Nancy Y. Lee, MD, FASTRO is a radiation oncologist who holds the positions of vice president of Department of Radiation Oncology, and service chief, for Head & Neck Radiation Oncology and Proton Therapy at Memorial Sloan Kettering Cancer Center.

Nancy Y. Lee, MD, FASTRO

Adding the PD-L1 monoclonal antibody avelumab (Bavencio) to standard-of-care chemoradiotherapy for unresected, locally advanced squamous cell carcinoma of the head and neck (HNSCC) failed to prolong the primary end point of progression-free survival (PFS). The recently reported findings were from JAVELIN HEAD AND NECK 100 (NCT02952586),1 the first randomized phase 3 clinical trial evaluating the role of an immune checkpoint inhibitor in the definitive treatment of patients with head and neck cancer.

The trial enrolled 697 patients from 22 countries around the world. Patients were randomized to intravenous avelumab vs placebo in addition to standard-of-care treatment with chemoradiation. Avelumab or placebo was delivered in a double-blind fashion starting with a 1- week lead-in prior to chemoradiation. This was followed by delivery every 2 weeks during chemoradiation and concluded with a maintenance phase for up to 12 months. Patients received standard-of-care intensity modulated radiotherapy with 70 Gy in 35 fractions with concurrent cisplatin with 100 mg/m2 every 3 weeks during radiotherapy.

The trial was closed at interim analysis due to futility for the primary end point of progression-free survival (PFS). The stratified HR for PFS was 1.21 favoring the placebo arm (95% CI, 0.93-1.57; one-sided 

 = .92). The treatment effect on overall survival (OS) also favored the placebo arm, with a stratified HR of 1.31 (95% CI, 0.93-1.85; one-sided 

 = .94). Given the improvements in PFS and OS that investigators observed in randomized clinical trials of immune checkpoint inhibitors in patients with metastatic HNSCCs, the results are disappointing.

Avelumab was well tolerated in conjunction with radiotherapy and cisplatin. The most common grade 3 or greater treatment-related toxicities were neutropenia (16%), mucosal inflammation (14%), dysphagia (14%), and anemia (12%). Grade 3 or greater immune-related adverse events occurred in 5% of patients receiving avelumab and most commonly involved thyroid disorders and rash. The overall rate of serious treatment-related adverse events was 36% in the avelumab group and 32% in the placebo group.

An exploratory analysis according to tumor PD-L1 expression revealed a potential improvement in PFS for avelumab in patients with high PD-L1 expression of 25% or greater (HR, 0.59 favoring avelumab; 95% CI, 0.28-1.22). This finding is consistent with other clinical trials of immune checkpoint inhibitors that have shown improved outcomes in patients with higher expression of PD-L12-5 and could help guide future clinical trials in patients with locally advanced disease. In contrast to the potential subgroup effect in patients with high PD-L1 expression, other subgroup analyses including tumor stage, nodal stage, human papillomavirus status, age, and gender all favored the placebo arm.

Although JAVELIN HEAD AND NECK 100 failed to meet its primary objective, the trial can inform future efforts to combine immune checkpoint inhibitors in the treatment of locally advanced HNSCC. The results in patients with high PD-L1 expression suggest that preferentially selecting for these patients could be a strategy for future clinical trials. JAVELIN HEAD AND NECK 100 also raises questions about the optimal sequencing of immune checkpoint inhibitors and radiation therapy.

Adjuvant delivery of an immune checkpoint inhibitor was successful at prolonging PFS and OS in non–small cell lung cancer.

 Future trials could investigate the timing of immune checkpoint inhibitors in conjunction with radiation therapy to help determine the optimal sequencing. Adjuvant delivery of immune checkpoint inhibitors can also allow for patient selection according to treatment response, a strategy that has been successful in esophageal cancers.

 Finally, investigators should further study differences in the effect of PD-1 and PD-L1 monoclonal antibody therapy.

The potential benefit of avelumab in the subgroup of patients with high PD-L1 expression in JAVELIN HEAD AND NECK 100 provides a basis for further investigation and suggests a potential role for immune checkpoint inhibitors for locally advanced HNSCC. The optimal sequencing of immune checkpoint inhibitors with radiation therapy and the groups of patients most likely to benefit remain to be determined. Future clinical trials addressing these questions will help improve the treatment outcomes for patients with locally advanced HNSCC.

1. Lee NY, Ferris RL, Psyrri A, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. 

. 2021;22(4):450-462. doi:10.1016/S1470-2045(20)30737-3du 

2. Ferris RL, Blumenschein Jr G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. 

d. 2016;375(19):1856-1867. doi:10.1056/NEJMoa1602252 

3. Burtness B, Harrington KJ, Greil R, et al; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. 

 2019;394(10212):1915-1928. doi:10.1016/S01406736(19)32591-7 

4. Cohen EEW, Soulières D, Le Tourneau C, et al; KEYNOTE-040 Investigators. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study.

. 2019;393(10167):156-167. doi:10.1016/S0140-6736(18)31999-8

5. Ferris RL, Blumenschein Jr G, Fayette J, et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. 

. 2018;81:45-51. doi:10.1016/j.oraloncology.2018.04.008

6. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. 

. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937

7. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. 

. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697

8. Kelly RJ, Ajani JA, Kuzdzal J, et al; CheckMate 577 Investigators. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. 

. 2021;384(13):1191-1203. doi:10.1056/NEJMoa2032125

Articles

The potential benefit of avelumab in the subgroup of patients with high PD-L1 expression in JAVELIN HEAD AND NECK 100 provides a basis for further investigation and suggests a potential role for immune checkpoint inhibitors for locally advanced HNSCC.

JAVELIN HEAD AND NECK 100 Informs Future Trials in HNSCC

The addition of the PD-L1 monoclonal antibody, avelumab (Bavencio), to standard of care chemoradiotherapy for unresected, locally advanced squamous cell carcinoma of the head and neck (HNSCC) failed to prolong the primary endpoint of progression-free survival in the recently reported Javelin Head and Neck 100 clinical trial (NCT02603432).

Javelin Head and Neck 100 is the first randomized phase 3 clinical trial evaluating the role of an immune checkpoint inhibitor in the definitive management of patients with head and neck cancer. The trial enrolled 697 patients from 22 countries around the world. Patients were randomized to intravenous avelumab vs placebo in addition to standard of care treatment with chemoradiation. Avelumab or placebo was delivered in a double-blind fashion starting with a 1 week lead-in prior to chemoradiation followed by delivery every 2 weeks during chemoradiation and concluding with a maintenance phase for up to 12 months. Patients received standard of care intensity modulated radiotherapy with 70 Gy in 35 fractions with concurrent cisplatin with 100mg/m

The trial was closed at interim analysis due to futility for the primary endpoint of progression-free survival. The stratified hazard ratio (HR) for progression-free survival (PFS) was 1.21 favoring the placebo arm (95% Confidence Interval [CI]l: 0.93-1.57; one-sided 

 =.92). The treatment effect on overall survival (OS) also favored the placebo arm with stratified hazard ratio of 1.31 (95% CI: 0.93 – 1.85; one-sided 

 =.94). The results are disappointing given the improvements in PFS and OS observed in randomized clinical trials of immune checkpoint inhibitors in patients with metastatic HNSCCs.

Avelumab was well tolerated in conjunction with radiotherapy and cisplatin. The most common grade 3 or worse treatment-related toxicities were neutropenia (16%), mucosal inflammation (14%), dysphagia (14%), and anemia (12%). Grade 3 or worse immune-related adverse events occurred in 5% of patients receiving avelumab and most commonly involved thyroid disorders and rash. The overall rate of serious treatment-related adverse events was 36% in the avelumab group and 32% in the placebo group.

An exploratory analysis according to tumor PD-L1 expression revealed a potential improvement in PFS for avelumab in patients with high PD-L1 expression of ≥25% (HR, 0.59 favoring avelumab; 95% CI, 0.28-1.22). This finding is consistent with other clinical trials of immune checkpoint inhibitors that have shown improved outcomes in patients with higher expression of PD-L12-5 and can potentially help guide future clinical trials in patients with locally advanced disease. In contrast to the potential subgroup effect in patients with high PD-L1 expression, other subgroup analyses including tumor stage, nodal stage, Human Papillomavirus status, age, and gender all favored the placebo arm.

Although Javelin Head and Neck 100 failed to meet its primary objective, this trial can inform future efforts to combine immune checkpoint inhibitors in the treatment of locally advanced HNSCC. The results in patients with high expression of PD-L1 suggest preferentially selecting for these patients could be a strategy for future clinical trials. Javelin Head and Neck 100 also raises questions about the optimal sequencing of immune checkpoint inhibitors and radiation therapy. Adjuvant delivery of an immune checkpoint inhibitor was successful at prolonging progression-free survival and overall survival in non-small cell lung cancer.

 Future clinical trials could investigate the timing of immune checkpoint inhibitors in conjunction with radiation therapy to help determine the optimal sequencing. Adjuvant delivery of immune checkpoint inhibitors can also allow for patient selection according to treatment response, a strategy that was successful in esophageal cancers.

 Finally, differences in the effect of PD-1 and PD-L1 monoclonal antibody therapy should be further studied.

The potential benefit of avelumab in the subgroup of patients with high PD-L1 expression in Javelin Head and Neck 100 provides a basis for further investigation and suggests a potential role for immune checkpoint inhibitors for locally advanced HNSCC. The optimal sequencing of immune checkpoint inhibitors with radiation therapy and the groups of patients most likely to benefit remain to be determined. Future clinical trials addressing these questions will help improve the treatment outcomes for patients with locally advanced HNSCC.

1. Lee NY, Ferris RL, Psyrri A, Haddad RI, Tahara M, Bourhis J, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. 

2. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. 

. 2016; 375(19):1856-1867. doi: 10.1056/NEJMoa1602252

3. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. 

4. Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. 

5. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. 

6. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage iii non-small-cell lung cancer. 

. 2017;377(20):1919-1929. doi: 10.1056/NEJMoa1709937

7. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. 

. 2018 ;379(24):2342-2350. doi: 10.1056/NEJMoa1809697

8. Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. 

Avelumab was explored in a clinical trial for the treatment of locally advanced head and neck squamous cell carcinoma, but more research is needed to position the agent and other checkpoint inhibitors in the treatment landscape, experts say.

Nancy Y. Lee, MD, FASTRO | Authors

Articles

JAVELIN HEAD AND NECK 100 Informs Future Trials in HNSCC

Further Research Needed to Support Use of Checkpoint Inhibitors in Locally Advanced HNSCC