial,” Elkhanany said.

All patients enrolled in SCARLET must be eligible for anthracycline therapy, Zhi pointed out, but additional information is needed for patients with early TNBC who are anthracycline-ineligible.

“If we know a patient can’t tolerate the anthracycline, what is the alternative chemotherapy backbone to give?” Zhi asked. NYU Langone is planning an investigator-initiated clinical trial to attempt to answer this question. The single-arm NeoCARD trial will also evaluate the efficacy of neoadjuvant carboplatin, paclitaxel, and pembrolizumab in anthracycline-ineligible patients.

Adjuvant Immunotherapy

Another unanswered question relates to the need for adjuvant immunotherapy in this patient population. In KEYNOTE-522, patients received up to nine cycles of adjuvant pembrolizumab.

“If we look at the adjuvant immunotherapy data alone, they were not that promising,” Elkhanany said. “There has been some conflict about the need for adjuvant immunotherapy, with data suggesting that immunotherapy works best when there is tumor still inside the body.”

This question will be addressed with the phase III OptimICE-PCR trial, which will evaluate whether observation is noninferior to adjuvant pembrolizumab in patients with early TNBC who achieve pCR after neoadjuvant pembrolizumab.

“A positive trial in this setting will change practice for thousands of patients right away,” Elkhanany said. “That could include patients who are already on immunotherapy who will basically be able to safely stop it.”

Residual Disease

Finally, Zhi said there are also questions remaining about how best to treat those patients who complete the KEYNOTE-522 regimen but do not have pCR. The current standard of care in this setting is based on the CREATE-X trial.

“This trial showed that 6 months of adjuvant capecitabine significantly decreased recurrence and improved survival,” Zhi said. “Now patients receive capecitabine plus immunotherapy in the adjuvant setting, except for those patients with BRCA1/2 mutation who would be eligible for olaparib [Lynparza].”

However, the treatment landscape for these patients is evolving.

The antibody-drug conjugate sacituzumab govitecan (Trodelvy) is approved in the pretreated setting for metastatic TNBC, and an FDA decision is expected later this year for a first-line indication in combination with pembrolizumab.

“Results reported at last year’s ASCO annual meeting showed significantly improved PFS [progression-free survival] with sacituzumab govitecan compared with the standard of care chemotherapy plus pembrolizumab in the frontline setting,” Zhi said. “Now the drug is being studied in the adjuvant setting for patients with residual disease.”

ASCENT-05/OptimICE-RD is comparing adjuvant sacituzumab govitecan plus pembrolizumab against capecitabine plus pembrolizumab in patients with TNBC with residual disease after neoadjuvant therapy and surgery.

“The study is ongoing,” Zhi said, “but I think it will answer the very important question of whether we have better treatment options for patients with residual disease.”