Atezolizumab Plus Chemo Falters in Rapidly Relapsing TNBC

Combining atezolizumab (Tecentriq) with chemotherapy for patients with rapidly relapsing, PD-L1-positive triple-negative breast cancer (TNBC) failed to significantly improve overall survival (OS) compared with chemotherapy alone, the phase III IMpassion132 trial showed.

Median OS was 12.1 months with atezolizumab plus chemotherapy compared with 11.2 months with chemotherapy plus placebo (HR 0.93, 95% CI 0.73-1.20, P=0.59), reported Rebecca A. Dent, MD, MSc, of the National Cancer Center Singapore and Duke-NUS Medical School in Singapore, during a presentation at the European Society for Medical Oncology Breast Cancer Congress in Berlin.

Results from the study were published simultaneously in Annals of Oncology.

“These patients have a dismal prognosis and represent a high clinical unmet need,” Dent said. “Novel therapies and trial designs are urgently required for this treatment-resistant population.”

She explained that rapidly relapsing TNBC “represents one of our most challenging clinical situations,” and pointed out that about half of all patients who develop metastatic TNBC following standard neoadjuvant/adjuvant chemotherapy will relapse within 12 months of completing therapy.

Rapidly relapsing TNBC is a “biologically and clinically distinct entity,” she added. “It’s aggressive, intrinsically resistant to standard therapies currently available, and more common in younger patients with large primary tumors without BRCA alterations. Most importantly, however, is that most trials actually exclude these patients, posing a real challenge for us in clinical practice.”

In the IMpassion132 trial, the researchers enrolled patients with disease relapsing <12 months after last chemotherapy dose or surgery for early TNBC. While patients were initially enrolled irrespective of PD-L1 status, the protocol was amended in August 2019 to restrict enrollment to patients with PD-L1-positive TNBC based on results from the IMpassion130 trial, which demonstrated a benefit with atezolizumab driven by patients with PD-L1-positive tumors.

Those results led to the accelerated approval of atezolizumab in combination with nab-paclitaxel for patients with unresectable, locally advanced or metastatic, PD-L1-positive TNBC. However, in 2021, drug maker Genentech announced the voluntary withdrawal of that accelerated approval, “due to changes in the treatment landscape.”

This study “highlights the importance of recognizing that triple-negative breast cancer is highly heterogeneous, especially in this first-line setting,” Dent said. “We now recognize that PD-L1-positive and PD-L1-negative patients have a very different prognosis.”

“We also know that patients who have de novo metastatic TNBC also have a clearly different prognosis than those patients who have received neoadjuvant therapy and were exposed to a number of agents by the time they reach their first-line status,” she added. “As we are here discussing novel trial designs for early-relapsing TNBC, I really think we need to take this into account.”

Discussant Sara M. Tolaney, MD, MPH, of the Dana-Farber Cancer Institute in Boston, questioned if the negative results from IMpassion132 could have been due to the choice of checkpoint inhibitor.

“We know that atezolizumab is a PD-L1 inhibitor, not a PD-1 inhibitor, and data to date in breast cancer with atezolizumab have been fairly inconsistent,” she said. However, looking at results from the KEYNOTE-355 study — which evaluated the PD-1 inhibitor pembrolizumab (Keytruda) plus chemotherapy in advanced TNBC — there was no benefit seen among the subgroup of patients who had relapsed within 6 to 12 months of completing adjuvant therapy, she noted.

“This makes me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition,” she added.

While IMpassion132 was negative, “I do think it presents a unique opportunity to better understand the biology of these rapidly relapsing tumors and hopefully use this information to develop more novel treatment approaches for this population,” Tolaney said. “That said, I think this is going to become an even more challenging area, because in the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many go on to receive additional systemic treatments in the adjuvant setting. Those patients who recur have highly treatment-refractory disease, making this an area of even more unmet need.”

IMpassion132 included 354 patients (median age 48 years). About 18% of patients in both arms had received prior platinum chemotherapy, while 29% of the atezolizumab arm and 27% of the chemotherapy-only arm received prior capecitabine. More than 90% of patients had metastatic disease, and about two-thirds in both arms had disease that recurred in less than 6 months. Median follow-up for the OS analysis was 9.8 months.

Patients were randomized to atezolizumab 1,200 mg or placebo every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Selected chemotherapy was carboplatin/gemcitabine for 73% of patients and capecitabine for 27% across both arms.

Median progression-free survival was 4.2 months with atezolizumab plus chemotherapy versus 3.6 months with chemotherapy alone (HR 0.84, 95% 0.67-1.06). The overall response rate was 40% in the atezolizumab group versus 28% with chemotherapy alone, with a median duration of response of 6.6 months and 4.1 months in the two arms, respectively.

No new safety signals were reported, and there was no difference between the groups in terms of adverse events of special interest.

Please enable JavaScript to view the

comments powered by Disqus.