First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.

BACKGROUND: Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC. METHODS: We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more. RESULTS: Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. CONCLUSIONS: Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.

BACKGROUND: Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rßγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS: In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 µg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS: Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 µg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION: ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING: Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions.

PURPOSE: Although several agents targeting epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. METHODS: This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. RESULTS: Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. CONCLUSION: Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

Association of age with survival in older patients with cutaneous melanoma treated with immune checkpoint inhibitors.

INTRODUCTION: Several types of immune checkpoint inhibitors (ICIs) are approved to treat advanced melanoma, but their effectiveness has not been compared in older patients treated outside of a clinical trial. Moreover, evidence suggests that a patient's response to ICI therapy may vary by age and type of ICI. The purpose of this study was to compare survival by ICI type in older patients with melanoma and to investigate treatment effect modification by age. MATERIALS AND METHODS: Using the SEER-Medicare database, we identified patients with cutaneous melanoma (2012-2015) treated with an ICI (CTLA-4, PD-1, or combination CTLA-4 + PD-1 inhibitors). Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for ICI types. We used an interaction term and stratified models to test for treatment effect modification by age. RESULTS: Of the 1435 patients included in our analysis, 790 (55.1%) received CTLA-4 inhibitors, 512 (35.7%) received PD-1 inhibitors, and 133 (9.3%) were treated with combination ICIs. Median survival ranged from 13.4 months (95%CI: 10.7-16.3) for CTLA-4 inhibitors to 23.5 months (95%CI: 16.2-30.0) for combination ICIs. In multivariable models, the risk of death was lower with PD-1 inhibitors compared to CTLA-4 inhibitors (HR = 0.78, 95%CI: 0.68-0.89). An age*ICI type interaction term was significant (p < 0.001), and survival gains were greater the older age group (≥80) compared to the younger group (65-79). DISCUSSION: In a population-based setting, we identified important differences in survival by ICI type in older patients with melanoma treated with ICIs, with prolonged survival associated with PD-1 inhibitors compared to CTLA-4 inhibitors.

Immune checkpoint inhibitors retain effectiveness in older patients with cutaneous metastatic melanoma.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have dramatically changed the treatment landscape for advanced melanoma, but their use in older patients remains understudied. An age-related decline in immune function is of concern when treating older patients because host immune factors can influence clinical outcomes with immunotherapy. Therefore, we aimed to evaluate the effectiveness of ICIs in patients 65 years and older. METHODS: Using the SEER-Medicare data, we evaluated survival by first systemic treatment type in a retrospective cohort study of patients aged 65 years and older who were diagnosed with stage IV cutaneous melanoma between 2012 and 2015. Cox proportional hazards regression was used to estimate hazard ratios (HR) and their corresponding 95% confidence intervals. RESULTS: A total of 541 patients were included in this study. Median survival differed significantly between groups (p < 0.0001) and was longest in patients treated with PD-1 inhibitors (34.0 months), followed by CTLA-4 inhibitors (16.8 months), targeted therapy (9.7 months), chemotherapy (7.1 months), and no systemic therapy (3.6 months). The ICI survival benefit persisted after adjusting for age, sex, comorbidities, M stage, the presence of brain metastases, and evaluation at an NCI-designated cancer center. Hazard ratios comparing ICIs to no systemic therapy were 0.35 (95% CI: 0.24-0.52) for PD-1 inhibitors and 0.48 (95% CI: 0.37-0.63) for CTLA-4 inhibitors. We did not observe a difference in ICI effectiveness by age group (65-74 vs ≥75). CONCLUSIONS: In a nationally representative cohort of patients with advanced melanoma, ICI therapy delivered in a real world setting significantly improved survival in patients aged 65 years and older.

A Phase 1-2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC.

INTRODUCTION: This open-label, phase 1-2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). METHODS: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. RESULTS: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. CONCLUSIONS: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.

Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma.

Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear. Using a Simon's two-stage design, we present results of a single-arm phase-II trial where 12 patients with stage II-IVA OCSCC received 3 to 4 biweekly doses of 3 mg/kg nivolumab followed by definitive surgical resection with curative intent. Presurgical nivolumab therapy in this cohort shows an overall response rate of 33% (n = 4 patients; 95% CI: 12%-53%). With a median follow up of 2.23 years, 10 out of 12 treated patients remain alive. Neoadjuvant nivolumab is safe, well-tolerated, and is not associated with delays in definitive surgical treatment in this study. This work demonstrates feasibility and safety for incorporation of nivolumab in the neoadjuvant setting for OCSCC (ClinicalTrials.gov: NCT03021993).

IL-2 and Beyond in Cancer Immunotherapy.

The development of the T- and natural killer (NK) cell growth factor IL-2 has been a sentinel force ushering in the era of immunotherapy in cancer. With the advent of clinical grade recombinant IL-2 in the mid-1980s, oncologists could for the first time directly manipulate lymphocyte populations with systemic therapy. By itself, recombinant IL-2 can induce clinical responses in up to 15% of patients with metastatic cancer or renal cell carcinoma. When administered with adoptively transferred tumor-reactive lymphocytes, IL-2 promotes T cell engraftment and response rates of up to 50% in metastatic melanoma patients. Importantly, these IL-2-driven responses can yield complete and durable responses in a subset of patients. However, the use of IL-2 is limited by toxicity and concern of the expansion of T regulatory cells. To overcome these limitations and improve response rates, other T cell growth factors, including IL-15 and modified forms of IL-2, are in clinical development. Administering T cell growth factors in combination with other agents, such as immune checkpoint pathway inhibitors, may also improve efficacy. In this study, we review the development of T- and NK cell growth factors and highlight current combinatorial approaches based on these reagents.

Enhanced Lymphodepletion Is Insufficient to Replace Exogenous IL2 or IL15 Therapy in Augmenting the Efficacy of Adoptively Transferred Effector CD8+ T Cells.

Effector CD8+ T cells conditioned with IL12 during activation mediate enhanced antitumor efficacy after adoptive transfer into lymphodepleted hosts; this is due in part to improved IL7 responsiveness. Therefore, we hypothesized that increasing the intensity or type of lymphodepletion would deplete more IL7-consuming host cells and improve the persistence and antitumor activity of IL12-conditioned CD8+ T cells. Using cyclophosphamide, fludarabine, and total body irradiation (TBI, 6 Gy) either individually or in combination, we found that combined lymphodepletion best enhanced T-cell engraftment in mice. This improvement was strongly related to the extent of leukopenia, as posttransfer levels of donor T cells inversely correlated to host cell counts after lymphodepletion. Despite the improvement in engraftment seen with combination lymphodepletion, dual-agent lymphodepletion did not augment the antitumor efficacy of donor T cells compared with TBI alone. Similarly, IL7 supplementation after TBI and transfer of tumor-reactive T cells failed to improve persistence or antitumor immunity. However, IL15 or IL2 supplementation greatly augmented the persistence and antitumor efficacy of donor tumor-reactive T cells. Our results indicate that the amount of host IL7 induced after single agent lymphodepletion is sufficient to potentiate the expansion and antitumor activity of donor T cells, and that the efficacy of future regimens may be improved by providing posttransfer support with IL2 or IL15.Significance: The relationship between lymphodepletion and cytokine support plays a critical role in determining donor T-cell engraftment and antitumor efficacy. Cancer Res; 78(11); 3067-74. ©2018 AACR.

Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma.

Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response.Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes.Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival.Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250-60. ©2018 AACR.

ß-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity.

ICOS costimulation generates Th17 cells with durable memory responses to tumor. Herein, we found that ICOS induces PI3K/p110δ/Akt and Wnt/ß-catenin pathways in Th17 cells. Coinhibiting PI3Kδ and ß-catenin altered the biological fate of Th17 cells. Th17 cells inhibited of both pathways expressed less RORγt, which, in turn, reduced their ability to secrete IL-17. Unexpectedly, these cells were more effective (than uninhibited cells) at regressing tumor when infused into mice, leading to long-term curative responses. PI3Kδ inhibition expanded precursor Th17 cells with a central memory phenotype that expressed nominal regulatory properties (low FoxP3), while ß-catenin inhibition enhanced Th17 multifunctionality in vivo. Remarkably, upon TCR restimulation, RORγt and IL-17 rebounded in Th17 cells treated with PI3Kδ and ß-catenin inhibitors. Moreover, these cells regained ß-catenin, Tcf7, and Akt expression, licensing them to secrete heightened IL-2, persist, and eradicate solid tumors without help from endogenous NK and CD8 T cells. This finding shines a light on ways to repurpose FDA-approved drugs to augment T cell-based cancer immunotherapies.

Neutrophil-to-lymphocyte ratio and overall survival in all sites of head and neck squamous cell carcinoma.

BACKGROUND: Current prognostic criteria are insufficient in predicting outcomes in head and neck cancer, necessitating new, readily available biomarkers. METHODS: Pretreatment neutrophil and lymphocyte counts and their ratio (NLR) were retrospectively investigated for correlation with overall survival while controlling for demographic and clinical confounders. RESULTS: Patients in the highest tertile of neutrophil counts and those in the lowest tertile of lymphocytes experienced shorter survival than the rest of the population. Patients in the highest tertile of the NLR were at a higher risk compared with those in the lowest tertile after multivariate analysis (hazard ratio [HR] = 2.39; p = .0001). Additionally, NLR was lower in patients with human papillomavirus (HPV)-positive tumors compared to HPV-negative tumors and predicted survival in both tumor types. CONCLUSION: Neutrophil and lymphocyte counts are strong biomarkers with opposing prognostic significance and the NLR is a robust predictor of overall survival in oral, pharyngeal, and laryngeal squamous cell carcinomas. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1068-E1074, 2016.

Chemoprevention of squamous cell carcinoma of the head and neck.

PURPOSE OF REVIEW: The aim of this article is to summarize progress in understanding of the biology of squamous cell carcinoma of the head and neck and of trials to prevent malignant conversion of oral premalignant lesions and the development of second primary tumors in those already treated for squamous cell carcinoma of the head and neck. RECENT FINDINGS: The understanding of squamous cell carcinoma of the head and neck biology is rapidly evolving. Clinical trials for chemoprevention are involving more diverse regimens, following disappointing results of retinoid monotherapy. In-vitro and animal studies form the rationale for the next generation of studies, employing combination, synergistic treatments. SUMMARY: Based on trial data to date, no recommendation for intervention with a chemopreventive agent can be made. It is clear, however, that smoking cessation is an effective intervention for preventing oral premalignant lesions and second primary tumors. Promising trials are being conducted and designed currently. The future of this area of study will involve rational choice of multidrug regimens based on current understanding of the biology of squamous cell carcinoma of the head and neck.