Frontline Atezolizumab Plus Sacituzumab Govitecan Elicits Responses in PD-L1+ Advanced TNBC

Peter Schmid, MD, PhD, FRCP

Treatment with the combination of atezolizumab (Tecentriq) plus sacituzumab govitecan-hziy (Trodelvy) led to responses in patients with locally advanced or metastatic triple-negative breast cancer (TNBC) who had a PD-L1 expression of at least 1% on immune cells, according to data from an 18-week interim analysis of the phase 1b/2 MORPHEUS-pan BC trial (NCT03424005).¹

Findings presented at the 2024 ESMO Breast Cancer Congress showed that evaluable patients randomly assigned to receive atezolizumab plus sacituzumab govitecan (n = 30) experienced an investigator-assessed overall response rate (ORR) of 76.7% per RECIST 1.1 criteria, including a complete response (CR) rate of 16.7%, a partial response (PR) rate of 60.0%, a stable disease (SD) rate of 20.0%, and a progressive disease (PD) rate of 3.3%. The clinical benefit rate (CBR) was 83.3%.

In patients randomly assigned to treatment with atezolizumab plus nab-paclitaxel (Abraxane; n = 9), the ORR was 66.7%, with all responders achieving a PR. The SD and PD rates were 33.3% and 0%, respectively, and the CBR was 66.7%.

"If you look at the performance of the small control arm, [atezolizumab plus nab-paclitaxel] performs relatively well [compared with] historic data. [However], all of these patients [in this control arm of MORPHEUS-pan BC] had PRs, and there were no CRs observed,” lead study author Peter Schmid, MD, PhD, FRCP, of the Barts Cancer Institute of Queen Mary University in London, United Kingdom, said in a presentation of the data.

Regarding safety, all patients in both arms experienced at least 1 any-grade adverse effect (AE). The rates of grade 3 and grade 4 AEs in the atezolizumab/sacituzumab govitecan arm were 46.7% and 23.3%, respectively. Those respective rates were 44.4% and 0% for patients treated with atezolizumab/nab-paclitaxel. AEs led to any treatment withdrawal in 1 patient (3.3%) treated on the experimental arm and 1 patient (11.1%) on the control arm; notably, both of these patients withdrew from treated due to treatment-related AEs (TRAEs). The rates of AEs leading to dose modification or interruption were 86.7% for atezolizumab/sacituzumab govitecan and 77.8% for atezolizumab/nab-paclitaxel. No fatal AEs occurred in either arm.

MORPHEUS-pan BC is an open-label, multicenter, randomized, umbrella study evaluating various treatment combinations for patients with metastatic or inoperable, locally advanced breast cancer.²

All patients are required to have measurable disease per RECIST 1.1 criteria, a tumor specimen for biopsy, and an ECOG performance status of 0 or 1. In cohort 1, patients need to have, inoperable, locally advanced or metastatic TNBC without any prior systemic therapy. PD-L1 positivity, defined as an expression of at least 1% on immune cells, is also required for this cohort.¹

Enrolled patients in cohort 1 were randomly assigned in a 3:1 fashion to receive 1200 mg of atezolizumab on day 1 and 10 mg/kg of sacituzumab govitecan on days 1 and 8 of each 21-day cycle; or 840 mg of atezolizumab on days 1 and 15 plus 100 mg/m2 of nab-paclitaxel on days 1, 8, and 15 of each 28-day cycle. Treatment continued until loss of clinical benefit or unacceptable toxicity.

ORR and safety served as the trial’s primary end points. Secondary end points included progression-free survival (PFS), disease control rate, overall survival, and duration of response (DOR). At baseline, tumors were evaluated for TROP-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes to evaluate associations with response.

Among all treated patients in the atezolizumab/sacituzumab govitecan arm (n = 31) and the atezolizumab/nab-paclitaxel arm (n = 11), the majority of patients were under 65 years of age (atezolizumab/sacituzumab govitecan, 83.9%; atezolizumab/nab-paclitaxel 63.6%), were not Hispanic or Latino (87.1%; 100%), were White (64.5%; 63.6%), and underwent prior surgery for cancer (80.6%; 54.5%).

Notably, 77.4% of patients in the atezolizumab/sacituzumab govitecan group received prior radiotherapy compared with 36.4% of patients in the atezolizumab/nab-paclitaxel group. Other prior treatments in the experimental arm include a taxane (35.5%), capecitabine (16.1%), and carboplatin (16.1%). Those respective rates in the control arm were 9.1%, 9.1%, and 0%.

At baseline, 25.8% of patients in the atezolizumab/sacituzumab govitecan arm had 1 metastatic site, 38.7% had 2 metastatic sites, 25.8% had 3 metastatic sites, and 9.7% had at least 4 metastatic sites. Metastatic sites included bone (35.5%), brain (6.5%), breast (6.5%), liver (19.4%), lung (51.6%), lymph node (67.7%), mediastinum (6.5%), and pleural (9.7%).

In the atezolizumab/nab-paclitaxel arm, 36.4%, 45.5%, and 18.2% of patients had 1, 2, and 4 or more metastatic sites at baseline, respectively. Metastatic sites consisted of bone (36.4%), brain (9.1%), breast (18.2%), liver (18.2%), lung (45.5%), lymph node (54.5%), and pleural (9.1%).

Schmid noted that PFS data were immature at the March 9, 2023, data cutoff. At a median follow-up of 10.6 months for the atezolizumab/sacituzumab govitecan group and 11.7 months for the atezolizumab/nab-paclitaxel group, the median PFS was 12.2 months (95% CI, 7.4–not evaluable [NE]) and 5.9 months (95% CI, 4.1-8.7), respectively (HR, 0.27; 95% CI, 0.1-0.7).

Additionally, atezolizumab plus sacituzumab govitecan elicited a median DOR of 14.0 months (95% CI, 8.7-NE) compared with 7.1 months (95% CI, 2.8-NE) for atezolizumab plus nab-paclitaxel (HR, 0.17; 95% CI, 0.0-0.7).

An analysis of baseline biomarkers showed all patients had a positive PD-L1 expression on at least 1% of immune cells by local or central testing using the Ventana PD-L1 assay. Most patients (n = 27/30) had a TROP-2 expression above 0. Additionally, Schmid explained that trend toward higher CD8 T-cell infiltration and stromal TILs was observed in responders vs non-responders.

Additional safety data showed that the rates of serious AEs were 23.3% for atezolizumab/sacituzumab govitecan and 44.4% for atezolizumab/nab-paclitaxel. The rates of immune-related AEs were 80.0% and 55.6%, respectively.

All patients in both arms experienced TRAEs. TRAEs led to dose modification or interruption in 83.3% of patients administered atezolizumab/sacituzumab govitecan and 33.3% of patients given atezolizumab/nab-paclitaxel.

The most common any-grade AEs reported in at least 20% of patients in the atezolizumab/sacituzumab govitecan arm included nausea; neutropenia or decreased neutrophil count; diarrhea; vomiting; alopecia; rash; fatigue; COVID-19; constipation; increased alanine aminotransferase (ALT); anemia; asthenia; headache; increased aspartate amino transferase (AST); and gastroesophageal reflux disease.

Immune-mediated AEs that were reported in at least 10% of patients in either arm consisted of rash, increased ALT, increased AST, maculopapular rash, hypertransaminasemia, folliculitis, dermatitis, acneiform dermatitis, hypothyroidism, and tubulointerstitial nephritis.

“Additional clinical research will have to clarify the potential synergy between immune therapy and targeted cytotoxic treatment—or antibody-drug conjugate therapy—and the potential benefit for patients with breast cancer,” Schmid concluded.

Disclosures: Dr Schmid reported serving in an advisory role for Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, Boehringer Ingelheim, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma; receiving honoraria from Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, Boehringer Ingelheim, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma; receiving research funding from AstraZeneca, Genetech, Roche, Oncogenex, Novartis, Astellas, and Medivation; and receiving medical writing support from F. Hoffmann-La Roche.

References

1. Schmid P, Loi S, de la Cruz-Merino L, et al. Interim analysis (IA) of the atezolizumab (atezo) + sacituzumab govitecan (SG) arm in patients (pts) with triple-negative breast cancer (TNBC) in MORPHEUS-pan BC: A phase Ib/II study of multiple treatment (tx) combinations in pts with locally advanced/metastatic BC (LA/mBC). Presented at: 2024 ESMO Breast Cancer Congress; May 15-17, 2024; Berlin, Germany. Abstract 181O.
2. A study evaluating the efficacy and safety of multiple treatment combinations in patients with metastatic or locally advanced breast cancer (Morpheus-panBC). ClinicalTrials.gov. Updated March 13, 2024. Accessed May 15, 2024. https://clinicaltrials.gov/study/NCT03424005