IMpassion132 is the only reported randomised phase III study focusing solely on patients with early relapsing triple-negative breast cancer (TNBC), a population with a dismal prognosis and high unmet need. Combining atezolizumab with standard chemotherapy in patients with PD-L1-positive tumours who replased within 12 months after the last chemotherapy or surgery for early TNBC did not significantly improve the poor outcomes observed in the control arm.
A biology-based definition of intrinsic resistance to immunotherapy in advanced TNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials according to Dr Rebecca A. Dent of the National Cancer Center Singapore, Duke-NUS Medical School in Singapore and colleagues who published the findings on 15 May 2024 in the Annals of Oncology.
The authors wrote in the background that among patients who develop metastatic TNBC following (neo)adjuvant anthracycline and/or taxane chemotherapy, approximately half of them experience relapse within 12 months of completing chemotherapy. Early relapsing TNBC is a biologically and clinically distinct entity characterised by aggressive disease that is intrinsically resistant to standard therapies, occurs in younger patients and has a lower prevalence of BRCA alterations, a higher prevalence of Ki-67 ≥50% and greater primary tumour burden, leading to dismal outcomes despite intensive therapy.
At first relapse, PD-(L)1 inhibitors (atezolizumab, pembrolizumab and toripalimab) significantly improve the efficacy of first-line chemotherapy for patients with PD-L1- positive TNBC. However, most recent trials of drugs targeting the PD1/PD-L1 and AKT pathways, excluded patients whose disease relapsed within 12 months of treatment for early TNBC. Moreover, up to one-third of patients in these trials had de novo metastatic disease, which generally has a better prognosis than relapsed TNBC. Consequently, data on prognosis and the effect of newer treatments in patients with rapidly relapsing disease are lacking. Guidelines advise against rechallenge with the same agent within 12 months of primary therapy, and the exclusion of patients with early relapse from clinical trials poses a real challenge in clinical practice.
The IMpassion132 study was designed to evaluate the anti-PD-L1 agent atezolizumab combined with chemotherapy specifically in patients relapsing within 12 months of standard-of-care chemotherapy (anthracycline and taxane required) or surgery for early TNBC. In the article published in the Annals of Oncology, the study team reports the overall survival (OS) results. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) advanced TNBC.
Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was OS, tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety.
Among 354 patients with rapidly relapsing PD-L1-positive advanced TNBC, 68% had a disease-free interval (DFI) of <6 months and 73% received carboplatin/gemcitabine. The hazard ratio (HR) for OS was 0.93 (95% confidence interval [CI] 0.73-1.20, p= 0.59) with median OS of 11.2 months with placebo versus 12.1 months with atezolizumab. mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations; ORRs were 28% with placebo versus 40% with atezolizumab.
IMpassion132 provides the first randomised data on the safety and tolerability of combining atezolizumab with non-taxane regimens in advanced TNBC. Adverse events, predominantly haematological, were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure.
The authors explained that exposure to therapeutic agents may trigger a variety of resistance mechanisms. This inherent biological complexity makes it challenging to select optimal patients for novel therapeutics in adequately powered trials. The only other available data from a prospective randomised study in a similar setting are from the subgroup of 65 patients with PD-L1-positive (defined as combined positive score ≥10 using the 22C3 assay) advanced TNBC and a DFI of 6-12 months treated with chemotherapy with/without pembrolizumab in the KEYNOTE-355 study.
In this small subgroup, the HR for OS was 1.44 (95% CI 0.73-2.82). However, cross-trial comparison between a fully powered IMpassion132 study and an exploratory subgroup analysis of KEYNOTE-355 study has limited value. To date, IMpassion132 represents the largest reported prospective dataset describing clinical outcomes in patients with TNBC relapsing <12 months after completing therapy for early TNBC.
Patients in IMpassion132 had experienced rapid relapse despite receiving multi-agent systemic therapy for early TNBC, which is likely to contribute to clonal evolution. This highlights the importance of ongoing translational research to decipher the heterogeneity of the multi-level ‘omic’ characteristics of these aggressive tumours and identify therapeutic strategies. In the future, patients who meet the clinical criteria of IMpassion132 may be candidates for innovative new agents and/or combination regimens in this poor-prognosis setting.
Recent data from small, non-randomised proof-of-concept studies suggest that modulation of the tumour microenvironment or combination with a more effective chemotherapy-delivering backbone regimen may be required to maximise the impact of immune checkpoint blockade. For example, combining atezolizumab and paclitaxel with bevacizumab in the single-arm phase II ATRACTIB study yielded encouraging activity in predominantly PD-L1-negative advanced TNBC with relapse after >12 months. Results from Arm 7 of the BEGONIA study suggested activity of immune checkpoint blockade combined with the antibody–drug conjugate datopotamab deruxtecan in predominantly PD-L1-negative late-relapsing or de novo advanced TNBC.
In the future, it is expected that more patients with early relapse will already have been exposed to immune checkpoint inhibitors as part of their primary therapy, and alternative strategies are likely to play a more prominent role.
The study was sponsored by F. Hoffmann-La Roche Ltd.
Reference
Dent R, André F, Gonçalves A, et al. IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer. Annals of Oncology; Published online 15 May 2024. DOI: https://doi.org/10.1016/j.annonc.2024.04.001