Measuring what counts in Aboriginal and Torres Strait Islander care: a review of general practice datasets available for assessing chronic disease care.

Background Large datasets exist in Australia that make de-identified primary healthcare data extracted from clinical information systems available for research use. This study reviews these datasets for their capacity to provide insight into chronic disease care for Aboriginal and Torres Strait Islander peoples, and the extent to which the principles of Indigenous Data Sovereignty are reflected in data collection and governance arrangements. Methods Datasets were included if they collect primary healthcare clinical information system data, collect data nationally, and capture Aboriginal and Torres Strait Islander peoples. We searched PubMed and the public Internet for data providers meeting the inclusion criteria. We developed a framework to assess data providers across domains, including representativeness, usability, data quality, adherence with Indigenous Data Sovereignty and their capacity to provide insights into chronic disease. Datasets were assessed against the framework based on email interviews and publicly available information. Results We identified seven datasets. Only two datasets reported on chronic disease, collected data nationally and captured a substantial number of Aboriginal and Torres Strait Islander patients. No dataset was identified that captured a significant number of both mainstream general practice clinics and Aboriginal Community Controlled Health Organisations. Conclusions It is critical that more accurate, comprehensive and culturally meaningful Aboriginal and Torres Strait Islander healthcare data are collected. These improvements must be guided by the principles of Indigenous Data Sovereignty and Governance. Validated and appropriate chronic disease indicators for Aboriginal and Torres Strait Islander peoples must be developed, including indicators of social and cultural determinants of health.

A Phase II Trial of Rivoceranib, an Oral Vascular Endothelial Growth Factor Receptor 2 Inhibitor, for Recurrent or Metastatic Adenoid Cystic Carcinoma.

PURPOSE: This open-label, single-arm, phase II study evaluated the vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) rivoceranib in patients with recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC). PATIENTS AND METHODS: Eligible patients had confirmed disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) with ≥20% increase in radiologically or clinically measurable lesions or appearance of new lesions within the preceding 6 months. Patients received oral rivoceranib 700 mg once daily. Primary outcomes were objective response rate (ORR) by investigator review and by blinded independent review committee (BIRC). RESULTS: Eighty patients were enrolled and 72 were efficacy evaluable. Seventy-four patients had distant metastases and 49 received prior systemic treatment (14 received VEGFR TKIs). Per investigator and BIRC, respectively, ORR was 15.3% [95% confidence interval (95% CI), 7.9-25.7] and 9.7% (95% CI, 4.0-19.0); median duration of response was 14.9 months (95% CI, 4.9-17.3) and 7.2 months (95% CI, 3.5-8.4); and median progression-free survival was 9.0 months (95% CI, 7.3-11.5) and 9.0 months (95% CI, 7.7-11.5). Grade ≥3 treatment-related adverse events occurred in 56 patients (70.0%); the most common were hypertension (34, 42.5%) and stomatitis (6, 7.5%). Four grade 5 events occurred with one attributed to rivoceranib (epistaxis). Sixty-eight patients (85.0%) had ≥1 dose modifications and 16 patients (20.0%) discontinued rivoceranib for toxicity. CONCLUSIONS: In patients with progressing R/M ACC, rivoceranib demonstrated antitumor activity and a manageable safety profile consistent with other VEGFR TKIs.

Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1-14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for practicing physicians and other health care providers on immunotherapy and biomarker testing for head and neck cancers. METHODS: ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, radiology, pathology, and patient advocacy experts to conduct a literature search, including systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2022. Outcomes of interest included survival, overall response, and locoregional control. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 28 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: When possible, evidence-based recommendations were developed to address biomarker testing, first-line treatment regimens based on programmed death ligand-1 scores, immunotherapy in platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma, immunotherapy in nasopharyngeal carcinoma, and radiation therapy in combination with immunotherapy for treatment of local recurrence.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

A Phase 1 First-in-Human Study of FS118, a Tetravalent Bispecific Antibody Targeting LAG-3 and PD-L1 in Patients with Advanced Cancer and PD-L1 Resistance.

PURPOSE: This phase 1 study (NCT03440437) evaluated the safety, tolerability, pharmacokinetics (PK), and activity of FS118, a bispecific antibody-targeting LAG-3 and PD-L1, in patients with advanced cancer resistant to anti-PD-(L)1 therapy. PATIENTS AND METHODS: Patients with solid tumors, refractory to anti-PD-(L)1-based therapy, received intravenous FS118 weekly with an accelerated dose titration design (800 µg to 0.3 mg/kg) followed by 3+3 ascending dose expansion (1 to 20 mg/kg). Primary objectives were safety, tolerability, and PK. Additional endpoints included antitumor activity, immunogenicity, and pharmacodynamics. RESULTS: Forty-three patients with a median of three prior regimens in the locally advanced/metastatic setting, including at least one anti-PD-(L)1 regimen, received FS118 monotherapy. FS118 was well tolerated, with no serious adverse events relating to FS118 reported. No dose-limiting toxicities (DLT) were observed, and an MTD was not reached. The recommended phase 2 dose of FS118 was established as 10 mg/kg weekly. The terminal half-life was 3.9 days. Immunogenicity was transient. Pharmacodynamic activity was prolonged throughout dosing as demonstrated by sustained elevation of soluble LAG-3 and increased peripheral effector cells. The overall disease control rate (DCR) was 46.5%; this disease control was observed as stable disease, except for one late partial response. Disease control of 54.8% was observed in patients receiving 1 mg/kg or greater who had acquired resistance to PD-(L)1-targeted therapy. CONCLUSIONS: FS118 was well tolerated with no DLTs observed up to and including 20 mg/kg QW. Further studies are warranted to determine clinical benefit in patients who have become refractory to anti-PD-(L)1 therapy. See related commentary by Karapetyan and Luke, p. 835.

Genomic Immune Evasion: Diagnostic and Therapeutic Opportunities in Head and Neck Squamous Cell Carcinomas.

Head and neck squamous cell cancers (HNSCCs) represent a diverse group of tumors emerging within different mucosal surfaces of the oral cavity, nasopharynx, oropharynx, larynx, and hypopharynx. HNSCCs share common clinical risk factors and genomic features, including smoking, alcohol, age, male sex, aneuploidy, and TP53 mutations. Viral initiating and contributing events are increasingly recognized in HNSCCs. While both Epstein-Barr Virus (EBV) and human papilloma virus (HPV) are observed, EBV is more frequently associated with nasopharyngeal cancers whereas HPV is associated with oropharyngeal cancers. HNSCCs are associated with high tumor mutational burden and loss of tumor suppressor gene function, especially in TP53 and X-linked genes. Multiple lines of evidence suggest that HNSCCs are subject to immunologic surveillance and immune-induced evolutionary pressure that correlate with negative clinical outcomes. This review will discuss genomic mechanisms related to immune-mediated pressures and propose prognostic and therapeutic implications of detectable immune escape mechanisms that drive tumorigenesis and disease progression.

Impact of early detection on cancer curability: A modified Delphi panel study.

Expert consensus on the potential benefits of early cancer detection does not exist for most cancer types. We convened 10 practicing oncologists using a RAND/UCLA modified Delphi panel to evaluate which of 20 solid tumors, representing >40 American Joint Committee on Cancer (AJCC)-identified cancer types and 80% of total cancer incidence, would receive potential clinical benefits from early detection. Pre-meeting, experts estimated how long cancers take to progress and rated the current curability and benefit (improvement in curability) of an annual hypothetical multi-cancer screening blood test. Post-meeting, experts rerated all questions. Cancers had varying estimates of the potential benefit of early cancer detection depending on estimates of their curability and progression by stage. Cancers rated as progressing quickly and being curable in earlier stages (stomach, esophagus, lung, urothelial tract, melanoma, ovary, sarcoma, bladder, cervix, breast, colon/rectum, kidney, uterus, anus, head and neck) were estimated to be most likely to benefit from a hypothetical screening blood test. Cancer types rated as progressing quickly but having comparatively lower cure rates in earlier stages (liver/intrahepatic bile duct, gallbladder, pancreas) were estimated to have medium likelihood of benefit from a hypothetical screening blood test. Cancer types rated as progressing more slowly and having higher curability regardless of stage (prostate, thyroid) were estimated to have limited likelihood of benefit from a hypothetical screening blood test. The panel concluded most solid tumors have a likelihood of benefit from early detection. Even among difficult-to-treat cancers (e.g., pancreas, liver/intrahepatic bile duct, gallbladder), early-stage detection was believed to be beneficial. Based on the panel consensus, broad coverage of cancers by screening blood tests would deliver the greatest potential benefits to patients.

Durable response of anaplastic thyroid carcinoma to FS118, a bispecific LAG-3/PD-L1 antibody, after checkpoint inhibitor progression: a case report.

Anaplastic thyroid cancer represents a rare, highly aggressive form of thyroid cancer with a poor prognosis and an overall survival ranging from 5 to 12 months. Unfortunately, treatment options remain limited, even for patients with a targetable driver mutation. Here, we present a case of a patient with a BRAF V600E-mutated, PD-L1 positive (tumor proportion score of 95%) anaplastic thyroid cancer refractory to standard therapies, including debulking surgery, followed by chemoradiation, who had further progressed on PD-1 monotherapy, and was unable to tolerate BRAF/MEK inhibition. Ongoing treatment with FS118, a bispecific LAG-3/PD-L1 antagonist, has afforded 3 years of disease control, including a late confirmed partial response, with excellent tolerability. Given this response, further investigation is required to delineate the mechanism by which dual PD-L1/LAG-3 blockade by FS118 overcomes initial PD-1 pathway resistance, and therefore, identify which patients are most likely to benefit. Simultaneously, expanded use should be considered for those with refractory disease, especially if PD-L1 positive. Insights Dual PD-L1/LAG-3 blockade may be an effective treatment strategy for refractory metastatic tumors, including anaplastic thyroid cancer.

Need for numbers: assessing cancer survivors' needs for personalized and generic statistical information.

BACKGROUND: Statistical information (e.g., on long-term survival or side effects) may be valuable for healthcare providers to share with their patients to facilitate shared decision making on treatment options. In this pre-registered study, we assessed cancer survivors' need for generic (population-based) versus personalized (tailored towards patient/tumor characteristics) statistical information after their diagnosis. We examined how information coping style, subjective numeracy, and anxiety levels of survivors relate to these needs and identified statistical need profiles. Additionally, we qualitatively explored survivors' considerations for (not) wanting statistical information. METHODS: Cancer survivors' need for statistics regarding incidence, survival, recurrence, side effects and quality of life were assessed with an online questionnaire. For each of these topics, survivors were asked to think back to their first cancer diagnosis and to indicate their need for generic and personalized statistics on a 4-point scale ('not at all'- 'very much'). Associations between information coping style, subjective numeracy, and anxiety with need for generic and personalized statistics were examined with Pearson's correlations. Statistical need profiles were identified using latent class analysis. Considerations for (not) wanting statistics were analyzed qualitatively. RESULTS: Overall, cancer survivors (n = 174) had a higher need for personalized than for generic statistics (p < .001, d = 0.74). Need for personalized statistics was associated with higher subjective numeracy (r = .29) and an information-seeking coping style (r = .41). Three statistical need profiles were identified (1) a strong need for both generic and personalized statistics (34%), (2) a stronger need for personalized than for generic statistics (55%), and (3) a little need for both generic and personalized statistics (11%). Considerations for wanting personalized cancer statistics ranged from feelings of being in control to making better informed decisions about treatment. Considerations for not wanting statistics related to negative experience with statistics and to the unpredictability of future events for individual patients. CONCLUSIONS: In light of the increased possibilities for using personalized statistics in clinical practice and decision aids, it appears that most cancer survivors want personalized statistical information during treatment decision-making. Subjective numeracy and information coping style seem important factors influencing this need. We encourage further development and implementation of data-driven personalized decision support technologies in oncological care to support patients in treatment decision making.

Long-term avelumab in advanced non-small-cell lung cancer: summaries and post hoc analyses from JAVELIN Solid Tumor.

Background: This study examined patients with advanced non-small-cell lung cancer who received long-term avelumab (anti-PD-L1) in a large phase Ib trial (JAVELIN Solid Tumor). Methods: Patients receiving >2 years of avelumab were reviewed and exploratory descriptive analyses were conducted. Results: Individuals with varying baseline characteristics who had received up to 6 years of avelumab were reviewed. Overall, 37/340 (10.9%) had received ≥2 years of treatment; in this subgroup, best response was complete response in 5.4%, partial response in 59.5% and stable disease in 29.7%; 51.4% had continued treatment beyond disease progression. Conclusions: In this study, 11% of patients with advanced non-small-cell lung cancer received ≥2 years of avelumab treatment and experienced prolonged response or continued clinical benefit. Clinical Trial Registration: NCT02395172 (ClinicalTrials.gov).

Intralesional SD-101 in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naïve Head and Neck Squamous Cell Carcinoma: Results from a Multicenter, Phase II Trial.

PURPOSE: To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks. RESULTS: A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1-11.1] months. The response rate was higher in human papillomavirus-positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1-31.7) and 64.7% (95% CI: 45.3-78.7), respectively. CONCLUSIONS: SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.

Impact of a Palliative Care Nurse Practitioner in an Oncology Clinic: A Quality Improvement Effort.

PURPOSE: Guidelines support early integration of palliative care (PC) into standard oncology practice; however, little is known as to whether outcomes can be improved by modifying health care delivery in a real-world setting. METHODS: We report our 6-year experience of embedding a nurse practitioner in an oncology clinic (March 2014-March 2020) to integrate early, concurrent advance care planning and PC. RESULTS: Compared with patients with advanced cancer not enrolled in the palliative care nurse practitioner program, in March 2020, patients who are enrolled are more likely to have higher quality of PC (eg, goals of care note documentation [82% v 15%; P < .01], referral to the psychosocial oncology program [67% v 37%; P < .01], and referral to hospice [61% v 34%; P < .01]) and less inpatient utilization in the last 6 months of life (eg, hospital days [12 v 18; P < .01] and intensive care unit days [1.2 v 2.3; P < .01]). The program expanded over time with the support of faculty skills training for advance care planning and PC, supporting a shared mental model of PC delivery within the oncology clinic. CONCLUSION: Embedding a trained palliative care nurse practitioner in oncology clinics to deliver early integrated PC can lead to improved quality of care for patients with advanced cancer.

Safety and Clinical Activity of Atezolizumab Plus Ipilimumab in Locally Advanced or Metastatic Non-Small Cell Lung Cancer: Results From a Phase 1b Trial.

BACKGROUND: This phase 1b study investigated safety and activity of combined checkpoint inhibition (CPI) with programmed death-ligand 1 (PD-L1) antibody atezolizumab plus cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab in NSCLC. PATIENTS AND METHODS: Eligible patients had previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) or melanoma. A standard 3+3 dose escalation investigated atezolizumab (600-1200 mg IV every 3 weeks) plus ipilimumab starting at 1 mg/kg, administered as a single dose or 4 doses, administered every 3 weeks. The expansion stage included a cohort previously treated with atezolizumab. Patients were monitored for safety and tolerability; response was evaluated every 6 weeks. RESULTS: Twenty-seven patients were enrolled, 4 with melanoma and 23 with NSCLC; here, we focus on data for the NSCLC population. Three of 23 patients (13.0%) received prior CPI. No dose-limiting toxicities were reported during dose escalation; dose expansion occurred with atezolizumab 1200 mg plus 1 cycle of ipilimumab 1 mg/kg. Most common treatment-emergent adverse events were dyspnea (39%) and cough (35%); treatment-related Grade ≥3 adverse events occurred in 11 patients (48%), most frequently pneumonitis (17%) and amylase or lipase elevation (9% each). Six of 23 NSCLC patients (26%) achieved confirmed responses, 5 of whom (25%) were CPI naive. Median duration of response was 23.0 (95% CI, 3.2-36.9) months overall and 36.9 (95% CI, 2.9-36.9) months in CPI-naive patients. CONCLUSION: Preliminary efficacy of atezolizumab plus ipilimumab was observed in metastatic NSCLC. The combination had manageable toxicity, with a safety profile consistent with those of the individual agents.

Implementing a Tailored Psychosocial Distress Screening Protocol in a Head and Neck Cancer Program.

OBJECTIVES/HYPOTHESIS: Psychosocial distress is common among patients with head and neck cancer (HNC) and is associated with poorer quality of life and clinical outcomes. Despite these risks, distress screening is not widely implemented in HNC care. In this study, we investigated the prevalence of psychosocial distress and its related factors in routine care of patients with HNC. METHODS: Data from medical records between September 2017 and March 2020 were analyzed. Psychosocial distress was measured by the National Comprehensive Cancer Network's Distress Thermometer (DT), and a modified HNC-specific problem list; depression and anxiety were assessed using the Patient Health Questionnaire-4. Descriptive statistics and logistic regression were conducted to report prevalence of distress, depression and anxiety, and factors associated with clinical distress. Implementation outcomes, including rates of referrals and follow-up for distressed patients, are also reported. RESULTS: Two hundred and eighty seven HNC patients completed the questionnaire (age 64.3 ± 14.9 years), with a mean distress score of 4.51 ± 3.35. Of those, 57% (n = 163) reported clinical distress (DT ≥ 4). Pain (odds ratio [OR] = 3.31, 95% CI = 1.75-6.26), fatigue (OR = 2.43, 95% CI = 1.1.7-5.05), anxiety (OR = 1.63, 95% CI = 1.30-2.05), and depression (OR = 1.51, 95% CI = 1.04-2.18) were significantly associated with clinical distress (P < .05). Of patients identified as distressed, 79% received same-day psychosocial evaluation. CONCLUSIONS: Clinical distress was identified in 57% of patients who completed the questionnaire, suggesting that an ultra-brief psychosocial screening protocol can be implemented in routine ambulatory oncology care, and identifies patients whose distress might otherwise go unrecognized. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1600-1608, 2022.

Phase Ib Study of Atezolizumab Plus Interferon-α with or without Bevacizumab in Patients with Metastatic Renal Cell Carcinoma and Other Solid Tumors.

This Phase Ib study combined programmed death-ligand 1 inhibitor, atezolizumab, with other immunomodulatory agents in locally advanced and metastatic solid tumors. Arms B-D evaluated atezolizumab plus interferon-α, with/without vascular endothelial growth factor inhibitor, bevacizumab, in renal cell carcinoma (RCC) and other solid tumors. Arm B predominantly recruited patients with previously treated RCC or melanoma to receive atezolizumab plus interferon α-2b. Arm C investigated atezolizumab plus polyethylene glycol (PEG)-interferon α-2a in previously treated RCC. Arm D evaluated atezolizumab plus PEG-interferon α-2a and bevacizumab. Primary objectives were safety and tolerability; secondary objectives included clinical activity. Combination therapy was well tolerated, with safety profiles consistent with known risks of individual agents. The most frequent treatment-related toxicities were fatigue, chills, and pyrexia. The objective response rate (ORR) in arm B was 20.0% overall and 17.8% in patients with previously treated checkpoint inhibitor-naive RCC (n = 45). No responses were reported in arm C. The highest ORR in arm D was 46.7% in patients with treatment-naive RCC (n = 15). Data showed preliminary clinical activity and acceptable tolerability of atezolizumab plus interferon α-2b in patients with previously treated checkpoint inhibitor-naive RCC and of atezolizumab plus PEG-interferon α-2a and bevacizumab in patients with treatment-naive RCC.

Avelumab for platinum-ineligible/refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck: phase Ib results from the JAVELIN Solid Tumor trial.

BACKGROUND: Recurrent and/or metastatic (R/M) disease develops in approximately 65% of patients with squamous cell carcinoma of the head and neck (SCCHN) and is associated with a poor prognosis. Immune checkpoint inhibitors have proven effective in multiple tumor types, including R/M SCCHN. We report the efficacy and safety of avelumab (antiprogrammed death ligand 1 antibody) in an expansion cohort of patients with platinum-refractory/ineligible R/M SCCHN enrolled in the phase I JAVELIN Solid Tumor trial (NCT01772004). METHODS: Eligible patients with R/M SCCHN were aged ≥18 years and had received ≥1 line of platinum-based chemotherapy with disease progression or recurrence within 6 months of the last dose or were ineligible for platinum-based chemotherapy. All patients received avelumab 10 mg/kg every 2 weeks. Tumor assessments were carried out by a blinded independent review committee (IRC) and investigators according to Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST 1.1). Key endpoints included best overall response, duration of response (DOR) and progression-free survival (PFS) assessed by IRC and investigator per RECIST 1.1, overall survival (OS), and safety. RESULTS: Between April 24, 2015, and November 13, 2015, 153 patients were enrolled. Patients had a median of two prior lines of therapy for metastatic or locally advanced disease (range 0-6); 12 patients (7.8%) were not eligible for platinum-based chemotherapy. At data cut-off (December 31, 2017), the confirmed objective response rate was 9.2% (95% CI 5.1% to 14.9%) assessed by IRC and 13.1% (95% CI 8.2% to 19.5%) assessed by investigator. Median DOR was not reached (95% CI 4.2 to not estimable) based on IRC assessment. Median PFS was 1.4 months (95% CI 1.4 to 2.6) assessed by IRC and 1.8 months (95% CI 1.4 to 2.7) assessed by investigator; median OS was 8.0 months (95% CI 6.5 to 10.2). Any-grade treatment-related adverse events (TRAEs) occurred in 83 patients (54.2%) and were grade ≥3 in 10 patients (6.5%). The most common TRAEs were fatigue (n=19, 12.4%), fever (n=14, 9.2%), pruritus (n=12, 7.8%), and chills (n=11, 7.2%), and there were no treatment-related deaths. CONCLUSION: Avelumab showed clinical activity and was associated with a low rate of grade ≥3 TRAEs in heavily pretreated patients with platinum-refractory/ineligible R/M SCCHN.

Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial.

BACKGROUND: Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC. METHODS: This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants. FINDINGS: Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation. FUNDING: Merck Sharp & Dohme.

Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations.

PURPOSE: Mutations in the HRAS (mHRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M mHRAS HNSCC. METHODS: We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for mHRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with mHRAS variant allele frequency (VAF) data, enrollment was limited to those with a mHRAS VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. RESULTS: Of the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%). CONCLUSION: Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist (NCT02383927).