Combining Radiation Therapy with Immunotherapy for the Treatment of Metastatic Squamous Cell Carcinoma of the Head and Neck

Summary

Objectives

PRIMARY OBJECTIVE:
I. To compare overall survival (OS) between immunotherapy plus consolidative radiotherapy (CoRT) and immunotherapy alone following non-progression with systemic chemoimmunotherapy.

SECONDARY OBJECTIVES:
I. To compare progression-free survival (PFS) between the two arms.
II. To compare time-to-treatment failure (TTF) between the two arms.
III. To determine the risk of non-hematologic high-grade (3 or higher) toxicity with the addition of CoRT.
IV. To establish the prognostic value of quantitative positron emission tomography (PET) biomarkers at baseline (standardized uptake value maximum [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG]) for overall survival in both arms.
V. To establish the predictive value of (a) structured qualitative read (Hopkins Criteria) and (b) quantitative analysis for assessment of the post-radiotherapy or chemotherapy restaging PET/computed tomography (CT) to evaluate its association with overall survival in both arms.

HEALTH-RELATED QUALITY-OF-LIFE (HRQL) OBJECTIVES:
I. To compare the time-to-definitive-deterioration (TTDD) between the two arms. (PRIMARY)
II. To compare the mean early change in the Functional Assessment of Cancer Therapy – Head & Neck (FACT-HN) trial outcome index (TOI) between the arms, defined as the difference between the cycle 7 time point and randomization. (SECONDARY)
III. To compare the time-to-deterioration (TTD) between the arms (first deterioration). (SECONDARY)
IV. To compare the nadir of the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM) score over the course of study participation between the arms. (EXPLORATORY)
V. To compare quality-adjusted survival between the arms. (EXPLORATORY)

EXPLORATORY OBJECTIVES:
I. To identify differences in patterns-of-failure with respect to local regional and distant recurrences following CoRT versus immunotherapy alone.
II. To evaluate the risk of tracheostomy and/or gastrostomy in patients treated with CoRT versus immunotherapy alone.

OUTLINE:

STEP 1: Patients who have not completed initial systemic therapy prior to enrollment are assigned to Arm T and patients who have completed initial systemic therapy prior to enrollment are assigned to Arm S.

ARM T: Patients receive pembrolizumab intravenously (IV) with carboplatin IV on day 1 of each cycle and paclitaxel IV on day 1 of each cycle or days 1 and 8, or with cisplatin IV on day 1 of each cycle and fluorouracil IV on days 1-4 of each cycle, or with carboplatin IV on day 1 of each cycle and fluorouracil IV on days 1-4 of each cycle on study. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

ARM S: Patients proceed directly to Step II.

STEP II: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive one cycle of pembrolizumab IV with carboplatin IV on day 1 and paclitaxel IV on day 1 or days 1 and 8, or with cisplatin IV on day 1 and fluorouracil IV on days 1-4, or with carboplatin IV on day 1 and fluorouracil IV on days 1-4 on study and then receive pembrolizumab IV on day 1 of each cycle until progression or a total of 2 years with radiation therapy once daily for a total of 30 fractions on study. Patients also undergo CT, PET/CT, and/or magnetic resonance imaging (MRI) during baseline, after cycle 3 of step 1, then every 9 weeks as clinically indicated during the first two years after the initiation of treatment, then every 12 weeks during year 3.

ARM B: Patients receive one cycle of pembrolizumab IV with carboplatin IV on day 1 and paclitaxel IV on day 1 or days 1 and 8, or with cisplatin IV on day 1 and fluorouracil IV on days 1-4, or with carboplatin IV on day 1 and fluorouracil IV on days 1-4 on study and then receive pembrolizumab IV monotherapy on day 1 of each cycle for six cycles. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab IV on day 1 of each cycle on study. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity or a total of 2 years. Patients also undergo CT, PET/CT, and/or MRI during baseline, after cycle 3 of step 1, then every 9 weeks as clinically indicated during the first two years after the initiation of treatment, then every 12 weeks during year 3.

After completion of study treatment, participants are followed up for 3 years.