Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study.

PURPOSE: This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor]. EXPERIMENTAL DESIGN: Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks). RESULTS: A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR. CONCLUSIONS: Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors. SIGNIFICANCE: PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations.

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial.

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

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).

Tumor cell p38 inhibition to overcome immunotherapy resistance.

Patients with tumors that do not respond to immune-checkpoint inhibition often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-γ-associated CD8+ T cell and dendritic cell activation. Understanding the molecular mechanisms underlying immune exclusion in non-responding patients may enable the development of novel combination therapies. p38 MAPK is a known regulator of dendritic and myeloid cells however a tumor-intrinsic immunomodulatory role has not been previously described. Here we identify tumor cell p38 signaling as a therapeutic target to potentiate anti-tumor immunity and overcome resistance to immune-checkpoint inhibitors (ICI). Molecular analysis of tumor tissues from patients with human papillomavirus-negative head and neck squamous carcinoma reveals a p38-centered network enriched in non-T cell-inflamed tumors. Pan-cancer single-cell RNA analysis suggests that p38 activation may be an immune-exclusion mechanism across multiple tumor types. P38 knockdown in cancer cell lines increases T cell migration, and p38 inhibition plus ICI in preclinical models shows greater efficacy compared to monotherapies. In a clinical trial of patients refractory to PD1/L1 therapy, pexmetinib, a p38 inhibitor, plus nivolumab demonstrated deep and durable clinical responses. Targeting of p38 with anti-PD1 has the potential to induce the T cell-inflamed phenotype and overcome immunotherapy resistance.

Guidance for clinicians and patients with non-small cell lung cancer in the time of precision medicine.

Major advances in the diagnosis and treatment of non-small cell lung cancer (NSCLC) have resulted in a sharp decline in associated mortality rates, thereby propelling NSCLC to the forefront of precision medicine. Current guidelines recommend upfront comprehensive molecular testing for all known and actionable driver alterations/biomarkers (EGFR, ALK, ROS1, BRAF, KRAS, NTRK, MET, RET, HER2 [ERBB2], and PD-L1), especially in advanced disease stages, as they significantly influence response to therapy. In particular, hybrid capture-based next-generation sequencing (HC-NGS) with an RNA fusion panel to detect gene fusions is a veritable requirement at both diagnosis and progression (resistance) of any-stage non-squamous adenocarcinoma NSCLCs. This testing modality ensures selection of the most timely, appropriate, and personalized treatment, maximization of therapeutic efficacy, and prevention of use of suboptimal/contraindicated therapy. As a complement to clinical testing and treatment, patient, family, and caregiver education is also key to early screening and diagnosis, access to care, coping strategies, positive outcomes, and survival. The advent of social media and increased internet access has amplified the volume of educational and support resources, consequently changing the dynamics of patient care. This review provides guidance on integration of comprehensive genomic testing with an RNA fusion panel as a global diagnostic standard for all adenocarcinoma NSCLC disease stages and provides key information on patient and caregiver education and resources.

Emerging therapeutic strategies for enhancing sensitivity and countering resistance to programmed cell death protein 1 or programmed death-ligand 1 inhibitors in non-small cell lung cancer.

The availability of agents targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has transformed treatment of advanced and/or metastatic non-small cell lung cancer (NSCLC). However, a substantial proportion of patients treated with these agents do not respond or experience only a brief period of clinical benefit. Even among those whose disease responds, many subsequently experience disease progression. Consequently, novel approaches are needed that enhance antitumor immunity and counter resistance to PD-(L)1 inhibitors, thereby improving and/or prolonging responses and patient outcomes, in both PD-(L)1 inhibitor-sensitive and inhibitor-resistant NSCLC. Mechanisms contributing to sensitivity and/or resistance to PD-(L)1 inhibitors in NSCLC include upregulation of other immune checkpoints and/or the presence of an immunosuppressive tumor microenvironment, which represent potential targets for new therapies. This review explores novel therapeutic regimens under investigation for enhancing responses to PD-(L)1 inhibitors and countering resistance, and summarizes the latest clinical evidence in NSCLC.

A phase II clinical trial evaluating the safety and efficacy of durvalumab as first line therapy in advanced and metastatic non-small cell lung cancer patients with Eastern Cooperative Oncology Group performance status of 2.

Background: Approximately 30-40% of patients with advanced and metastatic non-small cell lung cancer (NSCLC) present with an impaired performance status (PS). There are limited prospective data on the safety and efficacy of durvalumab in these patients. Methods: In this single-arm phase II clinical trial (NCT02879617), patients with previously untreated Stage IIIB/IV NSCLC and ECOG PS of 2 received durvalumab 1500 mg every 28 days until progression or unacceptable toxicity. The primary endpoints were overall survival (OS) and safety determined by grade ≥3 treatment-related adverse events (TRAEs). Findings: Between April 2017 and March 2021, 50 patients were enrolled, of whom 47 received durvalumab. With a median follow-up of 28 months, median OS was 6 months (95% CI 4-10). TRAEs grade 3 occurred in nine of 47 patients (19%, 95% CI 9%-33%). OS in patients with a PD-L1 TPS of 0, 1-49%, and ≥50% was six months (95% CI 3-15), 11 months (95% CI 4-16), and 11 months (95% CI 0-not reached (NR)), respectively. Health related quality of life (HQRL) assessed at baseline and during therapy demonstrated no statistically significant change over the course of treatment. Interpretation: This study demonstrates that single agent durvalumab is safe and well tolerated in the 1st line treatment of patients with advanced NSCLC and ECOG PS of 2, with an encouraging OS benefit in patients with PD-L1 positive tumors. This trial is amongst the largest prospective studies evaluating durvalumab in the 1st line treatment of advanced stage NSCLC and a PS of 2. Funding: AstraZeneca, NCI P30CA047904.

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.

Overcoming KRAS-Mutant Lung Cancer.

More than 50 years after the discovery of RAS family proteins, which harbor the most common activating mutations in cancer, the U.S. Food and Drug Administration approved the first direct allele-specific inhibitor of mutant KRAS in lung cancer. We highlight the history of discovering RAS and decades of studies targeting KRAS-driven lung cancer. A landmark article by Shokat and colleagues in 2013 elucidated allosteric inhibition of this undruggable target and paved the way for the first-in-class direct KRASG12C inhibitor. Although these drugs have impressive 36%-45% objective response rates with a median duration of response of 10 months, many tumors do not respond, and diverse mechanisms of resistance have already been observed; this includes new KRAS alterations, activation of alternate RTK pathway proteins, bypass pathways, and transcriptional remodeling. These resistance mechanisms can be profiled using tissue-based and plasma-based testing and help to inform clinical trial options for patients. We conclude with a discussion of research informing ongoing clinical trials to rationally test promising treatments to thwart or overcome resistance to KRASG12C inhibitors and target other KRAS-altered lung cancers.

Short communication: The activity of brigatinib in patients with disease progression after next generation anaplastic lymphoma tyrosine kinase inhibitors and an exploratory analysis of circulating tumor DNA.

BACKGROUND: Brigatinib, a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is central nervous system (CNS) penetrant and active against anaplastic lymphoma kinase (ALK) resistance mutations. We prospectively studied the activity of brigatinib in patients with disease progression after second generation ALK TKIs. METHODS: Patients with stage IIIB/IV ALK + non-small cell lung cancer (NSCLC), and progressive disease after second ALK TKIs were eligible. Cohort A enrolled patients with disease progression on any second ALK TKI, cohort B enrolled patients with disease progression after first-line therapy with alectinib, and cohort C enrolled patients who experienced disease progression on standard dose brigatinib. Brigatinib treatment was 90 mg daily for seven days and then escalated to 180 mg daily in cohorts A and B, and 240 mg daily in cohort C. The primary endpoint was objective response rate (ORR), and a 2-stage design was used. The intended enrollment was 20 patients in stage 1, and 20 patients in stage 2. RESULTS: The study was closed due to slow accrual. Between March 2017 and June 2020, 32 patients received study therapy; three patients in cohort A moved to cohort C after initial progression for a total of 35 study subjects. Of the 32 patients, 16 (50%) were male, the median age was 55 years (range 32-76), and patients received a median number of 2 prior ALK TKI's (range 1-3). Cohort A enrolled 27 patients, cohort B enrolled four patients, and cohort C enrolled four patients. The ORR in cohorts A, B, and C was 33% (95% confidence interval (CI: 16% to 54%), 25% (95% CI: 0.63% to 81%), and 0%, respectively. CONCLUSION: Brigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs.

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.

IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain.

INTRODUCTION: Final overall survival (OS) analyses are presented for EGFR mutations and liver or brain metastases subgroups in the phase 3 IMpower150 study (NCT02366143) evaluating atezolizumab plus bevacizumab plus carboplatin and paclitaxel (ABCP) or atezolizumab plus carboplatin and paclitaxel (ACP) versus bevacizumab plus carboplatin and paclitaxel (BCP). METHODS: Overall, 1202 patients (intention-to-treat population) with chemotherapy-naive, metastatic, nonsquamous NSCLC were randomized to ABCP, ACP, or BCP. Patients with treated, stable brain metastases were permitted. OS was evaluated in EGFR mutations and baseline liver metastases subgroups; rate and time to development of new brain metastases were evaluated in the intention-to-treat patients. RESULTS: At data cutoff (September 13, 2019; median follow-up, 39.3 mo), OS improvements were sustained with ABCP versus BCP in sensitizing EGFR mutations (all: hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.31-1.14; previous tyrosine kinase inhibitor [TKI]: HR = 0.74; 95% CI: 0.38-1.46) and baseline liver metastases (HR = 0.68; 95% CI: 0.45-1.02) subgroups. ACP did not have survival benefit versus BCP in sensitizing EGFR mutations (all: HR = 1.0; 95% CI: 0.57-1.74; previous TKI: HR = 1.22; 95% CI: 0.68-2.22) or liver metastases (HR = 1.01; 95% CI: 0.68-1.51) subgroups. Overall, 100 patients (8.3%) developed new brain metastases. Although not formally evaluated, an improvement toward delayed time to development was found with ABCP versus BCP (HR = 0.68; 95% CI: 0.39-1.19). CONCLUSIONS: This final exploratory analysis revealed OS benefits for ABCP versus BCP in patients with sensitizing EGFR mutations, including those with previous TKI failures, and with liver metastases, although these results should be interpreted with caution. The impact of ABCP on delaying the development of new brain lesions requires further investigation.

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis.

INTRODUCTION: Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data. METHODS: Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS: At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5-78.5) and 16.3 (range: 0.4-80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8-80.1) and 63.9% (46.2-79.2), median progression-free survival (95% CI) was 10.2 (6.9-16.7) and 10.8 (7.0-14.5) months, and median overall survival (95% CI) was 18.2 (14.3-28.6) and 17.3 (12.3-40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation. CONCLUSIONS: Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment.

Macrovasculature and positron emission tomography (PET) standardized uptake value in patients with lung cancer.

PURPOSE: To investigate the relationship between macrovasculature features and the standardized uptake value (SUV) of positron emission tomography (PET), which is a surrogate for the metabolic activity of a lung tumor. METHODS: We retrospectively analyzed a cohort of 90 lung cancer patients who had both chest CT and PET-CT examinations before receiving cancer treatment. The SUVs in the medical reports were used. We quantified three macrovasculature features depicted on CT images (i.e., vessel number, vessel volume, and vessel tortuosity) and several tumor features (i.e., volume, maximum diameter, mean diameter, surface area, and density). Tumor size (e.g., volume) was used as a covariate to adjust for possible confounding factors. Backward stepwise multiple regression analysis was performed to develop a model for predicting PET SUV from the relevant image features. The Bonferroni correction was used for multiple comparisons. RESULTS: PET SUV was positively correlated with vessel volume (R = 0.44, p < 0.001) and vessel number (R = 0.44, p < 0.001) but not with vessel tortuosity (R = 0.124, p > 0.05). After adjusting for tumor size, PET SUV was significantly correlated with vessel tortuosity (R = 0.299, p = 0.004) and vessel number (R = 0.224, p = 0.035), but only marginally correlated with vessel volume (R = 0.187, p = 0.079). The multiple regression model showed a performance with an R-Squared of 0.391 and an adjusted R-Squared of 0.355 (p < 0.001). CONCLUSIONS: Our investigations demonstrate the potential relationship between macrovasculature and PET SUV and suggest the possibility of inferring the metabolic activity of a lung tumor from chest CT images.

Crizotinib in Patients With MET-Amplified NSCLC.

INTRODUCTION: MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC. METHODS: The influence of MET amplification on the clinical activity of the ALK, ROS1, and MET inhibitor, crizotinib (250 mg twice daily), was examined in patients with NSCLC (NCT00585195) who were enrolled into high (≥4 MET-to-CEP7 ratio), medium (>2.2 to <4 MET-to-CEP7 ratio), or low (≥1.8 to ≤2.2 MET-to-CEP7 ratio) amplification categories. Retrospective next-generation sequencing profiling was performed on archival tumor tissue. End points included objective response rate (ORR), duration of response, and progression-free survival. RESULTS: A total of 38 patients with a MET-to-CEP7 ratio greater than or equal to 1.8 by local fluorescence in situ hybridization testing received crizotinib. All patients were response-assessable, among whom 21, 14, and 3 had high, medium, and low MET amplification, respectively. ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively. MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations. CONCLUSIONS: Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib.

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.

Immune Checkpoint Blockade in Oncogene-Driven Non-Small-Cell Lung Cancer.

Patients with oncogene-driven lung cancer have limited therapeutic options after progressing on their targeted tyrosine kinase inhibitor (TKI) therapy. Given the growing role of immune checkpoint inhibitor (ICI) therapy in the treatment of lung cancer, oncogene-driven cancer has warranted further evaluation regarding ICI therapy. However, initial ICI studies have suggested that ICI monotherapy is not only lacking in efficacy, but that it may be less tolerable in oncogene-driven non-small-cell lung cancer (NSCLC). We performed a detailed review of the literature using Pubmed, and present the current and impactful findings here. Studies evaluating the use of concurrent ICI therapy and TKI therapy have also suggested increased toxicity and lack of increased activity in these patients. Larger studies have suggested that the sequence of ICI therapy and TKI, such as utilizing ICI therapy after TKI as opposed to before TKI, may play a role in reducing toxicity (hepatotoxicity, pneumonitis); however, these studies are limited in number. Novel methods of patient selection, including low tumor mutational burden, inflamed phenotyping, and  high CD8 + tumor infiltrating lymphocytes, may aid in determining ideal patients to give ICI therapy. Novel therapeutic combinations including the addition of anti-VEGF (vascular endothelial growth factor) therapy or radiotherapy show promising findings for these patients. Given the growing unmet need for therapeutic options in patients with oncogene-driven NSCLC who have failed TKI therapy, further research is warranted.

Nab-paclitaxel in older patients with non-small cell lung cancer who have developed disease progression after platinum-based doublet chemotherapy.

BACKGROUND: The selection of later-line treatment for older patients with AJCC (version 7) stage IV non-small cell lung cancer (NSCLC) remains controversial. Nanoparticle albumin-bound (nab)-paclitaxel is approved with carboplatin for the first-line treatment of patients with NSCLC and subgroup analysis of phase 3 data has suggested superior survival in older patients. METHODS: The authors conducted a phase 2 study of nab-paclitaxel in 42 patients aged ≥70 years who had been treated previously with a platinum doublet regimen; patients also could have received a PD-1 inhibitor. The primary endpoint of the current study was grade 3 to 5 toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). In addition to response rate, progression-free survival (PFS), and overall survival (OS), geriatric assessments also were performed before and during treatment, associations between baseline sarcopenia and outcomes were explored, and changes in T lymphocyte p16 before and during treatment were measured. The authors also performed a retrospective subgroup analysis of 19 older patients who were treated with nab-paclitaxel as part of a larger, randomized, phase 2 study; data were not combined. RESULTS: The rate of grade 3 to 5 toxicities was 33.7%. The most common grade 3 to 5 toxicities were decreased white blood cell count (11.9%), neutropenia (9.5%), and fatigue (11.9%). The response rate was 34.2% (2.6% complete response rate and 31.6% partial response rate). The median PFS was 5.2 months and the median OS was 9.3 months. Adverse prognostic factors were common: 42% of patients were frail and 39% of patients were prefrail, whereas 21% had an Eastern Cooperative Oncology Group performance status of 2 and 27% were sarcopenic. Only frailty was found to be predictive of inferior survival. A subgroup analysis of 19 older patients treated with nab-paclitaxel alone in a prior trial demonstrated a response rate of 15.8%, a PFS of 4.2 months, and an OS of 13.6 months. CONCLUSIONS: Fit and prefrail older patients with stage IV NSCLC should be considered for treatment with nab-paclitaxel after disease progression with doublet chemotherapy.