Pragmaticism in Cancer Clinical Trials.

Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.

A process to reanalyze clinical DNA sequencing data for biomarker matching in the Lung-MAP Master Protocol.

For cancer clinical trials that require central confirmation of tumor genomic profiling, exhaustion of tissue from standard-of-care testing may prevent enrollment. For Lung-MAP, a master protocol that requires results from a defined centralized clinical trial assay to assign patients to a therapeutic substudy, we developed a process to repurpose existing commercial vendor raw genomic data for eligibility: genomic data reanalysis (GDR). Molecular results for substudy assignment were successfully generated for 369 of the first 374 patients (98.7%) using GDR for Lung-MAP, with a median time from request to result of 9 days. During the same period, 691 of 791 (87.4%) tissue samples received successfully yielded results, in a median of 14 days beyond sample acquisition. GDR is a scalable bioinformatic pipeline that expedites reanalysis of existing data for clinical trials in which validated integral biomarker testing is required for participation.

Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial.

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. CONCLUSIONS: The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC.

Perioperative Chemotherapy and Chemoradiotherapy for Patients With Resectable and Borderline Resectable Pancreatic Adenocarcinoma.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the United States. Most patients who undergo resection develop recurrence. Standard treatment confers a median overall survival (OS) of 24 months. Exposure to alternate regimens may prevent chemoresistance. This study evaluated multiagent perioperative therapy for potentially resectable PDA patients to improve OS. METHODS: A single center, phase 2, trial of patients with resectable or borderline resectable PDA. Patients received neoadjuvant therapy with induction chemotherapy (gemcitabine, docetaxel, capecitabine) for 3 cycles, chemoradiation (intensity-modulated radiation therapy with capecitabine and oxaliplatin) followed by surgery, and 2 months of adjuvant gemcitabine and oxaliplatin and 2 months of gemcitabine. The primary endpoint was OS. The secondary endpoint was recurrence-free survival (RFS). RESULTS: Thirty-two eligible patients were enrolled. Twenty-two patients underwent surgical resection. After a median follow-up of 56.8 months, mOS was 31.6 months (95% confidence interval [CI], 14.2-58.1) for all patients, 58.1 months (95% CI, 31.6 to NR) for those who completed surgery. The mRFS was 31.3 months (95% CI, 12.5 to NR). CONCLUSIONS: Perioperative therapy with GTX, chemoradiotherapy, and adjuvant GemOx/Gem resulted in promising survival of 58 months for patients who underwent resection and may represent another treatment option for PDA.

Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).

PURPOSE: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. METHODS: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons. RESULTS: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001). CONCLUSION: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

Racial disparities in the screening mammography continuum within a heterogeneous health care system.

BACKGROUND: Decreased mammography drives breast cancer disparities. Black women have lower rates of mammography completion than White women, and this contributes to disparities in outcomes. Points of disparity along the continuum for screening mammography remain underresearched. METHODS: The authors compared mammography referrals for Black and White women aged 40-74 years at a heterogeneous academic medical center. Completion of steps of the screening mammography continuum was compared between Black and White women within two age cohorts: 40-49 and 50-74 years. Multivariable logistic regression was used to evaluate the association between race and mammogram completion. RESULTS: Among 26,476 women, 3090 (12%) were Black, and 23,386 (88%) were White. Among Black women aged 50-74 years who were due for mammography, 40% had referrals, 39% were scheduled, and 21% completed mammography; the corresponding values for White women were 42%, 41%, and 27%, respectively. Similar differences in referral outcomes were noted for women aged 40-49 years, although Black women had lower rates of provider-initiated referrals (9% vs. 13%). Adjusted analyses for those aged 40-49 and 50-74 years demonstrated an association between Black race and lower rates of mammography completion (odds ratio [OR] for 40-49 years, 0.74; 95% CI, 0.57-0.95; p = .02; OR for 50-74 years, 0.85; 95% CI, 0.74-0.98; p = .02). In multivariable analyses, noncommercial insurance and higher comorbidity were associated with lower rates of mammography. Provider-initiated referral was positively correlated to mammogram completion. CONCLUSIONS: Black race was associated with 15%-26% lower mammography completion (adjusted). Both groups experienced the highest attrition after scheduling mammograms, although attrition was more precipitous for Black women. These findings have implications for future interventions, including increasing provider-initiated referrals and decreasing barriers to attending scheduled mammograms.

Racial and sex differences in tumor genomics in urothelial carcinoma.

PURPOSE: Differences in bladder cancer outcomes have been demonstrated by sex and race/ethnicity, with studies showing a higher burden of adverse outcomes among women and racially minoritized populations. Despite these epidemiologic differences, populations with disproportionally adverse outcomes are often underrepresented in genomic cohorts. This exclusion impacts the accuracy and generalizability of genomic studies in bladder cancer and has the potential to widen disparities by sex and/or race/ethnicity. BASIC PROCEDURES: We analyzed pooled somatic mutational data from publicly available cohorts in the cBioPortal open access platform. FINDINGS: A total of 796 unique patients were identified. Average age for the cohort was 67 years (range: 25-98 years), 188 (24%) were female, and the majority were White (n = 423, 85% among those who report race). Median total mutation count was 91 (IQR: 20, 202) per patient. We used multivariable logistic regression to independently evaluate the association between race/sex and mutation status in each of 122 genes of interest, identified from TCGA, adjusting for age and bladder cancer invasive status. In adjusted analyses, male sex was associated with increased risk of mutation in ARID1A, CHD6, and NCOR1 compared with female sex. White race was associated with increased risk of mutation in ARID1A, EP300, PIK3CA, and TP53 and decreased risk of mutation in HRAS compared with non-White race. CONCLUSIONS: These differences highlight the importance of enriching cohorts for female and non-White patients in genomic studies and clinical trials, especially as we test the use of molecular biomarkers to personalize care for patients with bladder cancer.

Elevated EVL Methylation Level in the Normal Colon Mucosa Is a Potential Risk Biomarker for Developing Recurrent Adenomas.

BACKGROUND: Individuals with adenomatous colorectal polyps undergo repeated colonoscopy surveillance to identify and remove metachronous adenomas. However, many patients with adenomas do not develop recurrent adenomas. Better methods to evaluate who benefits from increased surveillance are needed. We evaluated the use of altered EVL methylation as a potential biomarker for risk of recurrent adenomas. METHODS: Patients with ≥1 colonoscopy had EVL methylation (mEVL) measured with an ultra-accurate methylation-specific droplet digital PCR assay on normal colon mucosa. The association between EVL methylation levels and adenoma or colorectal cancer was evaluated using three case/control definitions in three models: unadjusted (model 1), adjusting for baseline characteristics (model 2), and an adjusted model excluding patients with colorectal cancer at baseline (model 3). RESULTS: Between 2001 and 2020, 136 patients were included; 74 healthy patients and 62 patients with a history of colorectal cancer. Older age, never smoking, and baseline colorectal cancer were associated with higher levels of mEVL (P ≤ 0.05). Each log base 10 difference in mEVL was associated with an increased risk of adenoma(s) or cancer at/after baseline for model 1 [OR, 2.64; 95% confidence interval (CI), 1.09-6.36], and adenoma(s) or cancer after baseline for models 1 (OR, 2.01; 95% CI, 1.04-3.90) and model 2 (OR, 3.17; 95% CI, 1.30-7.72). CONCLUSIONS: Our results suggest that EVL methylation level detected in the normal colon mucosa has the potential to be a biomarker for monitoring the risk for recurrent adenomas. IMPACT: These findings support the potential utility of EVL methylation for improving the accuracy for assigning risk for recurrent colorectal adenomas and cancer.

Phase II Study of Docetaxel and Trametinib in Patients with KRAS Mutation Positive Recurrent Non-Small Cell Lung Cancer (NSCLC; SWOG S1507, NCT-02642042).

PURPOSE: Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC. PATIENTS AND METHODS: S1507 is a single-arm phase II study assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients, with at least 25 with G12C mutation. The design was two-stage design to rule out a 17% RR, within the overall population at the one-sided 3% level and within the G12C subset at the 5% level. RESULTS: Between July 18, 2016, and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% [95% confidence interval (CI), 22-48] overall and 28% (95% CI, 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, and neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR, 2.85; 95% CI, 1.16-7.01), and RR (0% vs. 56%, P = 0.004) were worse in patients with TP53 mutated versus wild-type cancers. CONCLUSIONS: RRs were significantly improved in the overall population. Contrary to preclinical studies, the combination showed no improvement in efficacy in G12C patients. Comutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation. See related commentary by Cantor and Aggarwal, p. 3563.

Novel Approaches for Dynamic Visualization of Adverse Event Data in Oncology Clinical Trials: A Case Study Using Immunotherapy Trial S1400-I (SWOG).

PURPOSE: Clinical trial adverse event (AE) data are increasingly complex and high-dimensional, especially for trials evaluating novel targeted agents and immunotherapies. Standard approaches to summarize and analyze AEs remain generally tabular, failing to describe the nature of AEs. Novel dynamic and data visualization methods are needed to enable a more comprehensive assessment of the overall toxicity profile of treatments. METHODS: We developed methods for visualizing the numerous categorizations and types of AEs along with a dynamic approach to better reflect its highly dimensional nature without sacrificing the reporting of rare events. Circular plots displaying the proportion of maximal-grade AEs by system organ classes (SOCs) and butterfly plots displaying the proportion of AEs by severity for each AE term were developed to enable comparisons of AE patterns by treatment arm. These approaches were applied to a randomized phase III trial (S1400I; ClinicalTrials.gov identifier: NCT02785952) comparing nivolumab with nivolumab plus ipilimumab in patients with stage IV squamous non-small-cell lung cancer. RESULTS: Our visualizations revealed that patients randomly assigned to nivolumab and ipilimumab had higher rates of grade 3 or higher AEs compared with nivolumab alone for several SOCs, including musculoskeletal (5.6% v 0.8%), skin (5.6% v 0.8%), vascular (5.6% v 1.6%), and cardiac (4% v 1.6%) toxicities. They also suggested a pattern of higher prevalence of moderate GI and endocrine toxicities and showed that although the rates of cardiac and neurologic toxicities were similar, the types of events were discordant. CONCLUSION: The graphical approaches we proposed enable a more comprehensive and intuitive evaluation of toxicity types by treatment groups, which is not apparent in tabular and descriptive reporting methods.

Quality-of-life outcomes and risk prediction for patients randomized to nivolumab plus ipilimumab vs nivolumab on LungMAP-S1400I.

BACKGROUND: An important issue for patients with cancer treated with novel therapeutics is how they weigh the effects of treatment on survival and quality of life (QOL). We compared QOL in patients enrolled to SWOG S1400I, a substudy of the LungMAP biomarker-driven master protocol. METHODS: SWOG S1400I was a randomized phase III trial comparing nivolumab plus ipilimumab vs nivolumab for treatment of immunotherapy-naïve disease in advanced squamous cell lung cancer. The primary endpoint was the MD Anderson Symptom Inventory-Lung Cancer severity score at week 7 and week 13 with a target difference of 1.0 points, assessed using multivariable linear regression. A composite risk model for progression-free and overall survival was derived using best-subset selection. RESULTS: Among 158 evaluable patients, median age was 67.6 years and most were male (66.5%). The adjusted MD Anderson Symptom Inventory-Lung Cancer severity score was 0.04 points (95% confidence interval [CI] = -0.44 to 0.51 points; P = .89) at week 7 and 0.12 points (95% CI = -0.41 to 0.65; P = .66) at week 13. A composite risk model showed that patients with high levels of appetite loss and shortness of breath had a threefold increased risk of progression or death (hazard ratio [HR] = 3.06, 95% CI = 1.88 to 4.98; P < .001) and that those with high levels of both appetite loss and work limitations had a fivefold increased risk of death (HR = 5.60, 95% CI = 3.27 to 9.57; P < .001)-compared with those with neither risk category. CONCLUSIONS: We found no evidence of a benefit of ipilimumab added to nivolumab compared with nivolumab alone for QOL in S1400I. A risk model identified patients at high risk of poor survival, demonstrating the prognostic relevance of baseline patient-reported outcomes even in those with previously treated advanced cancer.

A prospective study of clinical outcomes of HIV-associated and HIV-negative Kaposi sarcoma in Uganda.

OBJECTIVE: Improved understanding of the effect of HIV infection on Kaposi sarcoma (KS) presentation and outcomes will guide development of more effective KS staging and therapeutic approaches. We enrolled a prospective cohort of epidemic (HIV-positive; HIV + KS) and endemic (HIV-negative; HIV - KS) KS patients in Uganda to identify factors associated with survival and response. METHODS: Adults with newly diagnosed KS presenting for care at the Uganda Cancer Institute (UCI) in Kampala, Uganda, between October 2012 and December 2019 were evaluated. Participants received chemotherapy per standard guidelines and were followed over 1 year to assess overall survival (OS) and treatment response. RESULTS: Two hundred participants were enrolled; 166 (83%) had HIV + KS, and 176 (88%) were poor-risk tumor (T1) stage. One-year OS was 64% (95% confidence interval [CI] 57-71%), with the hazard of death nearly threefold higher for HIV + KS (hazard ratio [HR] = 2.93; P  = 0.023). Among HIV + KS, abnormal chest X-ray (HR = 2.81; P  = 0.007), lower CD4 + T-cell count (HR = 0.68 per 100 cells/µl; P  = 0.027), higher HIV viral load (HR = 2.22 per log 10  copies/ml; P  = 0.026), and higher plasma Kaposi sarcoma-associated herpesvirus (KSHV) copy number (HR = 1.79 per log 10  copies/ml; P  = 0.028) were associated with increased mortality. Among HIV - KS, factors associated with mortality included Karnofsky score <70 (HR = 9.17; P  = 0.045), abnormal chest X-ray (HR = 8.41; P  = 0.025), and higher plasma KSHV copy number (HR = 6.21 per log 10  copies/ml; P  < 0.001). CONCLUSIONS: Although survival rates were better for HIV - KS than HIV + KS, the high mortality rate seen in both groups underscores the urgent need to identify new staging and therapeutic approaches. Factors associated with mortality, including high plasma KSHV, may serve as important targets of therapy.

Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A.

PURPOSE: Resistance to immune checkpoint inhibition (ICI) in advanced non-small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. METHODS: In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. RESULTS: Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. CONCLUSION: This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

Circulating Tumor DNA Kinetics Predict Progression-Free and Overall Survival in EGFR TKI-Treated Patients with EGFR-Mutant NSCLC (SWOG S1403).

PURPOSE: Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome. EXPERIMENTAL DESIGN: Serial plasma ctDNA (baseline, 8 weeks, and at progression) was prospectively incorporated into the SWOG S1403 clinical trial of afatinib ± cetuximab in tyrosine kinase inhibitor-naïve, EGFR mutation tissue-positive non-small cell lung cancer. RESULTS: EGFR mutations were detected in baseline ctDNA in 77% (82/106) of patients, associated with the presence of brain and/or liver metastases and M1B stage. Complete clearance of EGFR mutations in ctDNA by 8 weeks was associated with a significantly decreased risk of progression, compared with those with persistent ctDNA at Cycle 3 Day 1 [HR, 0.23; 95% confidence interval (CI), 0.12-0.45; P < 0.0001], with a median progression-free survival (PFS) of 15.1 (95% CI, 10.6-17.5) months in the group with clearance of ctDNA versus 4.6 (1.7-7.5) months in the group with persistent ctDNA. Clearance was also associated with a decreased risk of death (HR, 0.44; 95% CI, 0.21-0.90), P = 0.02; median overall survival (OS): 32.6 (23.5-not estimable) versus 15.6 (4.9-28.3) months. CONCLUSIONS: Plasma clearance of mutant EGFR ctDNA at 8 weeks was highly and significantly predictive of PFS and OS, outperforming RECIST response for predicting long-term benefit.

EGFR High Copy Number Together With High EGFR Protein Expression Predicts Improved Outcome for Cetuximab-based Therapy in Squamous Cell Lung Cancer: Analysis From SWOG S0819, a Phase III Trial of Chemotherapy With or Without Cetuximab in Advanced NSCLC.

BACKGROUND: The phase III S0819 trial investigated addition of cetuximab to first-line chemotherapy (CT) in NSCLC. Subgroup analyses suggested an OS benefit among patients with EGFR copy number gain in squamous cell carcinomas (SCC), (HR = 0.58 [0.39-0.86], P = .0071). A more detailed model based on EGFR FISH, EGFR IHC and KRAS mutation status was evaluated to yield a more precise predictive paradigm of cetuximab-based therapy in advanced NSCLC. METHODS: FISH was performed using the Colorado Scoring Criteria; H-Score was used to quantify EGFR IHC expression (cut-off ≥ 200). A Cox model was used to assess treatment effects for OS and PFS within biomarker and clinical subgroups. KRAS mutation was analyzed using Therascreen. The false discovery rate controlled for multiple comparisons. S0819 ClinicalTrials.gov Identifier: NCT00946712. RESULTS: Of 1,313 eligible patients, assay results were obtained for FISH on 976 patients (41% positive), for IHC on 945 patients (31% positive), and KRAS mutation status on 627 patients (26% positive). In SCC patients, OS was significantly improved with addition of cetuximab when both EGFR FISH and EGFR IHC were positive (N = 58), (OS HR: 0.32 [95% CI 0.18-0.59]; P = .0002, q = 0.08), median 12.6 versus 4.6 months. The results were independent of KRAS mutation status. In Non-SCC, no predictive value of EGFR IHC, EGFR FISH status and/or KRAS status was seen. CONCLUSIONS: In NSCLC SCC, a combination index of EGFR FISH plus EGFR IHC results was associated with improved OS when cetuximab was added to CT, representing a potential predictive molecular paradigm for patients suitable for EGFR-antibody therapy.

Phase II study of durvalumab plus tremelimumab as therapy for patients with previously treated anti-PD-1/PD-L1 resistant stage IV squamous cell lung cancer (Lung-MAP substudy S1400F, NCT03373760).

INTRODUCTION: S1400F is a non-match substudy of Lung Cancer Master Protocol (Lung-MAP) evaluating the immunotherapy combination of durvalumab and tremelimumab to overcome resistance to anti-programmed death ligand 1 (PD-(L)1) therapy in patients with advanced squamous lung carcinoma (sq non-small-cell lung cancer (NSCLC)). METHODS: Patients with previously treated sqNSCLC with disease progression after anti-PD-(L)1 monotherapy, who did not qualify for any active molecularly targeted Lung-MAP substudies, were eligible. Patients received tremelimumab 75 mg plus durvalumab 1500 mg once every 28 days for four cycles then durvalumab alone every 28 days until disease progression. The primary endpoint was the objective response rate (RECIST V.1.1). Primary and acquired resistance cohorts, defined as disease progression within 24 weeks versus ≥24 weeks of starting prior anti-PD-(L)1 therapy, were analyzed separately and an interim analysis for futility was planned after 20 patients in each cohort were evaluable for response. RESULTS: A total of 58 eligible patients received drug, 28 with primary resistance and 30 with acquired resistance to anti-PD-(L)1 monotherapy. Grade ≥3 adverse events at least possibly related to treatment were seen in 20 (34%) patients. The response rate in the primary resistance cohort was 7% (95% CI 0% to 17%), with one complete and one partial response. No responses were seen in the acquired resistance cohort. In the primary and resistance cohorts the median progression-free survival was 2.0 months (95% CI 1.6 to 3.0) and 2.1 months (95% CI 1.6 to 3.2), respectively, and overall survival was 7.7 months (95% CI 4.0 to 12.0) and 7.6 months (95% CI 5.3 to 10.2), respectively. CONCLUSION: Durvalumab plus tremelimumab had minimal activity in patients with advanced sqNSCLC progressing on prior anti-PD-1 therapy.Trial registration numberNCT03373760.

Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer: The Lung-MAP S1400I Phase 3 Randomized Clinical Trial.

IMPORTANCE: Nivolumab plus ipilimumab is superior to platinum-based chemotherapy in treatment-naive advanced non-small cell lung cancer (NSCLC). Nivolumab is superior to docetaxel in advanced pretreated NSCLC. OBJECTIVE: To determine whether the addition of ipilimumab to nivolumab improves survival in patients with advanced, pretreated, immunotherapy-naive squamous (Sq) NSCLC. DESIGN, SETTING, AND PARTICIPANTS: The Lung Cancer Master Protocol (Lung-MAP) S1400I phase 3, open-label randomized clinical trial was conducted from December 18, 2015, to April 23, 2018, randomizing patients in a 1:1 ratio to nivolumab alone or combined with ipilimumab. The median follow-up in surviving patients was 29.5 months. The trial was conducted through the National Clinical Trials Network and included patients with advanced immunotherapy-naive SqNSCLC and a Zubrod score of 0 (asymptomatic) to 1 (symptomatic but completely ambulatory) with disease progression after standard platinum-based chemotherapy. Randomization was stratified by sex and number of prior therapies (1 vs 2 or more). Data were analyzed from May 3, 2018, to February 1, 2021. INTERVENTIONS: Nivolumab, 3 mg/kg intravenously every 2 weeks, with or without ipilimumab, 1 mg/kg intravenously every 6 weeks, until disease progression or intolerable toxic effects. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (IA-PFS) and response per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1. RESULTS: Of 275 enrolled patients, 252 (mean age, 67.5 years [range 41.8-90.3 years]; 169 men [67%]; 206 White patients [82%]) were deemed eligible (125 randomized to nivolumab/ipilimumab and 127 to nivolumab). The study was closed for futility at a planned interim analysis. Overall survival was not significantly different between the groups (hazard ratio [HR], 0.87; 95% CI, 0.66-1.16; P = .34). Median survival was 10 months (95% CI, 8.0-14.4 months) in the nivolumab/ipilimumab group and 11 months (95% CI, 8.6-13.7 months) in the nivolumab group. The IA-PFS HR was 0.80 (95% CI, 0.61-1.03; P = .09); median IA-PFS was 3.8 months (95% CI, 2.7-4.4 months) in the nivolumab/ipilimumab group and 2.9 months (95% CI, 1.8-4.0 months) in the nivolumab alone group. Response rates were 18% (95% CI, 12%-25%) with nivolumab/ipilimumab and 17% (95% CI, 10%-23%) with nivolumab. Median response duration was 28.4 months (95% CI, 4.9 months to not reached) with nivolumab/ipilimumab and 9.7 months with nivolumab (95% CI, 4.2-23.1 months). Grade 3 or higher treatment-related adverse events occurred in 49 of 124 patients (39.5%) who received nivolumab/ipilimumab and in 41 of 123 (33.3%) who received nivolumab alone. Toxic effects led to discontinuation in 31 of 124 patients (25%) on nivolumab/ipilimumab and in 19 of 123 (15%) on nivolumab. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor-naive SqNSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02785952.