Pembrolizumab plus chemoradiotherapy shows favorable EFS trend in head/neck cancer
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The addition of pembrolizumab to chemoradiotherapy demonstrated a trend toward longer EFS among patients with locally advanced head and neck squamous cell carcinoma, according to data presented at ESMO Congress.
Although the difference in EFS compared with placebo and chemoradiotherapy (CRT) did not achieve statistical significance, the results of the phase 3 KEYNOTE-412 study provide valuable insights into how to develop immunotherapy in HNSCC, according to Jean-Pascal Machiels, MD, PhD, head of the department of medical oncology at Cliniques Universitaires Saint-Luc in Brussels.
“As observed in recurrent and/or metastatic disease, PD-L1 expression measured by CPS [combined positive score], with the methodology used in this study, may be an informative predictive biomarker,” Machiels told Healio.
Background, methods
Standard therapy for unresected locally advanced HNSCC remains concurrent CRT with high-dose cisplatin, with no progress in systemic treatment in more than 20 years, Machiels said.
“The prognosis remains poor, with less than 50% of patients disease free at 3 years and a 5-year survival rate of only 50%,” he said.
Pembrolizumab (Keytruda, Merck), and anti-PD-1 therapy, has shown sustained, long-term survival benefits and durable responses as first-line treatment for patients with recurrent or metastatic HNSCC, both as monotherapy for patients with a PD-L1 CPS of 1 or greater and in combination with chemotherapy.
“We sought to investigate whether pembrolizumab plus CRT followed by pembrolizumab as maintenance therapy could improve EFS for patients with unresected locally advanced HNSCC compared with placebo plus CRT,” Machiels said.
The study included 804 patients (median age, 59 years; 82% men; 77.4% white) with newly diagnosed, treatment-naive unresected locally advanced HNSCCC and an ECOG performance score of 0 or 1. Researchers randomly assigned patients to 200 mg pembrolizumab or placebo every 3 weeks plus CRT followed by 14 doses of maintenance pembrolizumab or placebo, for a total of 17 doses.
EFS served as the primary endpoint, with OS and safety as secondary endpoints.
Median follow-up was 47.7 months (range, 37-61.4).
Results
Median EFS had not been reached in the pembrolizumab group (95% CI, 44.7 months to not reached) compared with 46.6 months (95% CI, 27.5 to not reached) in the placebo group (HR = 0.83; 95% CI, 0.68-1.03). This did not achieve statistical significance, as the efficacy boundary for significance was one-sided P = 0.0242, Machiels said.
The pembrolizumab group had a numerically higher EFS rate than the placebo group at 24 months (63.2% vs. 56.2%) and 36 months (57.4% vs. 52.1%).
Researchers observed the nonsignificant EFS benefit in all prespecified subgroups except for among patients without tumor PD-L1 expression.
The groups had similar OS (HR = 0.9; 0.71-1.15). Median OS was not reached in either group.
Further analyses revealed that PD-L1 expression may be an informative predictive biomarker to better personalize treatment for these patients. Among patients with a PD-L1 CPS of 20 or higher, post hoc analysis showed 24-month EFS rates of 71.2% with pembrolizumab and CRT vs. 62.6% with placebo and CRT (HR for EFS = 0.73; 95% CI, 0.49-1.06) and 36-month OS rates of 79.1% vs. 73% (HR for OS = 0.67; 95% CI, 0.42-1.04).
Researchers reported no new safety signals with the pembrolizumab-CRT combination.
Next steps
The KEYNOTE-689 trial is exploring pembrolizumab administered prior to surgery and in combination with radiotherapy administered after surgery in patients with resectable HNSCC, Machiels told Healio.
“Locally advanced head and neck cancer remains a challenging disease to treat, and it’s probably time also to individualize treatment in this group of patients,” he said during the presentation.
Perspective
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Kevin Harrington, BSc, MBBS, MRCP, FRCR, FRCP, PhD
The data presented from the KEYNOTE-412 study represent a further important addition to our understanding of how immune checkpoint inhibitors should, or should not, be combined with curative-intent chemoradiotherapy in patients with locally advanced head and neck cancers.
In this study, pembrolizumab given as a lead-in dose, concomitantly with chemoradiotherapy and then adjuvantly for 1 year, failed to deliver a statistically significant improvement in EFS as a primary endpoint when compared with placebo. Even though there was a trend in favor of the pembrolizumab arm in the intention-to-treat and PD-L1-positive (CPS 1) populations, the current study cannot be interpreted as an indication for use of anti-PD-1 therapy in combination with chemoradiotherapy in any patient group.
Indeed, in light of the recent presentations of negative findings from the JAVELIN Head and Neck 100, REACH and PembroRad studies, these data should signal the need for a change in thinking in how to design optimal combination regimens. Focus is now likely to shift to neoadjuvant and true adjuvant therapy approaches.
Perspective
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Michael K. Gibson, MD, PhD
Similar to the previously reported JAVELIN-100 study and the concurrent arm of the study by Clump and colleagues presented at this year’s ASCO Annual Meeting, this randomized, phase 3 trial did not detect a benefit of adding pembrolizumab concurrently to definitive chemoradiation treatment (followed by adjuvant pembrolizumab) for patients with locally advanced HNSCC. Although HPV-related oropharyngeal cancer was excluded, larynx/hypopharynx/oral cavity/p16-negative oropharynx cancers were not.
Machiels and colleagues reported a favorable trend toward better EFS, and a trend toward benefit among patients with a PD-L1 CPS of 1 or higher, but OS was not significant.
Given the improvement provided by sequential pembrolizumab in the Clump trial, perhaps this approach deserves more study.
Reference:
Clump DA, et al. Abstract 6007. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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Machiels, et al. Abstract LBA5. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
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