Frontline treatment with the PD-L1 inhibitor atezolizumab combined with nab-paclitaxel showed a confirmed objective response rate of 66.7% in patients with metastatic triple-negative breast cancer.
Sylvia Adams, MD
Upfront treatment with the PD-L1 inhibitor atezolizumab (MPDL3280A) plus nab-paclitaxel (Abraxane) showed a confirmed objective response rate (ORR) of 66.7% in patients with metastatic triple-negative breast cancer (TNBC), according to data presented at the 2015 San Antonio Breast Cancer Symposium.
In the phase Ib study, atezolizumab plus nab-paclitaxel was explored across several lines of treatment regardless of PD-L1 status for patients with metastatic TNBC. In the second-line setting, the confirmed ORR was 25% and in the third-line and beyond the ORR was 28.6%. Across the full trial, the ORR was 41.7%.
“For the efficacy, we saw a very high response rate, which is extremely exciting and encouraging,” said lead investigator Sylvia Adams, MD, associate professor of Medicine, NYU Perlmutter Cancer Center. “The combination was well-tolerated without additive toxicity. We saw only toxicity that was predictable for the single agents alone.”
In the ongoing study, 32 patients received concurrent treatment with nab-paclitaxel at 125 mg/m2 and atezolizumab at 800 mg. In the initial safety cohort of the study (n = 8), atezolizumab was administered on days 1 and 15 along with nab-paclitaxel on days 1, 8, and 15 in a 28-day cycle. In a serial biopsy cohort, 24 patients received nab-paclitaxel on days 1 and 8 for the first cycle followed by concurrent treatment with both agents using the safety cohort schedule.
In the serial biopsy arm, a pretreatment biopsy was taken ≥7 days before the first cycle. Additional biopsies were obtained between days 10 and 15 during the first cycle then again 4 weeks after the first dose of atezolizumab. Responses were confirmed if seen on two or more sequential scans. The primary endpoint of the study was safety, with key secondary endpoints focused on ORR, duration of response, progression-free survival, and biomarker analyses.
The median age of patients in the study was 55.5 years, and most had an ECOG PS of 0 (19%) or 1 (81%). The number of prior systemic therapies received was 5, although a group of patients were enrolled in the frontline setting (n = 9). Prior to entering the study, 87% of patients had received a taxane.
At the time of the data cutoff, 24 patients with a minimum follow-up of ≥3 months were evaluable for efficacy. Across all groups, when considering unconfirmed responses, the ORR was 70.8%, which included a complete response rate of 4.2%. Additionally, the stable disease rate was 20.8%, for an overall disease control rate of 91.6%. At the time of the analysis, 11 of 17 responses (65%) remained ongoing.
"Patients with TNBC usually have low response rates to conventional chemotherapy and quick progression in the metastatic disease setting,” said Adams. “Therefore, the response rate, and particularly the durability of responses, seen were remarkable. Several patients have now been treated for over one year.”
In the frontline setting, the confirmed/unconfirmed ORR was 88.9% for nab-paclitaxel and atezolizumab. The complete response in the frontline setting was 11.1%. In the second-line setting, the ORR was 75% and in the third-line setting or beyond the ORR was 42.9%, which consisted of all partial responses.
“Observed responses were significantly higher than what is observed with either therapy alone. These responses were at times dramatic in enlarged tumors, including liver metastases,” explained Adams. “As one can see with immunotherapy, there were 'pseudoprogressors', which means by conventional RECIST criteria patients would have come off the trial due to interval development of new metastases, but they were allowed to continue. One of these women had resolution of all lesions later on.”
For the biomarker analysis, PD-L1 expression in archival and fresh tumor specimens were centrally evaluated by immunohistochemistry using the Ventana PD-L1 assay. Levels were examined on both tumor cells and immune cells. Additionally, blood was analyzed for changes in proliferating CD8+ T cells.
In this analysis, activated CD8+ T cells transiently peaked at the end of the first cycle of atezolizumab. Moreover, PD-L1 expression appeared to be primarily restricted to immune cells. Out of those evaluable for efficacy (n = 24), 9 had PD-L1 expression on immunes cells, 7 were negative for PD-L1, and 8 had unknown biomarker status.
In patients with PD-L1—positive TNBC, the ORR was 77.8% and the stable disease rate was 22.2%. In the unknown biomarker arm, the ORR was 75%, which included 1 complete response and 2 patients with progressive disease. In the PD-L1–negative group, the ORR was 57.1% and the stable disease rate was 42.9%.
“You see responses, even in patients without expression of PD-L1 within the tumor, granted that these tumors might be archival tumors and PD-L1 being a dynamic marker, this might not reflect the true PD-L1 status at the time of treatment,” said Adams. “Responses seem to be higher in the PD-L1 enriched patients, but it has been encouraging not to be restricted to that group.”
After a median follow-up of 5.2 months for all 32 patients, grade 3/4 adverse events (AEs) had occurred in 56% of patients, including neutropenia (41%), thrombocytopenia (9%), and anemia (6%). At least one AE of any grade occurred in all patients in the trial.
Overall, there were no treatment-related deaths observed in the study. Five patients discontinued nab-paclitaxel as a result of an AE. Per the protocol, these patients continued single-agent atezolizumab. Treatment discontinuations were related to fatigue (n = 1; grade 2), asthenia (n = 1; grade 2), and peripheral neuropathy (n = 3; grade 1, 2, and 3).
“The first-line confirmed responses were 67%, and this is the population of patients who will now be enrolled in the phase III study, which is randomizing patients to a nab-paclitaxel backbone plus or minus atezolizumab,” said Adams. “This phase III study is ongoing, and is called IMpassion130. This global study will hopefully bring immunotherapy to the market for patients with TNBC.”
In the phase III IMpassion130 trial, patients with previously untreated metastatic TNBC will be randomized to nab-paclitaxel plus placebo or atezolizumab. The primary endpoint of the study is progression-free survival in the full population and in a PD-L1-positive group. Secondary endpoints include overall survival, ORR, and duration of response. The target enrollment goal for the trial is 350 patients (NCT02425891).
Atezolizumab is a humanized IgG1 monoclonal antibody that is directed against PD-L1 to prevent the ligand from binding to PD-1 and B7.1. Inhibition of this signaling pathway prevents antitumor immune suppression, resulting in T-cell priming and restored tumor-specific T-cell immunity.
As a single-agent, atezolizumab demonstrated an ORR of 18% in pretreated patients with PD-L1-positive TNBC. Additionally, in other settings, including non—small cell lung cancer (NSCLC) and bladder cancer, the antibody demonstrated impressive efficacy, leading to several breakthrough therapy designations from the FDA.
Prior trials exploring nab-paclitaxel plus atezolizumab demonstrated high response rates for patients with NSCLC. Nab-paclitaxel offers an appealing option for combination strategies with immunotherapy, since the agent does not require premedication with steroids, which cause immunosuppresion. Additionally, preclinical models have shown synergy between the two agents.
Adams S, Diamond J, Hamilton E, et al. Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract P2-11-06.