Atezolizumab Fails to Improve Survival Outcomes After Definitive Local Therapy in High-Risk HNSCC

Patients with high-risk, locally advanced head and neck squamous cell carcinoma (HNSCC) who received atezolizumab (Tecentriq) following completion of multi-modal definitive therapy did not experience a statistically significant improvement in survival outcomes compared with placebo, according to data from the phase 3 IMvoke010 study (NCT03452137) presented during the 2024 AACR Annual Meeting.¹

At the data cutoff of September 17, 2023, the 2-year investigator-assessed event-free survival (EFS) rate in the intent-to-treat population was 67.4% with atezolizumab (n = 203) vs 63.8% with placebo (n = 203). Moreover, the median time to event (TTE) was 59.5 months (95% CI, 46.8-not evaluable [NE]) with atezolizumab and 52.7 months (95% CI, 41.4-NE) with placebo (HR, 0.94; 95% CI, 0.70-1.26; P = .680).

Atezolizumab also produced a 2-year independent review facility-assessed EFS of 66.3% vs 65.9% with placebo. The median TTE was 59.5 months (95% CI, 45.2-NE) vs 52.7 months (95% CI, 43.1-NE) with these respective regimens (HR, 0.98; 95% CI, 0.73-1.32). Further assessment of secondary end points demonstrated 2- and 3-year overall survival (OS) rates of 82.0% and 72.3% with atezolizumab; these rates were 79.2% and 73.6%, respectively, with placebo. The median TTE was NE (95% CI, 59.5-NE) with atezolizumab and NE (95% CI, NE-NE) with placebo (HR, 0.96; 95% CI, 0.68-1.36).

“Overall, these data contribute to the body of evidence regarding the limited activity of checkpoint inhibitors in an unselected patient population with locally advanced HNSCC,” lead study author Deborah J. Wong, MD, PhD, explained in an oral presentation during the meeting. “The role of immunotherapy for patients with locally advanced disease is still to be determined.” Wong is HS associate clinical professor of medicine at the University of California Los Angeles School of Medicine.

The standard treatment approach in high-risk, locally advanced HNSCC is multimodal comprising surgery, chemotherapy, and radiation therapy. However, following definitive local therapy, less than 50% of patients remain disease-free at 2 years and 5-year survival rates range between 40% to 50%.

“Following the completion of the definitive local therapy, the standard of care is for patients to be monitored for local recurrence or the development of distant metastatic disease,” Wong explained during the presentation. “Unfortunately, despite the intensive nature of such therapy, treatment outcomes are quite poor. Therefore, novel treatment options are sorely needed.”

Both chemotherapy and radiotherapy have been shown to influence the tumor microenvironment in HNSCC and may have the potential to upregulate PD-L1 expression. This indicates that patients who received these treatments may experience clinical benefit from immune checkpoint inhibition. Notably, the anti–PD-L1 agent atezolizumab has demonstrated signals of antitumor activity in advanced recurrent metastatic HNSCC.

Based on this evidence, the IMvoke010 study was designed to assess the efficacy and safety of atezolizumab vs placebo in an earlier setting for patients with HNSCC who had not experienced disease progression after completion of multi-modal definitive therapy.

Enrollment Criteria in IMvoke010

The randomized, global, double-blind, placebo-controlled study enrolled patients 18 years of age or older with histologically or cytologically confirmed locally advanced HNSCC and an ECOG performance status of 0 or 1. Patients could have had stage IVA or IVB disease of the oral cavity, larynx, hypopharynx, HPV-negative oropharynx, or stage III HPV-positive oropharynx. Notably, surgical and nonsurgical treatment was permitted after the completion of multi-modal definitive treatment.

One enrolled, patients were stratified according to whether they achieved a complete response (CR), partial response (PR), or stable disease (SD) with prior multimodal definitive treatment, the type of prior multi-modal definitive treatment received, and positive vs negative HPV status. Wong noted that the enrollment of HPV-positive patients in the study was capped at 20%.

The trial recruited patients from 127 sites across 23 countries between April 3, 2018, and February 14, 2020. Patients were randomly assigned 1:1 to receive intravenous placebo or atezolizumab at a fixed dose of 1200 mg on day 1 of each 21-day cycle for 16 cycles or up to 1 year. The primary end point of the trial was investigator-assessed EFS, with key secondary end points including independent review facility-assessed EFS, OS, and safety.

The majority of patients in both arms were over 65 years of age (70.0% in atezolizumab arm; 76.4% in placebo arm) and male (82.8%; 85.7%). Patients were enrolled from Europe and the Middle East (50.2%; 55.7%), Asia (33.0%; 30.0%); North America (8.4%; 6.9%), and the rest of the world (8.4%; 7.4%). In the experimental arm, 17.2% of patients had HPV-positive status compared with 17.7% in the control arm; 44.6% and 44.8% of patients had an ECOG performance status of 1 in these respective arms. Prior tobacco use was reported by most patients (63.5%; 68.0%), followed by current use (20.7%; 18.7%), and no prior use (15.8%; 13.3%). Primary tumor sites were located in the oropharynx (35.0%; 38.4%), oral cavity (26.6%; 28.1%), hypopharynx (22.2%; 15.3%), and larynx (16.3%; 18.2%). Over half of patients had stage IVA disease (59.6%; 54.2%), and PD-L1 tumor area positivity scores were 5% or greater in 75.4% and 79.8% of patients, respectively.

All patients enrolled in the study received treatment with the exception of 1 patient in the atezolizumab arm. The majority of patients across both arms completed treatment (63.9%; 65.5%) and currently remain on the study in follow-up (63.1%; 62.1%). Among the patients in the atezolizumab and placebo arms who withdrew from treatment (36.1%; 34.5%), reasons included progressive disease (19.3%; 23.2%), adverse effects (AEs; 8.9%; 4.4%), patient withdrawal (5.4%; 3.9%), death (1.0%; 2.5%), physician’s decision (1.5%; 0.0%), and deviation from protocol (0.0%; 0.5%). Reasons for study discontinuation included death (31.5%; 32.0%), patient withdrawal (4.4%; 4.9%), loss to follow-up (0.5%; 1.0%), and physician’s decision (0.5%; 0.0%), respectively.

Additional Findings and Safety Data

Regarding the type of prior multi-modal treatment administered, the majority of patients in both arms did not receive primary surgery (61.1%; 62.1%). CRs were achieved in 83.7% of patients in the atezolizumab arm and 84.7% of patients in the placebo arm, respectively, with PRs/SDs experienced by 16.3% and 15.3% of patients, respectively. In both arms, the median duration of treatment was 10.4 months (range, 0-12.0), the median dose intensity was 100 (range, 6-100; 100-100), and the median number of treatment cycles received was 16 (range, 1-16.0).

Additional analyses revealed that investigator-assessed EFS across subgroups was generally consistent with that of the overall population. However, point estimates in some subgroups may suggest a trend towards improved EFS with atezolizumab.

“[These include] the site of the primary tumor being the oral cavity, HPV status, stage at enrollment, and potentially PD-L1 status,” Wong expanded, adding that “However, it should be noted that the subgroup numbers were quite small. In addition, not all these subgroups [aligned with] stratification factors. Therefore, this may result in some imbalances between groups. Ultimately, as the confidence intervals cross 1, these were not statistically significant.”

Safety analysis revealed that atezolizumab was well-tolerated, with no new safety signals. Any-grade AEs were observed in 95.0% and 91.6% of patients in the atezolizumab and placebo arms, respectively. Grade 3/4 AEs occurred in 27.2% vs 21.2% of patients, 9.9% and 5.9% of which were deemed treatment-related. Grade 5 AEs were seen in 1.5% vs 2.5% of patients, 0.5% and 0.0% of which were deemed related to treatment. Serious AEs occurred in 15.8% of patients across both arms; related serious AEs were seen in 3.5% of patients treated with atezolizumab and 0.5% of patients treated with placebo.

In the atezolizumab arm, 51.5% of patients experienced AEs of special interest, 6.9% of which were grade 3/4. These were seen in 35.5% of patients treated with placebo, 2.5% of which were grade 3/4. Systemic corticosteroids were thus required in 5.4% and 2.5% of patients in the atezolizumab and placebo arms, respectively.

Editor’s Note: Dr Wong has a consultancy advisory role with Blueprint Medicines, Bristol-Myers Squibb, Genentech/Roche, Regeneron, and Sanofi/Aventis. She cited receiving grant research support from ARMO Biosciences, Astellas Pharma, AstraZeneca/Medimmune, Bicara Therapeutics, Bristol-Myers Squibb, Checkmate Pharmaceuticals, Elevar Therapeutics, Enzychem Lifesciences, FSTAR, Genentech/Roche, Gilead Sciences, Kura Oncology, Lily, Merck Serono, Merck Sharp & Dohme, Pfizer, Regeneron, and TopAlliance Biosciences Inc.

Reference

Wong DJ, Fayette J, Teixeira M, et al. IMvoke010: A phase III, double-blind randomized trial of atezolizumab (atezo) after definitive local therapy vs placebo in patients (pts) with high-risk locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT009.