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Shorter Reirradiation Intervals for Head and Neck Cancer Are Associated With Severe Long-Term Toxicity
Volume 94 Number 4 2016
250 Synergistic Combination of PD-1 and EGFR Antibodies: A Proposed Phase 1 Clinical Trial Using Nivolumab and Cetuximab B. Bastos and A. Zaharcu; Cleveland Clinic Florida, Weston, FL Purpose/Objective(s): Cetuximab induces head and neck cancer cell death through ADCC mediated by NK cells. NK cells when activated by the Fc exposed region of cetuximab bound to EGFR increase production of IFN-gamma. The high levels of IFN-gamma produced dendritic cell maturation and also increase CD8 T cell expression of PD1. The combination of an EGFR mab with a checkpoint (PD1) inhibitor may be synergistic through an enhancement of CD8 T cell activation and dendritic cell engagement which will increase cancer cytolysis. Based on this preclinical data, we proposed a phase 1 clinical trial exploring the combination of cetuximab plus nivolumab in recurrent head and neck cancer patients. The goal of the trial is to identify the maximal tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary endpoints would be the assessment of response rate, progression-free survival (PFS), and overall survival (OS). Materials/Methods: Patients with recurrent head and neck cancers will be eligible. We recommended a phase 1 clinical trial with a 3+3 dose escalation design as described here: (1) dose Level 1: cetuximab 200 mg/m2 IV loading dose followed by weekly cetuximab 125 mg/m2 IV nivolumab 1.5 mg/kg IV every 14 days; (2) dose Level 2: cetuximab 300 mg/m2 IV loading dose followed by weekly cetuximab 187.5 mg/m2 IV nivolumab 2.25 mg/kg IV every 14 days; and (3) dose Level 3: cetuximab 400 mg/m2 IV loading dose followed by weekly 250 mg/m2 IV nivolumab 3 mg/kg IV every 14 days. Results: Since cetuximab as single agent has a response rate of 10% to 20% as a single agent in metastatic head and neck cancer, we anticipate a response rate of 30% with the proposed combination therapy. Since the agents do not have overlap toxicity, we do not anticipate major toxicities. Conclusion: PD-1 and EGFR Ab therapy may be synergistic, and further exploration in a clinical setting is proposed on this abstract. Author Disclosure: B. Bastos: Advisory Board; Boehringer Ingelheim. A. Zaharcu: None.
251 Shorter Reirradiation Intervals for Head and Neck Cancer Are Associated With Severe Long-Term Toxicity J.Y. Lee, E. Sapir, and A. Eisbruch; University of Michigan, Ann Arbor, MI Purpose/Objective(s): Reirradiation to the head and neck for recurrent disease or a second primary malignancy is increasing in frequency. A retreatment interval cutoff of 6 months is often cited when considering reirradiation, as studies have demonstrated a correlation between retreatment interval and survival. However, treatment-related toxicity can be substantial after reirradiation, and little is known regarding its determinants. We sought to identify factors that correlate with severe longterm toxicity. Materials/Methods: We reviewed treatment plans and outcomes of patients who underwent intensity modulated radiation therapy (IMRT)-based reirradiation to the head and neck at a single institution from 2008 to 2015 with data available for both the initial and reirradiation course. Graded (Common Terminology Criteria for Adverse Events version 4.0) treatmentrelated acute and long-term toxicities were analyzed. Patient-, tumor-, and treatment-related variables including retreatment interval were analyzed as predictors of outcomes such as locoregional control, overall survival, and toxicity. Univariate analysis was performed with 2-tailed t tests, covariates were assessed with multiple regression modeling, and survival was assessed by the Kaplan-Meier method. Results: Seventy-one reirradiation patients were identified with a median retreatment dose of 68 Gy. Reirradiation followed resection in 27 patients (38%), and concurrent chemotherapy was delivered to 42 patients (59%). After a median follow-up of 26 months, 21 (30%) were alive and free of
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disease. For all patients, median overall survival was 22 months and median locoregional control was 31 months. Of the 62 of 71 patients that survived longer than 3 months after reirradiation, 16 patients (26%) experienced severe long-term toxicity ( grade 3), with 12 (75%) suffering PEG tubeedependent dysphagia. The median treatment interval in patients who experienced severe toxicity after reirradiation was 20 months (9-167) compared to 53 months (8-304) in patients who did not (PZ.017). On multivariable analysis, only retreatment interval was significant in predicting severe toxicity. Neither concurrent chemotherapy nor surgery prior to reirradiation was associated with severe long-term toxicity. Using the median retreatment interval at which patients experienced severe longterm toxicity (20 months) as the threshold, median survival was 8 months versus 27 months, favoring longer intervals (PZ.04). Conclusion: In a cohort treated with modern IMRT-based reirradiation to the head and neck, rates of severe long-term toxicity was 26%. To our knowledge, this is the first report showing that shorter retreatment intervals are significantly associated with severe long-term toxicities. The increase in severe toxicity should also be considered in addition to poor survival in patients with short reirradiation intervals. Author Disclosure: J.Y. Lee: None. E. Sapir: None. A. Eisbruch: None.
252 Patterns of Failure in Human Papillomavirus (HPV)-Positive Versus HPV-Negative Oropharyngeal Cancer E. Dave,1 U. Ozbek,1 V. Gupta,2 E. Genden,1 B. Miles,1 M. Teng,1 E. Demicco,1 M. Posner,1 K. Misiukiewicz,1 and R.L. Bakst1; 1 Icahn School of Medicine at Mount Sinai, New York, NY, 2 Roswell Park Cancer Institute, Buffalo, NY Purpose/Objective(s): Human papillomavirus positivity in oropharyngeal squamous cell carcinomas (OSCC) generally confers a more favorable prognosis. However, a limited number of patients still develop recurrent and distant disease posttreatment. We sought to better understand failure patterns and survival in HPV-positive (HP+) versus HPV-negative (HP-) patients using data from a single institution’s experiences with OSCC. Materials/Methods: We identified all OSCC patients in our head and neck database of 546 patients who had developed local and/or distant failures, and retrospectively analyzed their treatment, survival, and failure patterns with regards to their HPV status. Thirty-three such patients were identified and analyzed. The HPV status of all patients was determined either by p16 immunostaining or polymerase chain reaction. When available, the HPV genotype was specified for a given patient. All patients were treated with intensity modulated radiation therapy (IMRT) with/without chemotherapy, or IMRT with/without chemotherapy adjuvantly with surgery. Primary endpoints included locoregional failure, distant failure, sites of distant failure, and overall survival (OS) since time of failure. The Kaplan-Meier method was used to calculate survival among the patients. Results: The mean age of our patients was 58.8 years. Thirty (91%) were male, and 3 (9%) were female. Within this group, 20 (61%) patients were HPV+ and 13 (39%) HPV-. HPV genotypes were available for 12 patients: 10 HPV16, 1 HPV33, and 1 HPV35. Primary sites included 15 base of tongue (45.5%), 13 tonsils (39.3%), and 5 oropharynx nonspecified site (15.1%). Median follow-up time since local or distant failure for all patients was 16.2 months. Median OS following local failure was not significantly different between the 2 cohorts (17 months for HPV+ vs 14 months for HPV-, PZ.23). However, HPV+ patients who failed distantly lived significantly longer than HPV- patients who failed distantly (median 42 months vs 11 months, PZ.004). Two-year OS after distant metastasis was 65% for HPV+ patients versus 0% for HPV- patients. Notably, HPV+ patients were more likely to develop distant metastases to sites other than the lung and bones (Table 1). Conclusion: Following distant recurrences, HPV positivity indicates a much more favorable prognosis with the potential for long-term survival. By contrast, for patients with OSCC who fail locally, prognosis may not be driven by HPV status. Lastly, in HPV+ patients who are undergoing
250 Synergistic Combination of PD-1 and EGFR Antibodies: A Proposed Phase 1 Clinical Trial Using Nivolumab and Cetuximab B. Bastos and A. Zaharcu; Cleveland Clinic Florida, Weston, FL Purpose/Objective(s): Cetuximab induces head and neck cancer cell death through ADCC mediated by NK cells. NK cells when activated by the Fc exposed region of cetuximab bound to EGFR increase production of IFN-gamma. The high levels of IFN-gamma produced dendritic cell maturation and also increase CD8 T cell expression of PD1. The combination of an EGFR mab with a checkpoint (PD1) inhibitor may be synergistic through an enhancement of CD8 T cell activation and dendritic cell engagement which will increase cancer cytolysis. Based on this preclinical data, we proposed a phase 1 clinical trial exploring the combination of cetuximab plus nivolumab in recurrent head and neck cancer patients. The goal of the trial is to identify the maximal tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary endpoints would be the assessment of response rate, progression-free survival (PFS), and overall survival (OS). Materials/Methods: Patients with recurrent head and neck cancers will be eligible. We recommended a phase 1 clinical trial with a 3+3 dose escalation design as described here: (1) dose Level 1: cetuximab 200 mg/m2 IV loading dose followed by weekly cetuximab 125 mg/m2 IV nivolumab 1.5 mg/kg IV every 14 days; (2) dose Level 2: cetuximab 300 mg/m2 IV loading dose followed by weekly cetuximab 187.5 mg/m2 IV nivolumab 2.25 mg/kg IV every 14 days; and (3) dose Level 3: cetuximab 400 mg/m2 IV loading dose followed by weekly 250 mg/m2 IV nivolumab 3 mg/kg IV every 14 days. Results: Since cetuximab as single agent has a response rate of 10% to 20% as a single agent in metastatic head and neck cancer, we anticipate a response rate of 30% with the proposed combination therapy. Since the agents do not have overlap toxicity, we do not anticipate major toxicities. Conclusion: PD-1 and EGFR Ab therapy may be synergistic, and further exploration in a clinical setting is proposed on this abstract. Author Disclosure: B. Bastos: Advisory Board; Boehringer Ingelheim. A. Zaharcu: None.
251 Shorter Reirradiation Intervals for Head and Neck Cancer Are Associated With Severe Long-Term Toxicity J.Y. Lee, E. Sapir, and A. Eisbruch; University of Michigan, Ann Arbor, MI Purpose/Objective(s): Reirradiation to the head and neck for recurrent disease or a second primary malignancy is increasing in frequency. A retreatment interval cutoff of 6 months is often cited when considering reirradiation, as studies have demonstrated a correlation between retreatment interval and survival. However, treatment-related toxicity can be substantial after reirradiation, and little is known regarding its determinants. We sought to identify factors that correlate with severe longterm toxicity. Materials/Methods: We reviewed treatment plans and outcomes of patients who underwent intensity modulated radiation therapy (IMRT)-based reirradiation to the head and neck at a single institution from 2008 to 2015 with data available for both the initial and reirradiation course. Graded (Common Terminology Criteria for Adverse Events version 4.0) treatmentrelated acute and long-term toxicities were analyzed. Patient-, tumor-, and treatment-related variables including retreatment interval were analyzed as predictors of outcomes such as locoregional control, overall survival, and toxicity. Univariate analysis was performed with 2-tailed t tests, covariates were assessed with multiple regression modeling, and survival was assessed by the Kaplan-Meier method. Results: Seventy-one reirradiation patients were identified with a median retreatment dose of 68 Gy. Reirradiation followed resection in 27 patients (38%), and concurrent chemotherapy was delivered to 42 patients (59%). After a median follow-up of 26 months, 21 (30%) were alive and free of
Posters
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disease. For all patients, median overall survival was 22 months and median locoregional control was 31 months. Of the 62 of 71 patients that survived longer than 3 months after reirradiation, 16 patients (26%) experienced severe long-term toxicity ( grade 3), with 12 (75%) suffering PEG tubeedependent dysphagia. The median treatment interval in patients who experienced severe toxicity after reirradiation was 20 months (9-167) compared to 53 months (8-304) in patients who did not (PZ.017). On multivariable analysis, only retreatment interval was significant in predicting severe toxicity. Neither concurrent chemotherapy nor surgery prior to reirradiation was associated with severe long-term toxicity. Using the median retreatment interval at which patients experienced severe longterm toxicity (20 months) as the threshold, median survival was 8 months versus 27 months, favoring longer intervals (PZ.04). Conclusion: In a cohort treated with modern IMRT-based reirradiation to the head and neck, rates of severe long-term toxicity was 26%. To our knowledge, this is the first report showing that shorter retreatment intervals are significantly associated with severe long-term toxicities. The increase in severe toxicity should also be considered in addition to poor survival in patients with short reirradiation intervals. Author Disclosure: J.Y. Lee: None. E. Sapir: None. A. Eisbruch: None.
252 Patterns of Failure in Human Papillomavirus (HPV)-Positive Versus HPV-Negative Oropharyngeal Cancer E. Dave,1 U. Ozbek,1 V. Gupta,2 E. Genden,1 B. Miles,1 M. Teng,1 E. Demicco,1 M. Posner,1 K. Misiukiewicz,1 and R.L. Bakst1; 1 Icahn School of Medicine at Mount Sinai, New York, NY, 2 Roswell Park Cancer Institute, Buffalo, NY Purpose/Objective(s): Human papillomavirus positivity in oropharyngeal squamous cell carcinomas (OSCC) generally confers a more favorable prognosis. However, a limited number of patients still develop recurrent and distant disease posttreatment. We sought to better understand failure patterns and survival in HPV-positive (HP+) versus HPV-negative (HP-) patients using data from a single institution’s experiences with OSCC. Materials/Methods: We identified all OSCC patients in our head and neck database of 546 patients who had developed local and/or distant failures, and retrospectively analyzed their treatment, survival, and failure patterns with regards to their HPV status. Thirty-three such patients were identified and analyzed. The HPV status of all patients was determined either by p16 immunostaining or polymerase chain reaction. When available, the HPV genotype was specified for a given patient. All patients were treated with intensity modulated radiation therapy (IMRT) with/without chemotherapy, or IMRT with/without chemotherapy adjuvantly with surgery. Primary endpoints included locoregional failure, distant failure, sites of distant failure, and overall survival (OS) since time of failure. The Kaplan-Meier method was used to calculate survival among the patients. Results: The mean age of our patients was 58.8 years. Thirty (91%) were male, and 3 (9%) were female. Within this group, 20 (61%) patients were HPV+ and 13 (39%) HPV-. HPV genotypes were available for 12 patients: 10 HPV16, 1 HPV33, and 1 HPV35. Primary sites included 15 base of tongue (45.5%), 13 tonsils (39.3%), and 5 oropharynx nonspecified site (15.1%). Median follow-up time since local or distant failure for all patients was 16.2 months. Median OS following local failure was not significantly different between the 2 cohorts (17 months for HPV+ vs 14 months for HPV-, PZ.23). However, HPV+ patients who failed distantly lived significantly longer than HPV- patients who failed distantly (median 42 months vs 11 months, PZ.004). Two-year OS after distant metastasis was 65% for HPV+ patients versus 0% for HPV- patients. Notably, HPV+ patients were more likely to develop distant metastases to sites other than the lung and bones (Table 1). Conclusion: Following distant recurrences, HPV positivity indicates a much more favorable prognosis with the potential for long-term survival. By contrast, for patients with OSCC who fail locally, prognosis may not be driven by HPV status. Lastly, in HPV+ patients who are undergoing