Consensuses, controversies, and future directions in treatment deintensification for human papillomavirus-associated oropharyngeal cancer.

The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long-term morbidities with chemoradiation and the favorable prognosis of HPV-positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head-and-neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de-escalation. National database studies estimate that up to one third of patients receive nonstandard de-escalated treatments, which have subspecialty-specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV-positive OPC de-escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de-escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy-based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de-escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real-time surveillance.

A phase 2 open-label study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1): Final long-term analysis of groups 1, 2, and 3, and primary analysis of fixed-dose treatment group 6.

BACKGROUND: In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic cutaneous squamous cell carcinoma (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC). OBJECTIVES: To report final analysis of weight-based cemiplimab in mCSCC and laCSCC (groups 1 and 2), fixed-dose cemiplimab in mCSCC (group 3), and primary analysis of fixed-dose cemiplimab in mCSCC/laCSCC (group 6). METHODS: Patients received cemiplimab (3 mg/kg intravenously every 2 weeks [groups 1 and 2]) or cemiplimab (350 mg intravenously [groups 3 and 6]) every 3 weeks. The primary end point was objective response rate (ORR). Duration of response (DOR) and progression-free survival (PFS) are presented per protocol, according to post-hoc sensitivity analyses that only include the period of protocol-mandated imaging assessments. RESULTS: At 42.5 months, ORR for groups 1-3 (n = 193) was 47.2%, estimated 12-month DOR was 88.3%, and median PFS was 26.0 months. At 8.7 months, ORR for group 6 (n = 165 patients) was 44.8%; median DOR and median PFS were not reached. Serious treatment-emergent adverse event rates (grade ≥3) were groups 1-3: 31.1% and group 6: 34.5%. LIMITATIONS: Nonrandomized study, nonsurvival primary end point. CONCLUSION: EMPOWER-CSCC-1 provides the largest prospective data on long-term efficacy and safety for anti-programmed cell death-1 therapy in advanced CSCC.

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.

BACKGROUND: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. FINDINGS: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). INTERPRETATION: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.

Any day, split halfway: Flexibility in scheduling high-dose cisplatin-A large retrospective review from a high-volume cancer center.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m2 × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m2 × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.

PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma.

BACKGROUND: No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma. METHODS: We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review. RESULTS: In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event. CONCLUSIONS: Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).

Outcomes and toxicities of definitive radiotherapy and reirradiation using 3-dimensional conformal or intensity-modulated (pencil beam) proton therapy for patients with nasal cavity and paranasal sinus malignancies.

BACKGROUND: Proton therapy (PT) improves outcomes in patients with nasal cavity (NC) and paranasal sinus (PNS) cancers. Herein, the authors have reported to their knowledge the largest series to date using intensity-modulated proton therapy (IMPT) in the treatment of these patients. METHODS: Between 2013 and 2018, a total of 86 consecutive patients (68 of whom were radiation-naive and 18 of whom were reirradiated) received PT to median doses of 70 grays and 67 grays relative biological effectiveness, respectively. Approximately 53% received IMPT. RESULTS: The median follow-up was 23.4 months (range, 1.7-69.3 months) for all patients and 28.1 months (range, 2.3-69.3 months) for surviving patients. The 2-year local control (LC), distant control, disease-free survival, and overall survival rates were 83%, 84%, 74%, and 81%, respectively, for radiation-naive patients and 77%, 80%, 54%, and 66%, respectively for reirradiated patients. Among radiation-naive patients, when compared with 3-dimensional conformal proton technique, IMPT significantly improved LC (91% vs 72%; P < .01) and independently predicted LC (hazard ratio, 0.14; P = .01). Sixteen radiation-naive patients (24%) experienced acute grade 3 toxicities; 4 (6%) experienced late grade 3 toxicities (osteoradionecrosis, vision loss, soft-tissue necrosis, and soft tissue fibrosis) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 5.0]). Slightly inferior LC was noted for patients undergoing reirradiation with higher complications: 11% experienced late grade 3 toxicities (facial pain and brain necrosis). Patients treated with reirradiation had more grade 1 to 2 radionecrosis than radiation-naive patients (brain: 33% vs 7% and osteoradionecrosis: 17% vs 3%). CONCLUSIONS: PT achieved remarkable LC for patients with nasal cavity and paranasal sinus cancers with lower grade 3 toxicities relative to historical reports. IMPT has the potential to improve the therapeutic ratio in these malignancies and is worthy of further investigation.

The 3 Bs of cancer care amid the COVID-19 pandemic crisis: "Be safe, be smart, be kind"-A multidisciplinary approach increasing the use of radiation and embracing telemedicine for head and neck cancer.

Because of the national emergency triggered by the coronavirus disease 2019 (COVID-19) pandemic, government-mandated public health directives have drastically changed not only social norms but also the practice of oncologic medicine. Timely head and neck cancer (HNC) treatment must be prioritized, even during emergencies. Because severe acute respiratory syndrome coronavirus 2 predominantly resides in the sinonasal/oral/oropharyngeal tracts, nonessential mucosal procedures are restricted, and HNCs are being triaged toward nonsurgical treatments when cures are comparable. Consequently, radiation utilization will likely increase during this pandemic. Even in radiation oncology, standard in-person and endoscopic evaluations are being restrained to limit exposure risks and preserve personal protective equipment for other frontline workers. The authors have implemented telemedicine and multidisciplinary conferences to continue to offer standard-of-care HNC treatments during this uniquely challenging time. Because of the lack of feasibility data on telemedicine for HNC, they report their early experience at a high-volume cancer center at the domestic epicenter of the COVID-19 crisis.

Phase 2 study of vascular endothelial growth factor trap for the treatment of metastatic thyroid cancer.

BACKGROUND: Several multitargeted tyrosine kinase inhibitors (TKIs) have demonstrated activity in patients with thyroid cancer that is refractory to radioactive iodine (RAI). The antitumor effect is attributed at least in part to the ability of these TKIs to inhibit angiogenesis in these vascular tumors. Vascular endothelial growth factor (VEGF) Trap (VT) is a recombinantly produced fusion protein consisting solely of human sequences for VEGF receptors 1 and 2 extracellular domains and human immunoglobulin 1. Evaluating VT in patients with thyroid cancer is reasonable considering the activity observed with TKIs targeting VEGF. METHODS: The current study was a single-institution, phase 2, Simon 2-stage design (21 to >41 patients) study based on the objective response rate and/or 6-month progression-free survival as the primary endpoints. Eligible patients were required to have progressive, RAI-refractory and/or [18 F]fludeoxyglucose-avid, recurrent and/or metastatic, nonmedullary, nonanaplastic thyroid cancer; disease that was measurable using Response Evaluation Criteria In Solid Tumors (RECIST) criteria; and adequate organ and bone marrow function. VT at a dose of 4 mg/kg intravenously was administered every 14 days. RESULTS: A total of 40 patients were included in the analysis. Of these patients, 24 had papillary thyroid cancer, 2 had follicular thyroid cancer, and 11 had Hurthle cell thyroid cancer. The final 3 tumors were classified as poorly differentiated. There were no complete and/or partial responses noted; 34 patients achieved stable disease and 6 patients experienced disease progression as their best response. Of the 34 patients with stable disease, 16 remained on the study for >6 months and 6 patients remained on the study for >12 months. The median duration on treatment was 4.1 months (range, 0.6-30.8 months). CONCLUSIONS: Unlike TKIs, which have shown responses in this setting, to the authors' knowledge there have been no responses observed with the use of single-agent VT to date. It does not appear to be a promising drug for the treatment of patients with thyroid cancer.

Tumor Board Conferences for Multidisciplinary Skin Cancer Management: A Survey of US Cancer Centers.

Background: Tumor board conferences (TBCs) are used by oncologic specialists to review patient cases, exchange knowledge, and discuss options for cancer management. These multidisciplinary meetings are often a cornerstone of treatment at leading cancer centers and are required for accreditation by certain groups, such as the American College of Surgeons' Commission on Cancer. Little is known regarding skin cancer TBCs. The objective of this study was to characterize the structure, function, and impact of existing skin cancer TBCs in the United States. Methods: A cross-sectional online survey was administered to physician leaders of skin cancer TBCs at NCI-designated Comprehensive and Clinical Cancer Centers. Results: Of the 59 centers successfully contacted, 14 (24%) reported not having a conference where skin cancer cases were discussed, and 45 (76%) identified 53 physician leaders. A total of 38 physicians (72%) completed the survey. Half of the meeting leaders were medical and/or surgical oncologists, and dermatologists led one-third of meetings. TBCs had a moderate to significant impact on patient care according to 97% of respondents. All respondents indicated that the meetings enhanced communication among physicians and provided an opportunity for involved specialists and professionals to discuss cases. The most frequently cited barrier to organizing TBCs was determining a common available date and time for attendees (62%). The most common suggestion for improvement was to increase attendance, specialists, and/or motivation. Conclusions: Results showed overall consistency in meeting structure but variability in function, which may be a reflection of institutional resources and investment in the conference. Future directions include defining metrics to evaluate changes in diagnosis or management plan after tumor board discussion, attendance, clinical trial enrollment, and cost analysis. Results of this survey may aid other institutions striving to develop and refine skin cancer TBCs.

Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer.

BACKGROUND: Patients with recurrent and/or metastatic, radioactive iodine-refractory thyroid carcinoma have limited treatment options. Sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first-line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results. METHODS: In this single-institution, phase 2 study, 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was the radiographic response rate. RESULTS: The best response was a partial response in 8 patients (22%), stable disease in 21 (58%), and progressive disease in 1 (3%). Six patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10% compared with 38% of those who had not received prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. The progression-free survival rate at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis. CONCLUSIONS: Sorafenib and temsirolimus appear to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity is also observed in patients who previously received sorafenib. This regimen warrants further investigation. Cancer 2017;123:4114-4121. © 2017 American Cancer Society.

Oncology for the rhinologist.

PURPOSE OF REVIEW: The purpose of this review is to summarize current evidence regarding the use of induction chemotherapy for a variety of histopathologies of sinonasal malignancy (SNMs) and to review the potential adverse effects of cytotoxic agents. RECENT FINDINGS: Historically, patients with locally advanced SNMs have had relatively poor prognoses and high morbidity from treatment. The available retrospective data suggests that induction chemotherapy may improve outcomes for patients with sinonasal undifferentiated carcinoma (SNUC), neuroendocrine carcinoma, squamous cell carcinoma (SSCC), and esthesioneuroblastoma. For SNUC and SSCC, response or nonresponse to induction chemotherapy may prognosticate outcomes and for SNUC specifically, drive selection of definitive therapy. In chemosensitive pathologies, induction chemotherapy appears to improve organ preservation. SUMMARY: Induction chemotherapy may improve functional and oncologic outcomes for patients with SNMs. Because of the rarity of these pathologies, the available data is primarily retrospective. Future randomized, prospective studies should be performed to further optimize and elucidate the role of induction chemotherapy for SNMs.

Phase II, Single-Arm Trial of Induction and Concurrent Vismodegib With Curative-Intent Radiation Therapy for Locally Advanced, Unresectable Basal Cell Carcinoma.

PURPOSE: Locally advanced, unresectable basal cell carcinoma (LA BCC) can be treated with radiation therapy (RT), but locoregional control (LRC) rates are unsatisfactory. Vismodegib is a hedgehog pathway inhibitor (HPI) active in BCC that may radiosensitize BCC. We evaluated the combination of vismodegib and RT for patients with LA BCC. METHODS: In this multicenter, single-arm, phase II study, patients with unresectable LA BCC received 12 weeks of induction vismodegib, followed by 7 weeks of concurrent vismodegib and RT. The primary end point was LRC rate at 1 year after the end of treatment. Secondary end points included objective response, progression-free survival (PFS), overall survival (OS), safety, and patient-reported quality of life (PRQOL). RESULTS: Twenty-four patients received vismodegib; five were unable to complete 12 weeks of induction therapy. LRC was achieved in 91% (95% CI, 68 to 98) of patients at 1 year. The response rate was 63% (95% CI, 38 to 84) after induction vismodegib and 83% (95% CI, 59 to 96) after concurrent vismodegib and RT. With a median follow-up of 5.7 years, 1-year PFS and OS rates were 100% and 96%, and at 5 years PFS and OS rates were 78% and 83%, respectively. Distant metastasis or BCC-related death has not been observed. The most frequent treatment-related adverse events (AEs) were dysgeusia, fatigue, and myalgias occurring in 83%, 75%, and 75% of patients. No grade 4 to 5 treatment-related AEs occurred. PRQOL demonstrated clinically meaningful improvements in all subscales, with emotions and functioning improvements persisting for a year after the end of treatment. CONCLUSION: In patients with unresectable LA BCC, the combination of vismodegib and RT yielded high rates of LRC and PFS and durable improvements in PRQOL.

A phase 1 study of concurrent cabozantinib and cetuximab in recurrent or metastatic head and neck squamous cell cancer.

OBJECTIVES: Epidermal growth factor receptor (EGFR) inhibition with cetuximab is a standard treatment for head and neck squamous cell carcinoma (HNSCC). Activation of the receptor tyrosine kinases AXL, MET and VEGFR can mediate resistance to cetuximab. Cabozantinib, a multikinase inhibitor (MKI) targeting AXL/MET/VEGFR, has demonstrated antitumor activity in preclinical models of HNSCC. This investigator- initiated phase I trial evaluated the safety and efficacy of cetuximab plus cabozantinib in patients with recurrent/metastatic (R/M) HNSCC. MATERIALS AND METHODS: Patients received cetuximab concurrently with cabozantinib daily on a 28-day cycle. Using a 3 + 3 dose-escalation design, the primary endpoint was to determine the maximally tolerated dose (MTD) of cabozantinib. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) RESULTS: Among the 20 patients enrolled, most had prior disease progression on immune checkpoint inhibitors (95 %), platinum-based chemotherapy (95 %), and cetuximab (80 %). No dose-limiting toxicities were recorded and the MTD for cabozantinib was established to be 60 mg. Grade ≥ 3 adverse events occurred in 65 % of patients (n = 13). ORR was 20 %, with 4 partial responses (PRs). Two PRs were observed in cetuximab-naïve patients (n = 4), with an ORR of 50 % in this subgroup. In the overall population, DCR was 75 %, median PFS was 3.4 months and median OS was 8.1 months. CONCLUSION: Cetuximab plus cabozantinib demonstrated a manageable toxicity profile and preliminary efficacy in patients with heavily treated R/M HNSCC. The combination of cetuximab with MKIs targeting the AXL/MET/VEGFR axis warrants further investigation, including in cetuximab-naïve patients.

Phase 2 trial of regorafenib in recurrent or metastatic adenoid cystic carcinoma.

BACKGROUND: There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multi-targeted, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC. METHODS: Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The primary endpoints were best overall response (BOR) and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants. RESULTS: Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR-TKIs. No objective responses were observed. Six-month PFS was 45%, and median PFS was 7.2 months (95%CI 5.2-11.9 months). Presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS (HR 2.6, 95%CI 1.1-6.1, p=0.03). Bulk RNA sequencing of pre-treatment tumors revealed that regorafenib clinical benefit (CB; PFS≥6 months; n=11) was associated with native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS<6 months; n=9) had greater expression of signatures related to cell cycle progression (E2F targets, G2/M checkpoint). CONCLUSION: The trial failed to meet the pre-specified 6-month PFS and BOR targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, while programs promoting cell cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR-TKI should be considered.

Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.

PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Evaluation of Proton Therapy Reirradiation for Patients With Recurrent Head and Neck Squamous Cell Carcinoma.

Importance: Use of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret. Objective: To evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma. Design, Setting, and Participants: This retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and grade early and late toxic effects. Exposures: Proton therapy reirradiation. Main Outcomes and Measures: Follow-up was defined from the start of PT-ReRT. The Kaplan-Meier method was used for outcomes of interest, including local control (LC), locoregional control, distant metastatic control, progression-free survival, and overall survival (OS). Cox proportional hazards regression modeling was used to assess associations of covariates with OS. Results: A total of 242 patients (median [range] age, 63 [21-96] years; 183 [75.6%] male) were included. Of these patients, 231 (95.9%) had a Karnofsky performance status score of 70 or higher, and 145 (59.9%) had at least a 10-pack-year smoking history. Median (range) follow-up was 12.0 (5.8-26.0) months for all patients and 24.5 (13.8-37.8) months for living patients. A total of 206 patients (85.1%) had recurrent disease vs second primary or residual disease. The median (range) interval between radiation courses was 22 (1-669) months. Median PT-ReRT dose was 70 cobalt gray equivalents (CGE) for the fractionated cohort and 44.4 CGE for the quad shot cohort. For the fractionated cohort, the 1-year LC was 71.8% (95% CI, 62.8%-79.0%) and the 1-year OS was 66.6% (95% CI, 58.1%-73.8%). For the quad shot cohort, the 1-year LC was 61.6% (95% CI, 46.4%-73.6%) and the 1-year OS was 28.5% (95% CI, 19.4%-38.3%). Higher Karnofsky performance status scores (hazard ratio [HR], 0.50; 95% CI, 0.25-0.99; P = .046) and receipt of salvage surgery prior to PT-ReRT (HR, 0.57; 95% CI, 0.39-0.84; P = .005) were associated with improved OS, whereas receipt of quad shot (HR, 1.97; 95% CI, 1.36-2.86; P < .001) was associated with worse OS. There were a total of 73 grade 3 and 6 grade 4 early toxic effects. There were 79 potential grade 3, 4 grade 4, and 5 grade 5 late toxic effects. Conclusions and Relevance: The findings of this cohort study suggest that, compared with previous reports with photon-based reirradiation, patients are living longer with aggressive PT-ReRT; however, surviving patients remain at risk of early and late complications.

Nivolumab plus ipilimumab in advanced salivary gland cancer: a phase 2 trial.

Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier: NCT03172624 .

Introducing Checkpoint Inhibitors Into the Curative Setting of Head and Neck Cancers: Lessons Learned, Future Considerations.

The emergence of immunotherapy, in the form of immune checkpoint inhibitors, has irrevocably altered the paradigm of cancer treatment over the past decade. Multiple characteristics of the immune landscape in head and neck squamous cell carcinoma suggest a strong rationale for the use of immunotherapies in this disease. Data from studies with both single-agent immunotherapies and chemotherapy and immunotherapy combinations in patients with incurable, relapsed disease have confirmed the potential for immune checkpoint inhibitors to be translated into settings in which patients with head and neck squamous cell carcinoma are treated with curative intent. Indeed, a number of single-arm and randomized studies, including trials of immunotherapy with surgery, chemotherapy, or radiotherapy, have already been completed or are ongoing. In this review, we present promising data from studies in which immunotherapy has been used in conjunction with curative-intent surgery, both as neoadjuvant/induction treatment and as an adjuvant approach. In addition, we discuss the fact that immune checkpoint inhibitor therapy is, once again, allowing oncologists to revisit the potential role of neoadjuvant chemotherapy as part of definitive treatment regimens for patients with locally advanced head and neck squamous cell carcinoma. Finally, we address the increasing interest in exploiting synergistic interactions between radiotherapy and immunotherapy in the context of radical radiotherapy and chemoradiotherapy regimens. As a consequence of these new areas of research, we are optimistic that the next decade may see immunotherapy embedded within recommended standard-of-care curative regimens for patients with locally advanced head and neck squamous cell carcinoma.

Metastatic Cutaneous Squamous Cell Carcinoma Involving the Parotid Gland: Experience Outside of the Sun Belt.

OBJECTIVE: To characterize a subset of patients with metastatic head and neck cutaneous squamous cell carcinoma in a tertiary North American center and describe oncologic outcomes following definitive treatment. STUDY DESIGN: Retrospective chart review. SETTING: National Cancer Institute-designated Comprehensive Cancer Center. METHODS: We conducted a retrospective chart review of patients with cutaneous squamous cell carcinoma with metastases to intraparotid lymph nodes who underwent parotidectomy between 1993 and 2020. Baseline patient and tumor characteristics were assessed. Regional control, disease-specific survival, and overall survival were estimated using Kaplan-Meier method. Multivariate analysis was used to determine the relationship between adverse pathological features and survival. RESULTS: A total of 122 patients were included. The median age was 76, 84.4% of patients were male, and 17.2% were immunosuppressed. Regional control, disease-specific survival, and overall survival were 68.5%, 70.7%, and 59.4% at 5 years, respectively. Perineural and lymphovascular invasion were predictive of worse disease-specific survival. Extracapsular spread was observed in 90.2% of patients and was not a significant predictor of outcome. CONCLUSIONS: We found the demographics and oncologic outcomes of our cohort in the Northeast United States to be comparable with those previously reported in Australia and the Sun Belt of the United States. We noted a high rate of extracapsular spread but did not find it to be a significant predictor of recurrence or survival. Future efforts should address the impact of extracapsular spread on prognosis and adjuvant treatment decisions.

Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Nasopharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy.

Importance: Patients with nonmetastatic nasopharyngeal carcinoma (NPC) are primarily treated by radiotherapy with curative intent with or without chemotherapy and often experience substantial treatment-related toxic effects even with modern radiation techniques, such as intensity-modulated radiation therapy (IMRT). Intensity-modulated proton therapy (IMPT) may improve the toxicity profile; however, there is a paucity of data given the limited availability of IMPT in regions with endemic NPC. Objective: To compare toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic NPC when treated with IMPT vs IMRT with or without chemotherapy. Design, Setting, and Participants: This retrospective cohort study included 77 patients with newly diagnosed nonmetastatic NPC who received curative-intent radiotherapy with IMPT or IMRT at a tertiary academic cancer center from January 1, 2016, to December 31, 2019. Forty-eight patients with Epstein-Barr virus (EBV)-positive tumors were included in a 1:1 propensity score-matched analysis for survival outcomes. The end of the follow-up period was March 31, 2021. Exposures: IMPT vs IMRT with or without chemotherapy. Main Outcomes and Measures: The main outcomes were the incidence of acute and chronic treatment-related adverse events (AEs) and oncologic outcomes, including locoregional failure-free survival (LRFS), progression-free survival (PFS), and overall survival (OS). Results: We identified 77 patients (25 [32.5%] women; 52 [67.5%] men; median [interquartile range] age, 48.7 [42.2-60.3] years), among whom 28 (36.4%) were treated with IMPT and 49 (63.6%) were treated with IMRT. Median (interquartile range) follow-up was 30.3 (17.9-41.5) months. On multivariable logistic regression analyses, IMPT was associated with lower likelihood of developing grade 2 or higher acute AEs compared with IMRT (odds ratio [OR], 0.15; 95% CI, 0.03-0.60; P = .01). Only 1 case (3.8%) of a chronic grade 3 or higher AE occurred in the IMPT group compared with 8 cases (16.3%) in the IMRT group (OR, 0.21; 95% CI, 0.01-1.21; P = .15). Propensity score matching generated a balanced cohort of 48 patients (24 IMPT vs 24 IMRT) and found similar PFS in the IMPT and IMRT groups (2-year PFS, 95.7% [95% CI, 87.7%-100%] vs 76.7% [95% CI, 60.7%-97.0%]; hazard ratio [HR], 0.31; 95% CI, 0.07-1.47; P = .14). No locoregional recurrence or death was observed in the IMPT group from the matched cohort. Two-year LRFS was 100% (95% CI, 100%-100%) in the IMPT group and 86.2% (95% CI, 72.8%-100%) in the IMRT group (P = .08). Three-year OS was 100% (95% CI, 100%-100%) in the IMPT group and 94.1% (95% CI, 83.6%-100%) in the IMRT group (P = .42). Smoking history was the only clinical factor significantly associated with both poor LRFS (HR, 63.37; 95% CI, 3.25-1236.13; P = .006) and poor PFS (HR, 6.33; 95% CI, 1.16-34.57; P = .03) on multivariable analyses. Conclusions and Relevance: In this study, curative-intent radiotherapy with IMPT for nonmetastatic NPC was associated with significantly reduced acute toxicity burden in comparison with IMRT, with rare late complications and excellent oncologic outcomes, including 100% locoregional control at 2 years. Prospective trials are warranted to direct the optimal patient selection for IMPT as the primary radiotherapy modality for nonmetastatic NPC.