Purpose/Objective(s) Immuno-STATs are T cell engagers which activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101 is a human leukocyte antigen (HLA) complex, HLA-A*0201, plus an HPV16 E7 peptide, and 4 molecules of attenuated IL-2 designed activate HPV16-specific CD8+ T cells. Materials/Methods CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ R/M HNSCC. Escalating doses of CUE-101 were evaluated in platinum or ICB refractory R/M HNSCC, or with pembrolizumab in 1st line R/M HNSCC, followed by expanded enrollment at the RP2D. Safety, PK/PD, and antitumor activity were assessed. Results As of Oct 1, 2023, 76 patients have been enrolled. Following monotherapy and combination therapy dose escalation, 4 mg/kg of CUE-101 was chosen as the RP2D for both cohorts. Enrollment in both monotherapy and combination cohorts is now complete. Grade 3 treatment-related AEs reported include infusion-related reaction (4.2%), fatigue, maculopapular rash, stomatitis and diarrhea (all 2.7%). Among 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) were observed, with mOS of 20.8 months. Among 17 evaluable RP2D combination patients, 1 CR, 7 PRs, and 3 durable SDs were observed. Complete Response and 5 out of 7 PRs occurred in tumors with CPS of 20 or less. Of the 8 patients with objective responses, 5 achieved >99% reduction in HPV16 cfDNA, 4 by week 6, with 3 patients pending analysis at time of data cut-off. Conclusion CUE-101 demonstrates safety, tolerability and meaningful anti-cancer activity. Patients treated with CUE-101 monotherapy in 3L showed a long OS. CUE-101 and pembrolizumab combination resulted in an ORR of 47% and decrease in HPV16 cfDNA in the 1L treatment of patients with HPV16+ R/M HNSCC. Immuno-STATs are T cell engagers which activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101 is a human leukocyte antigen (HLA) complex, HLA-A*0201, plus an HPV16 E7 peptide, and 4 molecules of attenuated IL-2 designed activate HPV16-specific CD8+ T cells. CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ R/M HNSCC. Escalating doses of CUE-101 were evaluated in platinum or ICB refractory R/M HNSCC, or with pembrolizumab in 1st line R/M HNSCC, followed by expanded enrollment at the RP2D. Safety, PK/PD, and antitumor activity were assessed. As of Oct 1, 2023, 76 patients have been enrolled. Following monotherapy and combination therapy dose escalation, 4 mg/kg of CUE-101 was chosen as the RP2D for both cohorts. Enrollment in both monotherapy and combination cohorts is now complete. Grade 3 treatment-related AEs reported include infusion-related reaction (4.2%), fatigue, maculopapular rash, stomatitis and diarrhea (all 2.7%). Among 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) were observed, with mOS of 20.8 months. Among 17 evaluable RP2D combination patients, 1 CR, 7 PRs, and 3 durable SDs were observed. Complete Response and 5 out of 7 PRs occurred in tumors with CPS of 20 or less. Of the 8 patients with objective responses, 5 achieved >99% reduction in HPV16 cfDNA, 4 by week 6, with 3 patients pending analysis at time of data cut-off. CUE-101 demonstrates safety, tolerability and meaningful anti-cancer activity. Patients treated with CUE-101 monotherapy in 3L showed a long OS. CUE-101 and pembrolizumab combination resulted in an ORR of 47% and decrease in HPV16 cfDNA in the 1L treatment of patients with HPV16+ R/M HNSCC.

Purpose/Objective(s) Immuno-STATs are T cell engagers which activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101 is a human leukocyte antigen (HLA) complex, HLA-A*0201, plus an HPV16 E7 peptide, and 4 molecules of attenuated IL-2 designed activate HPV16-specific CD8+ T cells. Materials/Methods CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ R/M HNSCC. Escalating doses of CUE-101 were evaluated in platinum or ICB refractory R/M HNSCC, or with pembrolizumab in 1st line R/M HNSCC, followed by expanded enrollment at the RP2D. Safety, PK/PD, and antitumor activity were assessed. Results As of Oct 1, 2023, 76 patients have been enrolled. Following monotherapy and combination therapy dose escalation, 4 mg/kg of CUE-101 was chosen as the RP2D for both cohorts. Enrollment in both monotherapy and combination cohorts is now complete. Grade 3 treatment-related AEs reported include infusion-related reaction (4.2%), fatigue, maculopapular rash, stomatitis and diarrhea (all 2.7%). Among 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) were observed, with mOS of 20.8 months. Among 17 evaluable RP2D combination patients, 1 CR, 7 PRs, and 3 durable SDs were observed. Complete Response and 5 out of 7 PRs occurred in tumors with CPS of 20 or less. Of the 8 patients with objective responses, 5 achieved >99% reduction in HPV16 cfDNA, 4 by week 6, with 3 patients pending analysis at time of data cut-off. Conclusion CUE-101 demonstrates safety, tolerability and meaningful anti-cancer activity. Patients treated with CUE-101 monotherapy in 3L showed a long OS. CUE-101 and pembrolizumab combination resulted in an ORR of 47% and decrease in HPV16 cfDNA in the 1L treatment of patients with HPV16+ R/M HNSCC.

Background: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131 refractory DTC. Patients and methods: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (>18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. Results: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. Conclusions: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Purpose/Objective(s)Studies have shown that induction chemotherapy (IC) is a viable pathway to chemoradiation therapy (CRT) de-intensification in HPV-related head and neck cancer (HNC). However, reliance on imaging alone for eligibility may incorrectly exclude cases where radiographic response lags or otherwise confounds biological response. We report serial cell free HPV DNA (cfHPV DNA) dynamics as a quantitative measure of early treatment responsiveness for HPV-related HNC patients receiving IC followed by CRT.Materials/MethodsStarting Sept 26, 2021, we enrolled patients with locally advanced, high-risk HPV positive HNC who received 1-2 cycles of platinum/taxane IC followed by standard definitive CRT. Peripheral blood was collected biweekly during IC and weekly during CRT to measure cfHPV DNA levels using HPV-SEQ, a CLIA-certified assay that uses SafeSEQ technology to sensitively detect and quantify HPV16 and HPV18 DNA in plasma (Sysmex Inostics). The treating radiation oncologist delineated tumor volumes on pre- and post-IC CT simulation scans.ResultsAt present, 86 plasma samples have been examined across 12 enrolled patients. The median age was 65 years (range: 35-79). The primary disease sites included 8 oropharynx (OPX), 2 nasopharynx, 1 sinonasal, and 1 larynx, with all tumors being high-risk HPV positive by in-situ hybridization. All patients had at least cT3 disease or cN3 disease by AJCC 8 criteria, with 7 patients having cT4 disease. Half of the patients have a >10 pack-year smoking history. Tumor volume measurements and cfHPV DNA levels at key time-points for the 8 patients who have completed IC are summarized in Table 1 below.ConclusionSerial cfHPV DNA may provide an earlier and more quantitative readout of individualized treatment responsiveness compared with imaging assessment alone in HPV-related HNC. We identify a group of patients with locally advanced disease who had complete or near-complete cfHPV DNA clearance during IC. Rapid and effective clearance of cfHPV DNA may ultimately serve as a preferred metric for identifying "exceptional responders" who are ideal biological candidates for short-course CRT after IC. Our granular cfHPV DNA dataset with biweekly measurements during IC and weekly measurements during CRT should lead to a more precise evaluation of cfHPV DNA clearance velocity and tumor response kinetics with this paradigm.

Purpose/Objective(s) Head and neck squamous cell carcinoma (HNSCC) represents the 8th most common cancer worldwide.1 However, survival rates remain low at ≈50%, despite standard first-line treatment with the immune checkpoint inhibitor (ICI) pembrolizumab (PEMBRO) ± chemotherapy.2 Recombinant interleukin-2 (IL-2) is associated with improved overall survival (OS) in HNSCC patients.3 Research has shown that high levels of tumor-infiltrating lymphocytes are prognostic of disease-free survival in this patient population. Bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class immunostimulatory IL-2 cytokine prodrug, is engineered to deliver a controlled, sustained, and preferential signal to the clinically validated IL-2 pathway to selectively stimulate antitumor responses. Earlier studies of BEMPEG in combination with ICIs evaluated in patients with immune-sensitive cancers have shown the potential to increase and deepen treatment responses vs historical rates for ICIs alone.4 Here, we present the design of the PROPEL-36 study (NCT04969861) that evaluates BEMPEG + PEMBRO vs PEMBRO alone in patients with previously untreated metastatic or recurrent programmed death ligand-1 (PD-L1)-positive HNSCC (combined positive score ≥1). Materials/Methods This phase 2/3, multicenter study is enrolling ≈500 patients with cancer of the oropharynx, oral cavity, hypopharynx, or larynx (excluding nasopharyngeal tumors) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Randomization will be stratified by disease status, PD-L1 expression, and human papillomavirus status. Patients are treated with BEMPEG and/or PEMBRO every 3 weeks for up to 35 cycles (≈2 years). The primary endpoints are OS and objective response rate. Secondary endpoints include progression-free survival, time to deterioration in global health status/quality of life, pain, and swallowing, change in quality of life, and safety. This study is now enrolling. Results TBD Conclusion TBD Head and neck squamous cell carcinoma (HNSCC) represents the 8th most common cancer worldwide.1 However, survival rates remain low at ≈50%, despite standard first-line treatment with the immune checkpoint inhibitor (ICI) pembrolizumab (PEMBRO) ± chemotherapy.2 Recombinant interleukin-2 (IL-2) is associated with improved overall survival (OS) in HNSCC patients.3 Research has shown that high levels of tumor-infiltrating lymphocytes are prognostic of disease-free survival in this patient population. Bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class immunostimulatory IL-2 cytokine prodrug, is engineered to deliver a controlled, sustained, and preferential signal to the clinically validated IL-2 pathway to selectively stimulate antitumor responses. Earlier studies of BEMPEG in combination with ICIs evaluated in patients with immune-sensitive cancers have shown the potential to increase and deepen treatment responses vs historical rates for ICIs alone.4 Here, we present the design of the PROPEL-36 study (NCT04969861) that evaluates BEMPEG + PEMBRO vs PEMBRO alone in patients with previously untreated metastatic or recurrent programmed death ligand-1 (PD-L1)-positive HNSCC (combined positive score ≥1). This phase 2/3, multicenter study is enrolling ≈500 patients with cancer of the oropharynx, oral cavity, hypopharynx, or larynx (excluding nasopharyngeal tumors) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Randomization will be stratified by disease status, PD-L1 expression, and human papillomavirus status. Patients are treated with BEMPEG and/or PEMBRO every 3 weeks for up to 35 cycles (≈2 years). The primary endpoints are OS and objective response rate. Secondary endpoints include progression-free survival, time to deterioration in global health status/quality of life, pain, and swallowing, change in quality of life, and safety. This study is now enrolling. TBD TBD

BACKGROUND:Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC. PATIENTS AND METHODS:Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed. RESULTS:Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively. CONCLUSIONS:In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.

Since 2008, the EXTREME regimen (six cycles of infusional fluorouracil, platinum, and cetuximab, followed by weekly cetuximab maintenance) has been considered the standard of care first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma, who have either never previously received a platinum agent or are at least 6 months out from concurrent radiotherapy and platinum in the curative setting. 1 Vermorken JB Mesia R Rivera F et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008; 359: 1116-1127 Crossref PubMed Scopus (2245) Google Scholar Cetuximab, docetaxel, and cisplatin versus platinum, fluorouracil, and cetuximab as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma (GORTEC 2014-01 TPExtreme): a multicentre, open-label, randomised, phase 2 trialAlthough the trial did not meet its primary endpoint, with no significant improvement in overall survival with TPEx versus EXTREME, the TPEx regimen had a favourable safety profile. The TPEx regimen could provide an alternative to standard of care with the EXTREME regimen in the first-line treatment of patients with recurrent or metastatic HNSCC, especially for those who might not be good candidates for up-front pembrolizumab treatment. Full-Text PDF Correction to Lancet Oncol 2021; 22: 413–15Hwang M, Seiwert TY. Are taxanes the future for head and neck cancer? Pragmatism in the immunotherapy era. Lancet Oncol 2021; 22: 413–15—In this Comment, the penultimate sentence should read "…in whom it should be tested against the KEYNOTE-048 regimen of pembrolizumab, fluorouracil, and platinum". This correction has been made to the online version as of March 29, 2021, and the print version is correct. Full-Text PDF

The incidence of HPV-associated OPSCC is rising rapidly. Patients with HPV-positive tumors have excellent prognosis, and we may be overtreating this patient population. Strategies to de-escalate therapy are being investigated, but the optimal strategy is not defined. Response to induction chemotherapy indicates favorable prognosis and may identify candidates for de-intensified locoregional therapy. Here we describe a low-risk subset of patients from the OPTIMA 2 de-escalation trial with a deep response to induction chemoimmunotherapy.

Purpose: To report functional outcomes for patients with human papillomavirus-positive oropharyngeal cancer treated on a phase 2 protocol of risk- and induction chemotherapy response-adapted dose and volume de-escalated radiation therapy (RT)/chemoradiation (CRT). Methods and Materials: Patients were stratified as low risk (LR) or high risk (HR) according to T/N-stage and smoking history. Induction chemotherapy was followed by radiographic response assessment. LR patients with >= 50% response received 50 Gy RT (RT50), whereas LR patients with 30% to 50% response or HR patients with >= 50% response received 45 Gy CRT (CRT45). All other patients received 75 Gy CRT (CRT75) with RT limited to the first echelon of uninvolved nodes. Pre- and post-RT/CRT modified barium swallow studies were performed. Percutaneous endoscopic gastrostomy (PEG) tube placement, body mass index (BMI), and narcotic use were recorded. Statistical comparisons used linear or logistic regression, the Mann-Whitney U test, the chi(2) test, or Fisher's exact test as appropriate. Results: Twenty-eight LR and 34 HR patients were enrolled; 49 completed RT50/CRT45 and 11 completed CRT75. PEG-tube dependency at the end of RT/CRT and 3 months post-RT/CRT significantly differed according to risk and treatment groups (all P < .05). Treatment intensity was independently associated with 3-month PEG status while adjusting for risk group (P = .002). The CRT75 group had a median -8.42% change from baseline BMI at 1 year post-RT/CRT versus -2.54% for the RT50/CRT45 group (P = .01). At the end of RT/CRT, CRT75 patients were less likely to tolerate a normal diet, more likely to have swallowing performance status scale scores >= 4, more likely to have Rosenbek's penetration-aspiration scores >= 7, more likely to have developed trismus, and more likely to require narcotics >2 months (all P < .05). Conclusions: Induction chemotherapy followed by risk- and response-adapted dose and volume de-escalated RT/CRT is associated with clinically meaningful functional outcomes including (1) improved swallowing function, (2) higher BMI, and (3) shorter narcotic use for patients receiving de-escalation. (C) 2020 Elsevier Inc. All rights reserved.

The dismal 5-year survival rate for advanced stage smoking related SCCHN of <30% has not changed in the past 30 years. Akt/mTOR is activated in most SCCHN and pathway activation in surrounding normal mucosa is associated with recurrences. Oral mTOR inhibitors appear well tolerated and effective in window of opportunity SCCHN trials. The purpose of this trial (NCT01111058) was to determine whether adjuvant everolimus improves 2-year progression-free survival (PFS) in patients with advanced SCCHN and investigate correlative biological factors associated with response.

Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Currently 7 clinical trials are underway to evaluate NBTXR3+RT. To date, no dose limiting toxicities (DLTs) have been observed. Given that RT can prime an anti-tumor immune response we hypothesized that this response could be enhanced by NBTXR3+RT in both animals and humans. Immunocompetent mice were injected in both flanks with CT26 cells. An intratumoral injection of NBTXR3 (or vehicle) was performed in right flank tumors, followed by RT (3x4Gy). Tumor growth was followed, and animals sacrificed when tumors reached 800mm3. Alternatively, tumors were collected 3 days after last RT fraction and immune cell infiltrates analyzed by immunohistochemistry (IHC). Pts with locally advanced soft tissue sarcoma (STS) [NCT02379845] received either NBTXR3+RT or RT alone. Pre- and post-treatment tumor tissues (biopsy and tumor resection respectively) from pts were analyzed by IHC and Digital Pathology for immune biomarkers (>16 pts per arm). Animal studies demonstrated that NBTXR3+RT can induce an immune response which was not observed with RT alone. IHC analyses showed that significantly more CD8+ cells were present in NBTXR3+RT treated and untreated tumors, compared to tumors from mice treated with RT alone. Similarly, increased CD8+ T cell infiltration pre- vs post-treatment was observed in tumor tissues from STS pts treated with NBTXR3+RT. An increase in biomarkers, including CD8 and PD1, following NBTXR3 +RT was also observed by IHC in tumor samples from STS pts compared to RT alone. These results demonstrate that NBTXR3+RT induces a specific adaptive immune profile in both mice and STS pts. As such, it may convert immunologically "cold" tumors into "hot" tumors, opening the potential for combination with immunotherapeutic agents. We have therefore sought to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with anti-PD-1 antibody in pts with locoregionally recurrent or metastatic (to lung or liver) head and neck squamous cell carcinoma (HNSCC), as well as in metastatic non-small cell lung cancer (NSCLC) and liver metastasis patients [NCT03589339].

Local interventional treatments of cancers include interventional radiology and radiotherapy (RT). NBTXR3, hafnium oxide nanoparticles, is deeply associated to both. Given as a single local administration it increases energy dose deposit inside tumor cells only when activated by ionizing radiation. Various interventional treatments have been used to treat cancers such as liver, lung, bone. Because entirely new therapies such as NBTXR3 are being introduced, implementation of interventional approaches is continuously growing. NBTXR3 is being evaluated in soft tissue sarcoma (STS, extremity, trunk wall) [NCT02379845], head and neck (HN) [NCT01946867, NCT02901483], prostate [NCT02805894], liver [NCT02721056] and rectal cancers [NCT02465593]. NBTXR3 injected volume is a percentage of baseline tumor volume, and therefore heterogeneous. Image guidance allowed for accurate injection. Standard catheters, needles, and syringes were used for preparation and injection. Importantly, percutaneous needle positioning was done within the region to be irradiated to control potential seeding of cancer cells. NBTXR3 was then activated by IMRT (STS, HN), EBRT or combination brachytherapy/EBRT boost (prostate), SBRT (liver), IMRT or IMAT (rectum). Thus far, NBTXR3 has been administered to 171 patients by intratumoral/lesional, and intraprostate injections depending on indication. NBTXR3 injections have been demonstrated safe and very well tolerated. Local infection, ulceration or massive tumor necrosis were never observed. This has been confirmed by adequate application of treatment schedules, fitting planned irradiation onset 1 to 5 days post-injection. Importantly, grade 1 ecchymosis and hematoma at puncture site (needle entry) observed in few cases always resolved spontaneously and did not impact dosimetry. Indeed, change of tumor/lesion/prostate volume resolved when water (NBTXR3 vehicle) was drained via lymphatic system. So far, inflammatory response to injection procedure itself was mild. Concerning AEs, grade 3 pain was observed in conscious patients under local anesthesia with STS close to joints (limited extensibility), and in needle shift in injection within a subcapsular liver tumor. Across 7 clinical trials involving tumors in extremity, trunk wall, liver, rectum, prostate and HN, NBTXR3 injection was well tolerated and demonstrated a very good safety profile. The savoir faire of interventional radiology for local treatment of cancers supported implementation of injection procedures with specific parameters according to anatomy. Intratumoral/lesional or intraprostate injection ensures optimum bioavailability at site of irradiation, protecting patients from systemic toxicity. Future clinical research will involve other anatomical sites such as lymph nodes and lung lesions [NCT03589339].

BACKGROUND Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy. PATIENTS AND METHODS Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history) or high-risk (T4 or ≥N2C or >10 PYH). After three cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%-50% response or high-risk patients with ≥50% response received 45 Gy CRT (CRT45). Patients with lesser response received standard-of-care 75 Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary end point was 2-year progression-free survival compared with a historic control of 85%. Secondary end points included overall survival and toxicity. RESULTS Sixty-two patients (28 low risk/34 high risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% noninferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (P < 0.0001). CONCLUSIONS Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified. CLINICAL TRIAL REGISTRATION Clinical trials.gov identifier: NCT02258659.

Objectives: Definitive chemoradiation (CRT) for oral cavity squamous cell carcinoma (OC-SCC) is often criticized for poor efficacy or toxicity. We describe a favorable 20-year experience of primary CRT for locally-advanced OC-SCC. Materials and Methods: Patients with locally-advanced, stage III/IV OC-SCC receiving primary concomitant CRT on protocols from 1994 to 2014 were analyzed. Chemotherapy included fluorouracil and hydroxyurea with other third agents. Radiotherapy (RT) was delivered once or twice daily to a maximum dose of 70-75 Gy. Intensity-modulated RT (IMRT) was exclusively used after 2004. Progression-free survival (PFS), overall survival (OS), locoregional control (LRC), and distant control (DC) were calculated by the Kaplan-Meier method and compared across treatment decades using the log-rank test. Rates of osteoradionecrosis (ORN) requiring surgery were compared across treatment decades using the Chi-square test. Results: 140 patients with locally-advanced OC-SCC were treated with definitive CRT. Of these, 75.7% had T3/T4 disease, 68.6% had >= N2 nodal disease, and 91.4% had stage IV disease. Most common primary sites were oral tongue (47.9%) and floor of mouth (24.3%). Median follow-up was 5.7 years. Five-year OS, PFS, LRC, and DC were 63.2%, 58.7%, 78.6%, and 87.2%, respectively. Rates of ORN and long-term feeding tube dependence were 20.7% and 10.0%, respectively. Differences in LRC (P = 0.90), DC (P = 0.24), PFS (P = 0.38), OS (P = 0.10), or ORN (P = 0.38) were not significant across treatment decades. Conclusion: Definitive CRT is a viable and feasible strategy for organ preservation for patients with locallyadvanced OC-SCC.

To improve radiotherapy (RT) in terms of tumor response and to reduce irradiation of healthy tissues, innovative therapeutic approaches are needed. In response, NBTXR3, injectable hafnium oxide nanoparticles, was developed for the treatment of solid tumors. Once injected intratumorally, NBTXR3 can deposit high energy within tumors only when activated by an ionizing radiation source, like current standard RTs. Upon activation, the high energy radiation physically kills the tumor cells by triggering DNA damage and cell destruction improving clinical outcomes. Since its first successful clinical evaluation in a completed phase I trial in patients with locally advanced soft tissue sarcoma, NBTXR3 is currently evaluated in numerous indications worldwide (EU, Asia, US). NBTXR3 was the object of numerous in vitro and in vivo tumor models to determine its mechanism of action, performance and biocompatibility profile. Once they were assessed, NBTXR3 entered clinical development and was administered as a single intratumoral (IT) injection activated by RT. NBTXR3 is clinically evaluated in head and neck [NCT01946867; NCT02901483], prostate [NCT02805894], liver [NCT02721056] and rectum cancers [NCT02465593] with the scope of determining the Recommended Dose or observing any Dose Limiting Toxicities (DLTs) in each indication. A phase II/III trial in soft tissue sarcoma (STS) of the trunk and extremities [NCT02379845] is about to be finalized. Preclinically, in vitro results showed an increase of cancer cells death and in vivo results demonstrated antitumor efficacy with NBTXR3 + RT compared to RT alone. This physical cell killing could open a potential systemic activity through immune response by triggering immunogenic cell death, reinforcing local effect. Clinically, across the 7 clinical trials and 6 indications, NBTXR3 demonstrated an overall positive safety profile. The numerous types of tumors and different body locations involved in these trials confirmed feasibility of IT injection and persistence of NBTXR3 in the tumor, with no leakage in the surrounding healthy tissues. NBTXR3 antitumor activity is currently evaluated in its first phase II/III in patients with STS. Besides, analysis of tumor biopsies collected pre- and post-radiotherapy suggested a release of tumor antigens during cancer cell death and stimulation of local immunological effects. NBTXR3 have shown promising results in non-clinical studies with marked antitumor efficacy and in clinical development in terms of safety and preliminary evaluations of efficacy. Considering the preliminary results of the 145 patients injected across all clinical trials, these first-in-class nanoparticles have already proven to be an encouraging innovative treatment in various types of tumors.

6066 Background: In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Methods: Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or > 10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45Gy (CRT45). 3) All other ( = poor response) pts received regular-dose CRT (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. CRT consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Results: 62 pts were enrolled. 28 pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, p = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, p = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, p < .001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, p = .066) post-treatment. Conclusions: Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50Gy RT or 45Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Toxicity and functional outcomes are significantly improved. Clinical trial information: NCT02258659.

Patients (Pts) with favorable response to induction chemotherapy (IC) are significantly less likely to experience locoregional failure (LRF). Additionally, the majority of LRF after definitive chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) are in-field failures which occur in areas of previous gross tumor. Therefore, we investigated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction. Pts with measurable LA-HNSCC received 2 cycles of IC (cisplatin, paclitaxel, and weekly cetuximab ± everolimus). Pts with “good” response (GR), defined as ≥50% reduction in the sum of gross tumor diameters, received TFHX2 (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to 75 Gy with the planning target volume (PTV1) encompassing exclusively gross disease. Pts with <50% response (NR) were treated with volumes encompassing PTV1 and the next nodal station at risk (PTV2) to 45 Gy, followed by a sequential boost to PTV1 to 75 Gy. Survival and control rates were estimated by the Kaplan-Meier method and compared between groups using the log-rank test. Cox proportional hazards regression models were fitted to assess the effects of covariates. Ninety-four pts were enrolled: median age 57 (range 27-76), 84% male, 63% HPV+ oropharynx (OPX), 54% ≥10 pack-year tobacco use, 56% ≥T3, and 88% ≥N2b. IC response was evaluable in 89 pts. Thirty-seven patients (41.6%) had GR and 52 (58.4%) had NR. Thirty of 37 pts with GR had HPV+ OPX SCC. With median follow-up of 41 months, there was no significant difference in progression-free survival (PFS, P = 0.25) or overall survival (OS, P = 0.96) in GR vs NR. The 3-year PFS and OS were 78.7% and 78.2% for GR and 72.1% and 85.2% for NR, respectively. Locoregional control (LRC) trended towards improvement in GR vs NR (P = 0.065), but there was no significant difference in distant control (DC, P = 0.35). The 3-year LRC and DC were 94.4% and 94.4% for GR and 79.7% and 89.8% for NR, respectively. The majority of LRF (12/13) were in-field failures, of which the majority (11/12) occurred in PTV1. Regression analysis for PFS revealed only HPV-positivity as a significant predictor on multivariate modeling (HR 0.30, P = 0.03), whereas only T-stage significant on univariate modeling for OS (HR = 2.96, P = 0.03). The use of RAVD to eliminate elective nodal coverage in GR to IC did not appear to compromise outcomes on long-term follow-up. Further investigation is warranted.

It is unknown how late toxicity varies between hyperfractionated and accelerated CRT platforms for LA-HNSCC. Additionally, it is unclear to what extent recent efforts utilizing response-adapted volume de-escalation (RAVD) have reduced late toxicity compared to treatment with conventional radiation therapy (RT) volumes. In Trial 1, pts with LA-HNSCC were randomized to 2 cycles of induction chemotherapy (IC; cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (cetuximab, 5-FU, hydroxyurea, and 1.5 Gy twice-daily RT every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated RT with delayed concomitant boost to 72 Gy in 42 fractions). Conventional RT volumes were used. In Trial 2, pts with LA-HNSCC received 2 cycles of IC (cisplatin, paclitaxel, cetuximab ± everolimus) followed by RAVD. Good responders (GR) with ≥50% reduction in the sum of gross tumor diameters received radical volume de-escalation with TFHX (paclitaxel, 5-FU, hydroxyurea, and 1.5 Gy twice-daily RT every other week to 75 Gy) encompassing exclusively gross disease. Pts with <50% response (NR) received limited volume de-escalation treating only the first echelon of uninvolved nodes to 45 Gy, followed by a sequential boost to gross disease to 75 Gy. Intensity-modulated RT was used in both trials. Pooled baseline characteristics for N = 57 on Cetux-FHX, N = 53 on Cetux-PX, N = 37 GR, and N = 52 NR include: median age 57; 84.4% male; 67.8% oropharynx; 52.3% HPV-positive; 55.8% ≥T3; 92.5% ≥N2; 31.7% ≥10 pack-year history; 42.7% underwent post-CRT neck dissection. G-tube rates during CRT and post-CRT are shown in the Table. There was no significant difference in G-tube rates within Trial 1 for Cetux-FHX vs Cetux-PX during CRT (P = 0.84) or at 6 mos (P = 1.00), 12 mos (P = 0.76), and 24 mos (P = 0.68) post-CRT. G-tube rates were significantly less within Trial 2 for GR vs NR during CRT (P = 0.02) and at 6 mos (P < 0.01) and 12 mos (P = 0.03) post-CRT. The rates of G-tube dependency for NR and Trial 1 pts were similar on treatment (P = 0.28) and at 6 mos (P = 1.00), 12 mos (P = 0.78), and 24 mos (P = 0.65) post-CRT. Regression analysis revealed only T-stage as a significant predictor of G-tube dependency during CRT (OR 1.94 for ≥T3, P = 0.03), while treatment arm (OR 0.15 for GR, P = 0.03) and tumor site (OR 1.99 for larynx/hypopharynx, P = 0.04) were significant predictors at 6 mos post-CRT. Only tumor site remained significant at 12 and 24 mos post-CRT. Severe late swallowing toxicity was similar with hyperfractionated and accelerated CRT platforms. Toxicity was improved with the use of RAVD in GR, but not in NR who received more limited volume de-escalation (typically excluding the low neck).Abstract 2865; Table 1.TrialArmG-tube Dependent (%)During Treatment6 Mos Post-CRT12 Mos Post-CRT24 Mos Post-CRT1Cetux-FHX66.134.010.68.91Cetux-PX64.235.413.04.82GR51.45.70.00.02NR75.035.414.66.5 Open table in a new tab

BACKGROUNDEfforts to reduce the late toxicity associated with chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) have focused on radiotherapy (RT) dose de-escalation. In this phase I/II protocol investigating the addition of everolimus to induction chemotherapy (IC), we incorporated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction.PATIENTS AND METHODSPatients with measurable LA-HNSCC received two cycles of IC (cisplatin, paclitaxel, cetuximab ± everolimus). Patients with ≥50% reduction in the sum of tumor diameters [good response (GR)] received TFHX (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to a dose of 75 Gy with the single planning target volume (PTV1) encompassing exclusively gross disease. Patients with <50% response [non-response (NR)] were treated with TFHX encompassing PTV1 and the next nodal station at risk (PTV2) to a dose of 45 Gy followed by a sequential boost to PTV1 to a dose of 75 Gy.RESULTSNinety-four patients were enrolled. Randomization to everolimus was discontinued on interim analysis after 50 patients due to futility. IC response was evaluable in 89 patients. Thirty-seven patients (41.6%) had GR and 52 (58.4%) had NR. There was a trend for improved progression-free (P = 0.086) but not overall survival (P = 0.94) for GR versus NR. The 2-year PFS and OS were 86.0% and 83.5% for GR and 68.7% and 85.4% for NR, respectively. NR were significantly more likely to undergo G-tube placement during treatment (50.0% GR versus 73.5% NR, P = 0.040) and be G-tube dependent at 6-month follow-up (5.7% GR versus 32.6% NR, P = 0.005).CONCLUSIONSThe addition of everolimus to IC was not beneficial. The elimination of elective nodal coverage in patients with GR to IC did not appear to compromise outcomes and resulted in significantly decreased late toxicity. Further investigation of RAVD is warranted.CLINICALTRIALSGOVNCT01133678.

Efforts to reduce the late toxicity associated with chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) have focused on radiation therapy (RT) dose de-escalation in select populations. In this phase 1/randomized 2 trial investigating the addition of everolimus to induction chemotherapy (IC), we incorporated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction in a nonselected population of patients (pts) with LA-HNSCC. Pts with measurable LA-HNSCC received 2 cycles of IC (cisplatin 75 mg/m2, paclitaxel 175 mg/m2 day 1, and weekly cetuximab, with or without everolimus). Pts with "good" response (GR), defined as ≥50% reduction in the sum of gross tumor diameters, received TFHX2 (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to 75 Gy with the planning target volume (PTV1) encompassing exclusively gross disease. Pts with <50% response (NR) were treated with volumes encompassing PTV1 and the next nodal station at risk (PTV2) to 45 Gy, followed by a sequential boost to PTV1 to 75 Gy. Survival rates were estimated by the Kaplan-Meier method and compared between groups using the log-rank test. Ninety-four pts were enrolled: median age 57 (range 27-76) years, 84% male, 63% HPV+ oropharynx (OPX), 54% ≥10 pack-year tobacco use, 56% ≥T3, 88% ≥N2b. Everolimus was discontinued on interim analysis after 43 pts due to futility. IC response was evaluable in 89 pts. Thirty-seven (41.6%) had GR, and 52 (58.4%) had NR. Thirty out of thirty-seven pts with GR had HPV+ OPX SCC. With mean follow-up of 2 years, there were no significant differences in progression-free survival (PFS; P=.086) or overall survival (OS; P=.94) between GR and NR. Two-year PFS and OS were 86.0% and 83.5% for GR and 68.7% and 85.4% for NR, respectively. Two-year PFS and OS were 93.1% and 92.1% for HPV+ OPX GR and 74.0% and 95.2% for HPV+ OPX NR, respectively. There was no statistically significant difference in PFS between the HPV+ OPX GR and NR groups (P=.10). There were too few deaths to provide reliable comparisons for OS between the HPV+ OPX GR and NR groups. RAVD is a novel treatment approach that uses IC response to determine the extent of RT volume reduction. In this study, elimination of elective nodal coverage did not appear to compromise outcomes in the entire cohort nor specifically in the HPV+ OPX subgroup. Further investigation is warranted.