Cabozantinib Plus Atezolizumab or Cabozantinib Alone in Patients With Advanced NSCLC Previously Treated With an Immune Checkpoint Inhibitor: Results From the Phase 1b COSMIC-021 Study.

Introduction: We evaluated efficacy and safety of cabozantinib plus atezolizumab or cabozantinib alone in advanced NSCLC previously treated with an immune checkpoint inhibitor (ICI). Methods: COSMIC-021 (NCT03170960) is a phase 1b, multicenter study in advanced solid tumors. This analysis included patients with stage IV non-squamous NSCLC without actionable genomic aberrations in EGFR, ALK, ROS1, or BRAF-V600E who progressed on one prior ICI and less than or equal to two prior lines of systemic anticancer therapy. Patients received cabozantinib 40 mg orally/day plus atezolizumab 1200 mg intravenously every three weeks (combination cohort) or cabozantinib 60 mg orally/day (single-agent cabozantinib cohort). Primary end point of the combination cohort was objective response rate per Response Evaluation Criteria in Solid Tumors v1.1 by investigator. Outcomes in the single-agent cabozantinib cohort were exploratory. Results: Eighty-one patients assigned to combination therapy and 31 assigned to single-agent cabozantinib received greater than or equal to one dose of study treatment. Median (range) follow-up was 26.1 months (12.1-44.2) and 22.4 months (1.5-29.0), respectively. Objective response rate was 20% (95% confidence interval: 11.7%-30.1%) in combination cohort and 6% (95% confidence interval: 0.8%-21.4%) in single-agent cabozantinib cohort. Treatment-related adverse events (TRAEs) occurred in 86% of patients in the combination cohort and 90% in the single-agent cabozantinib cohort; grade 3/4 TRAEs were 44% and 48%, respectively. There were two grade 5 TRAEs: pneumonitis (n = 1, combination) and gastric ulcer hemorrhage (n = 1, single-agent). Neither PD-L1 expression in tumor cells nor tumor mutation burden correlated with outcomes. Conclusions: Cabozantinib plus atezolizumab demonstrated modest clinical activity and manageable toxicity in advanced NSCLC after progression on prior ICI.

Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

BACKGROUND: Major histocompatibility complex class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression. METHODS: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single-cell neighborhoods from mIF images followed by multivariate discriminant analysis. RESULTS: Spatial quantitation of tumor cell MHC-I expression revealed intratumoral and intertumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56+ cell numbers in patient tumors were positively associated with disease-free survival (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56+ and CD8+ cells (HR=0.199, p<1×10-3). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3+CD8+ T cells and CD3-CD56+ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single-cell neighborhood profiles to delineate the cellular environments of IFNγ+/- NK cells and T cells. We discovered that both IFNγ+ NK and CD8 T cells were more frequently associated with other IFNγ+ lymphocytes in comparison to IFNγ- NK cells and CD8 T cells (p<1×10-30). Moreover, IFNγ+ lymphocytes were most often found clustered near MHC-I+ tumor cells. CONCLUSIONS: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Coassociation of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent colocalization of IFNγ+ NK cells with other IFNγ+ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.

Dynamic Changes in Circulating Tumor Fraction as a Predictor of Real-World Clinical Outcomes in Solid Tumor Malignancy Patients Treated with Immunotherapy.

INTRODUCTION: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. METHODS: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15-180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. RESULTS: The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). CONCLUSIONS: xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy.

Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

Background: MHC class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression. Methods: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single cell neighborhoods from mIF images followed by multivariate discriminant analysis. Results: Spatial quantitation of tumor cell MHC-I expression revealed intra- and inter-tumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56+ cell numbers in patient tumors were positively associated with disease-free survival (DFS) (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56+ and CD8+ cells (HR=0.199, p<1×10-3). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3+CD8+ T cells and CD3-CD56+ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single cell neighborhood profiles to delineate the cellular environments of IFNγ+/- NK cells and T cells. We discovered that both IFNγ+ NK and CD8 T cells were more frequently associated with other IFNγ+ lymphocytes in comparison to IFNγ- NK cells and CD8 T cells (p<1×10-30). Moreover, IFNγ+ lymphocytes were most often found clustered near MHC-I+ tumor cells. Conclusions: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Co-association of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent co-localization of IFNγ+ NK cells with other IFNγ+ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.

Impact of Opioid Use on Duration of Therapy and Overall Survival for Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes in patients receiving ICI either alone or with chemotherapy. We conducted a retrospective review of 209 patients with advanced NSCLC who received an ICI at the University of Virginia between 1 February 2015 and 1 January 2020. We performed univariate and multivariate analyses to evaluate the impact of opioid use on duration of therapy (DOT) and overall survival (OS). Patients with no or low opioid use (n = 172) had a median DOT of 12.2 months (95% CI: 6.9-17.4) compared to 1.9 months (95% CI: 1.8-2.0) for those with high opioid use (n = 37, HR 0.26 95% CI: 0.17-0.40, p < 0.001). Patients with no or low opioid use had a median OS of 22.6 months (95% CI: 14.8-30.4) compared to 3.8 months (95% CI: 2.7-4.9) for those with high opioid use (HR 0.26 95% CI: 0.17-0.40 p < 0.001). High opioid use was associated with a shorter DOT and worse OS. This difference remained significant when accounting for possible confounding variables. These data warrant investigation of possible mechanistic interactions between opioids, tumor progression, and ICIs, as well as prospective evaluation of opioid-sparing pain management strategies, where possible.

Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175.

BACKGROUND: Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non-small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown. We hypothesized nab-paclitaxel may be a well-suited platinum partner to use in combination with checkpoint inhibitor therapy for both adenocarcinoma and squamous histology and conducted a phase I/II trial to assess the efficacy of this regimen in advanced NSCLC. METHODS: Adult patients with previously untreated, stage IIIB/IV NSCLC (any histology) with an Eastern Cooperative Oncology Group performance status of 0-1, any PD-L1 expression, and no EGFR mutations or ALK translocations, received carboplatin area under the curve (AUC) 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3w. Co-primary endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS: Forty-six evaluable patients enrolled, 14 in phase I and 32 in phase II, from June 2015 to July 2018 with a median duration of follow-up of 35.4 months. Median time from enrollment to data lock was 42 months. In the ITT population, the ORR was 35%, median PFS was 5.6 months (95% CI, 4.6-8.2), and median OS was 15.4 months (CI, 12.4-28.1). There were no statistical differences in PFS or OS by PD-L1 status. The 2- and 3-year landmark OS rates were 33% and 24%, respectively. CONCLUSION: Carboplatin, nab-paclitaxel, and pembrolizumab are a safe and effective regimen for patients with both squamous and nonsquamous NSCLC. Although this study did not meet the prespecified endpoints, the median and landmark OS results are consistent with durable benefit of this regimen as seen in phase III trials for first-line treatment of advanced NSCLC.

Phase I Study of Entinostat, Atezolizumab, Carboplatin, and Etoposide in Previously Untreated Extensive-Stage Small Cell Lung Cancer, ETCTN 10399.

BACKGROUND: CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to targeting with HDAC inhibitors. METHODS: Patients with treatment-naïve extensive-stage SCLC, ECOG ≤2 were enrolled and treated with entinostat orally weekly (4 dose levels, DL) in combination with standard dose carboplatin, etoposide, and atezolizumab. Cohort allocation was determined by Bayesian optimal interval (BOIN) design targeting an MTD with a DLT rate of 20%. RESULTS: Three patients were enrolled and treated at DL1 with entinostat 2 mg. Patients were aged 69-83; 2 male, 1 female; 2 were ECOG 1, and 1 was ECOG 0. The most common adverse events (AEs) were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), and hypocalcemia (2). Two experienced DLTs during cycle 1: (1) grade (Gr) 4 febrile neutropenia, and (1) Gr 5 sepsis. BOIN design required stopping accrual to DL1, and the trial was closed to further accrual. Entinostat and atezolizumab pharmacokinetics were both comparable to historical controls. CONCLUSION: Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029).

Relevance of the Updated Recursive Partitioning Analysis (U-RPA) Classification in the Contemporary Care of Patients with Brain Metastases.

Patients with brain metastases (BMETS) need information about the prognosis and potential value of treatment options to make informed therapeutic decisions, but tools to predict survival in contemporary practice are scarce. We propose an Updated Recursive Partitioning Analysis (U-RPA) instrument to predict survival and benefit from brain-directed treatment (BDT) of contemporary patients. This was a retrospective analysis of patients with BMETS treated between 2017 and 2019. With survival as the primary endpoint, we calculated the U-RPA and generated estimates using Kaplan-Meier curves and hazard ratios. Of 862 eligible patients, 752 received BDT and 110 received best supportive care (BSC). Median overall survival with BDT and BSC was 9.3 and 1.3 months, respectively. Patients in RPA class 1, 2A, 2B and 3 who underwent BDT had median survival of 28.1, 14.7, 7.6 and 3.3 months, respectively. The median survival for patients in RPA 3 who received BDT (n = 147), WBRT (n = 79) and SRS (n = 54) was 3.3, 2.9 and 4.1 months, respectively. The U-RPA defines prognosis estimates, independent of tumor type and treatment modality, which can assist to make value-based care treatment decisions. The prognosis for patients in U-RPA class 2B and 3 remains poor, with consideration for early palliative care involvement in these cases.

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Association of sarcopenia with survival in advanced NSCLC patients receiving concurrent immunotherapy and chemotherapy.

Background: Frailty, sarcopenia and malnutrition are powerful predictors of clinical outcomes that are not routinely measured in patients with non-small cell lung cancer (NSCLC). The primary aim of this study was to investigate the association of sarcopenia, determined by the psoas muscle index (PMI) with overall survival (OS) in patients with advanced NSCLC treated with concurrent immune checkpoint inhibitor (ICI) and chemotherapy (CTX). Methods: We retrospectively reviewed data from a cohort of patients with locally advanced or metastatic NSCLC who were treated between 2015 and 2021 at the University of Virginia Medical Center. The cross-sectional area of the psoas muscle was assessed on CT or PET/CT imaging prior to treatment initiation. Multivariate analysis was performed using Cox proportional hazards regression models. Results: A total of 92 patients (median age: 64 years, range 36-89 years), 48 (52.2%) men and 44 (47.8%) women, were included in the study. The median follow-up was 29.6 months. The median OS was 17.8 months. Sarcopenia, defined by a PMI below the 25th percentile, was associated with significantly lower OS (9.1 months in sarcopenic patients vs. 22.3 months in non-sarcopenic patients, P = 0.002). Multivariate analysis revealed that sarcopenia (HR 2.12, P = 0.0209), ECOG ≥ 2 (HR 2.88, P = 0.0027), prognostic nutritional index (HR 3.02, P = 0.0034) and the absence of immune related adverse events (HR 2.04, P = 0.0185) were independently associated with inferior OS. Conclusions: Sarcopenia is independently associated with poor OS in patients with advanced NSCLC undergoing concurrent ICI and CTX.

A Phase II Trial of Atezolizumab Plus Carboplatin Plus Pemetrexed Plus Bevacizumab in the Treatment of Patients with Stage IV Non-Squamous Non-Small Cell Lung Cancer: Big Ten Cancer Research Consortium (BTCRC)- LUN 17-139.

INTRODUCTION: LUN17-139 evaluated the safety and efficacy of Atezolizumab (A) plus Carboplatin (C) plus Pemetrexed (Pem) plus Bevacizumab (B) (ACBPem) in treatment naïve patients with stage IV non-squamous non-small cell lung cancer (Ns-NSCLC). PATIENTS AND METHODS: In this multicenter, single-arm phase II trial, all patients received A (1200-mg, D1) + C (AUC 5, D1) + Pem (500-mg/m2, D1) + B (15-mg/kg D1) q3 week x4. If no PD (progressive disease), patients received maintenance ABPem until PD or intolerable side effects. The primary endpoint was progression-free survival (PFS). The positive PFS result was considered as PFS>6m (historical control). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) defined by complete response (CR) + partial response (PR) + stable disease (SD) ≥ 2 months, overall survival (OS), and safety. RESULTS: Thirty patients were enrolled from November 2018 to October 2020. The study was closed early due to 3 patient deaths, possibly related to treatment. Median age 64 (range 38-83); Men/Women 20/10; PD-L1 TPS < 1%/1-49%/ ≥ 50% (8/15/7). The median follow-up was 20.3 months ( 1-28.1). ORR 42.9% (95% CI, 24.5-62.8%), DCR 96.4% (95% CI, 81.7-99.9%). The median PFS and OS were 11.3m (5.5-14.9,P > .05) and 22.4m (22.4-NR), respectively. Four patients had G4 toxicity (anemia, febrile-neutropenia, severe neutropenia, sepsis), and 3 patients had G5 toxicity (thromboembolism, sepsis, colonic perforation). CONCLUSION: ABCPem was associated with increased PFS compared to historical controls but this difference did not meet the statistical significance. Three on-treatment deaths and 5 thromboembolic events prompted early closure.

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy. METHODS: This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab-tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete. FINDINGS: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12·4 months (IQR 7·8-15·1), there were no differences in overall response rates between the durvalumab-tremelimumab alone group (three [11·5%, 90% CI 1·2-21·8] of 26 patients) and the low-dose radiotherapy group (two [7·7%, 0·0-16·3] of 26 patients; p=0·64) or the hypofractionated radiotherapy group (three [11·5%, 1·2-21·8] of 26 patients; p=0·99). The most common grade 3-4 adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone group; three [12%] in the low-dose radiotherapy group; and three [12%] in the hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy group vs three [12%] in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy. INTERPRETATION: Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting. FUNDING: The US National Institutes of Health and the Dana-Farber Cancer Institute.

Bayesian Design for Identifying Cohort-Specific Optimal Dose Combinations Based on Multiple Endpoints: Application to a Phase I Trial in Non-Small Cell Lung Cancer.

Immunotherapy and chemotherapy combinations have proven to be a safe and efficacious treatment approach in multiple settings. However, it is not clear whether approved doses of chemotherapy developed to achieve a maximum tolerated dose are the ideal dose when combining cytotoxic chemotherapy with immunotherapy to induce immune responses. This trial of a modulated dose chemotherapy and Pembrolizumab, with or without a second immunomodulatory agent, uses a Bayesian design to select the optimal treatment combination by balancing both safety and efficacy of the chemotherapy and immunotherapy agents within each of two cohorts. The simulation study provides evidence that the proposed Bayesian design successfully addresses the primary study aim to identify the optimal dose combination for each of the two independent patient cohorts. This conclusion is supported by the high percentage of simulated trials which select a treatment combination that is both safe and highly efficacious. The proposed trial was funded and was being finalized when the sponsoring company decided not to proceed due to negative findings in another patient population. The proposed trial design will continue to be relevant as multiple chemotherapy and immunotherapy combinations become the standard of care and future research will require evaluating the appropriate doses of various components of multiple drug regimens.

Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial.

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non-small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%-63%) with median duration of response of 14 months (5.0-not reached) and median progression-free survival of 7.3 months (4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. SIGNIFICANCE: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer.

PURPOSE: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade. PATIENTS AND METHODS: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink. RESULTS: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1-7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3-4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3-5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki-67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood. CONCLUSIONS: We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC.

INTRODUCTION: In cohort G of KEYNOTE-021 (NCT02039674), first-line pembrolizumab plus pemetrexed-carboplatin significantly improved the objective response rate and progression-free survival versus chemotherapy alone with manageable toxicity in advanced nonsquamous NSCLC. We report the long-term outcomes from this study. METHODS: Patients with previously untreated advanced nonsquamous NSCLC without sensitizing EGFR or ALK alterations were randomly assigned 1:1 to receive open-label pemetrexed 500 mg/m2 plus carboplatin at area under the concentration-time curve of 5 mg/mL/min (four cycles) with or without pembrolizumab 200 mg (up to 2 years), with optional pemetrexed maintenance, each administered every 3 weeks. Eligible patients could crossover from the chemotherapy arm to pembrolizumab monotherapy after progression. Responses were assessed per the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: After the median time of 49.4 months from randomization to data cutoff, objective response rate (58% versus 33%) and progression-free survival (median: 24.5 versus 9.9 mo; hazard ratio: 0.54; 95% confidence interval: 0.35‒0.83) remained improved with pembrolizumab combination (n = 60) versus chemotherapy (n = 63), regardless of programmed death ligand 1 status. Median overall survival was 34.5 versus 21.1 months (hazard ratio: 0.71; 95% confidence interval: 0.45‒1.12), despite a 70% crossover rate from chemotherapy alone to anti‒programmed death (ligand) 1 therapy. Among the 12 patients who completed 2 years of pembrolizumab, 92% were alive at data cutoff; the estimated 3-year duration of response rate was 100%. Grade 3 to 5 treatment-related adverse events occurred in 39% of patients receiving pembrolizumab combination and 31% receiving chemotherapy. CONCLUSIONS: First-line pembrolizumab plus pemetrexed-carboplatin continued to show improved response and survival versus chemotherapy alone in advanced nonsquamous NSCLC, with durable clinical benefit in patients who completed 2 years of therapy. No new safety signals were observed with longer follow-up.

Phase IB Study of Osimertinib in Combination with Navitoclax in EGFR-mutant NSCLC Following Resistance to Initial EGFR Therapy (ETCTN 9903).

PURPOSE: Osimertinib is an effective therapy in EGFR-mutant non-small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of EGFR-mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance. PATIENTS AND METHODS: This single-arm phase Ib study evaluated safety, tolerability, and feasibility of osimertinib and navitoclax, including dose expansion in T790M-positive patients at the recommended phase II dose (RP2D). Eligible patients had advanced EGFR-mutant NSCLC with prior tyrosine kinase inhibitor exposure. Five dose levels were planned with osimertinib from 40 to 80 mg orally daily and navitoclax from 150 to 325 mg orally daily. RESULTS: A total of 27 patients were enrolled (18 in the dose-escalation cohort and nine in the dose-expansion cohort): median age 65, 67% female, 48% exon 19 del, and 37% L858R, median one prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No dose-limiting toxicities were seen in dose-escalation cohort; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received >95% of planned doses through three cycles. In expansion cohort, objective response rate was 100% and median progression-free survival was 16.8 months. A proapoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia. CONCLUSIONS: Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted.