Highlights
The Phase II TAPISTRY trial demonstrated that atezolizumab achieves an objective response rate (ORR) of 22.3% in patients with solid tumors having a tumor mutational burden (TMB) of ≥16 mutations/megabase (mut/Mb).
When using a lower threshold of ≥13 mut/Mb, the ORR remained consistent at 20.2%, suggesting that moderate antitumor activity is maintained across these high-TMB strata.
The safety profile was consistent with previous atezolizumab studies, with no new safety signals or treatment-related deaths reported, despite a high overall incidence of adverse events in this heavily pre-treated population.
While responses were observed across diverse tumor types, including colorectal, breast, and gastroesophageal cancers, the median progression-free survival (PFS) was relatively short (~2.8 months), highlighting the need for further patient stratification.
Background: The Evolving Role of Tumor Mutational Burden in Precision Oncology
Tumor mutational burden (TMB) has emerged as a critical tissue-agnostic biomarker in the landscape of immuno-oncology. Historically, the therapeutic focus was on specific genomic alterations or programmed death-ligand 1 (PD-L1) expression. However, the realization that a high frequency of somatic mutations leads to an increased neoantigen load—thereby enhancing the visibility of the tumor to the immune system—has shifted the paradigm toward TMB as a predictor of response to immune checkpoint inhibitors (ICIs).
Despite the FDA approval of pembrolizumab for TMB-high (≥10 mut/Mb) tumors based on the KEYNOTE-158 trial, the clinical community has debated the optimal cutoff for defining TMB-high status. Different assays and varying thresholds (ranging from 10 to 20 mut/Mb) have led to inconsistencies in clinical practice. The TAPISTRY trial was designed to address these gaps by evaluating atezolizumab, a monoclonal antibody targeting PD-L1, in patients with TMB-high tumors using specific cutoffs of ≥13 and ≥16 mut/Mb. This multicohort, phase II study aims to refine our understanding of which patients derive the most significant benefit from PD-L1 blockade in the context of high genomic instability.
Study Design and Methodology of the TAPISTRY Trial
TAPISTRY (NCT04589845) is a phase II, open-label, multicenter, multicohort study designed to evaluate the efficacy and safety of atezolizumab in patients with advanced or metastatic solid tumors that exhibit specific genomic alterations or high TMB. The cohort discussed here focused specifically on the TMB-high population.
Patient Population
Eligible patients were PD-L1 inhibitor-naïve and had documented TMB-high status, defined as ≥13 mut/Mb via a validated genomic assay. The study included both adult and pediatric populations. Adults received a fixed dose of 1200 mg of atezolizumab every 21 days, while pediatric patients received 15 mg/kg (up to 1200 mg). The cohort was diverse, reflecting the tissue-agnostic nature of the biomarker.
Endpoints
The primary endpoint was the objective response rate (ORR) as assessed by an independent review committee (IRC) using RECIST v1.1 criteria, specifically for the subgroup with TMB ≥16 mut/Mb. Secondary endpoints included ORR for the TMB ≥13 mut/Mb group, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. The use of an IRC ensures a standardized and unbiased evaluation of radiological responses, which is vital in multicenter trials.
Patient Characteristics and Baseline Demographics
As of the data cutoff on November 9, 2023, 148 patients had received at least one dose of atezolizumab. The median age of the participants was 63 years, indicating a predominantly older adult population, though the trial’s inclusive design allowed for broader insights. This was a heavily pre-treated cohort, with 31.8% of patients having received more than two prior lines of systemic therapy for advanced disease.
In terms of tumor distribution, the most common malignancies represented were colorectal cancer (29.1%), breast cancer (8.8%), and gastroesophageal cancer (8.8%). This distribution is significant because colorectal cancer, particularly the subset with high TMB, often overlaps with microsatellite instability-high (MSI-H) status, although TMB-high can also occur in microsatellite stable (MSS) tumors.
Key Efficacy Findings: Objective Response and Survival Outcomes
The results of the TAPISTRY trial indicate that atezolizumab possesses meaningful, albeit moderate, activity in the TMB-high setting. The median survival follow-up was 9.8 months at the time of analysis.
Objective Response Rates
For the primary analysis group (TMB ≥16 mut/Mb, n=112), the IRC-assessed ORR was 22.3% (95% CI, 15.0-31.2). In the broader TMB ≥13 mut/Mb group (n=129), the ORR was slightly lower at 20.2% (95% CI, 13.6-28.1). These figures suggest that while a higher TMB threshold might slightly enrich for responders, the clinical benefit is present across both defined high-TMB strata.
Duration of Response and Survival
One of the hallmarks of immunotherapy is the potential for durable responses. In this study, the median IRC-assessed DOR was not yet estimable (NE), suggesting that those patients who did respond tended to maintain their response over a significant period. However, the median IRC-assessed PFS was 2.8 months (95% CI, 1.7-5.4) for the ≥16 mut/Mb group and 2.7 months (95% CI, 1.5-4.2) for the ≥13 mut/Mb group. The discrepancy between the ORR and the short median PFS indicates that while a subset of patients achieves significant benefit, a substantial portion of the population experiences early disease progression.
Safety and Tolerability Profile
The safety of atezolizumab in this trial was consistent with its established profile in other indications. Adverse events (AEs) of any cause were reported in 93.2% of the 148 patients. Treatment-related adverse events (TRAEs) occurred in 53.4% of participants.
Severity of Adverse Events
Grade 3 or higher AEs were observed in 40.5% of the total population. Importantly, there were no grade 5 (fatal) treatment-related adverse events, which underscores the relative safety of atezolizumab compared to traditional cytotoxic chemotherapy in late-line settings. The most common toxicities were consistent with immune-mediated mechanisms, such as fatigue, rash, and gastrointestinal disturbances, which are typically manageable with established protocols including corticosteroids or treatment interruptions.
Clinical Interpretation and Expert Commentary
The TAPISTRY trial adds a significant layer of evidence to the tissue-agnostic use of TMB as a biomarker. An ORR of ~22% in a pre-treated, mixed-tumor population is clinically relevant, especially considering the lack of effective options for many of these patients. However, the results also invite a critical comparison with other ICIs.
Comparison with Previous Benchmarks
In the KEYNOTE-158 trial, pembrolizumab showed an ORR of 29% in TMB-high (≥10 mut/Mb) tumors. While the TAPISTRY ORR is slightly lower, direct comparisons are difficult due to differences in patient populations, tumor types, and the specific assays used to determine TMB. The TAPISTRY data suggests that atezolizumab is a viable alternative, though perhaps with varying efficacy across different histology types within the TMB-high umbrella.
The Challenge of the Median PFS
The short median PFS (~2.8 months) remains a challenge. It suggests that TMB alone may not be a perfect predictor of benefit. Factors such as the specific nature of the mutations (e.g., frameshift vs. missense), the presence of co-occurring mutations (like STK11 or KEAP1 which are associated with resistance), and the tumor microenvironment likely play a role in determining whether a high-TMB tumor will respond to PD-L1 inhibition.
Pediatric Considerations
The inclusion of pediatric patients in TAPISTRY is a notable strength. Pediatric tumors generally have lower TMB than adult tumors; therefore, identifying those rare pediatric cases that are TMB-high is essential for providing access to potentially life-saving immunotherapy.
Conclusion
The TAPISTRY Phase II study confirms that atezolizumab provides moderate antitumor activity in patients with a wide variety of solid tumors harboring a TMB of ≥13 or ≥16 mut/Mb. While the response rates are encouraging and the safety profile is manageable, the relatively short median PFS underscores the complexity of using TMB as a sole biomarker. Future research should focus on integrating TMB with other genomic and proteomic markers to better identify the subset of patients likely to achieve long-term survival. For now, atezolizumab represents a valuable option in the precision medicine toolkit for clinicians managing refractory, TMB-high malignancies.
Trial Registration and Funding
Clinical trial number: NCT04589845.
This study was funded by F. Hoffmann-La Roche/Genentech.
References
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