A Phase II Open-Label Trial of Binimetinib and Hydroxychloroquine in Patients With Advanced KRAS-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: In RAS-mutant tumors, combined MEK and autophagy inhibition using chloroquine demonstrated synthetic lethality in preclinical studies. This phase II trial evaluated the safety and activity of the MEK inhibitor binimetinib combined with hydroxychloroquine (HCQ) in patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC). METHODS: Eligibility criteria included KRAS-mutant NSCLC, progression after first-line therapy, ECOG PS 0-1, and adequate end-organ function. Binimetinib 45 mg was administered orally (p.o.) bid with HCQ 400 mg p.o. bid. The primary endpoint was objective response rate (ORR). A Simon's 2-stage phase II clinical trial design was used, with an α error of 5% and a power ß of 80%, anticipating an ORR of 30% to proceed to the 2-stage expansion. RESULTS: Between April 2021 and January 2022, 9 patients were enrolled to stage I: median age 64 years, 44.4% females, 78% smokers. The best response was stable disease in one patient (11.1%). The median progression free survival (PFS) was 1.9 months, and median overall survival (OS) was 5.3 months. Overall, 5 patients (55.6%) developed a grade 3 adverse event (AE). The most common grade 3 toxicity was rash (33%). Pre-specified criteria for stopping the trial early due to lack of efficacy were met. CONCLUSION: The combination of B + HCQ in second- or later-line treatment of patients with advanced KRAS-mutant NSCLC did not show significant antitumor activity. (ClinicalTrials.gov Identifier: NCT04735068).

Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

Impact of Healthcare Delivery System Type on Clinical, Utilization, and Cost Outcomes of Patient-Centered Medical Homes: a Systematic Review.

BACKGROUND: As healthcare reimbursement shifts from being volume to value-focused, new delivery models aim to coordinate care and improve quality. The patient-centered medical home (PCMH) model is one such model that aims to deliver coordinated, accessible healthcare to improve outcomes and decrease costs. It is unclear how the types of delivery systems in which PCMHs operate differentially impact outcomes. We aim to describe economic, utilization, quality, clinical, and patient satisfaction outcomes resulting from PCMH interventions operating within integrated delivery and finance systems (IDFS), government systems including Veterans Administration, and non-integrated delivery systems. METHODS: We searched PubMed, the Cochrane Library, and Embase from 2004 to 2017. Observational studies and clinical trials occurring within the USA that met PCMH criteria (as defined by the Agency for Healthcare Research and Quality), addressed ambulatory adults, and reported utilization, economic, clinical, processes and quality of care, or patient satisfaction outcomes. RESULTS: Sixty-four studies were included. Twenty-four percent were within IDFS, 29% were within government systems, and 47% were within non-IDFS. IDFS studies reported decreased emergency department use, primary care use, and cost relative to other systems after PCMH implementation. Government systems reported increased primary care use relative to other systems after PCMH implementation. Clinical outcomes, processes and quality of care, and patient satisfaction were assessed heterogeneously or infrequently. DISCUSSION: Published articles assessing PCMH interventions generally report improved outcomes related to utilization and cost. IDFS and government systems exhibit different outcomes relative to non-integrated systems, demonstrating that different health systems and populations may be particularly sensitive to PCMH interventions. Both the definition of PCMH interventions and outcomes measured are heterogeneous, limiting the ability to perform direct comparisons or meta-analysis.

The impact of an oncology urgent care center on health-care utilization.

INTRODUCTION: Studies suggest that many emergency department (ED) visits and hospitalizations for patients with cancer may be preventable. The Centers for Medicare & Medicaid Services has implemented changes to the hospital outpatient reporting program that targets acute care in-treatment patients for preventable conditions. Oncology urgent care centers aim to streamline patient care. Our cancer center developed an urgent care center called the direct referral unit in 2011. METHODS: We abstracted visits to our adjacent hospital ED and direct referral unit from January 2014 to June 2018. Patient demographics, cancer and visit diagnoses, visit charges, and 30-day therapy utilization were assessed. RESULTS: An analysis of 13 114 visits demonstrated that increased direct referral unit utilization was associated with decreased monthly ED visits (P < .001). Common direct referral unit visit diagnoses were dehydration, nausea and vomiting, abdominal pain, and fever. Patients receiving active cancer treatment more frequently presented to the direct referral unit (P < .001). The average charges were $2221 for the direct referral unit and $10 261 for the ED. CONCLUSION: The association of decreased ED visits with increased direct referral unit utilization demonstrates the potential for urgent care centers to reduce acute care visits. Many patients presented to our direct referral unit with preventable conditions, and these visits were associated with considerable cost savings, supporting its use as a cost-effective method to reduce acute care costs.

Overall Survival, Treatment Duration, and Rechallenge Outcomes With ICI Therapy for Recurrent or Metastatic HNSCC.

Importance: Immune checkpoint inhibition (ICI) is a frontline treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but questions remain surrounding optimal duration of therapy, benefits and risks of ICI rechallenge, and efficacy in first vs subsequent lines of therapy. Objectives: To estimate survival in US patients receiving ICI-based treatment for R/M HNSCC, compare outcomes associated with treatment discontinuation vs continuation at 1 or 2 years, and assess outcomes after immunotherapy rechallenge. Design, Setting, and Participants: This retrospective, population-based cohort study included adult patients in the Flatiron Health nationwide oncology database treated with immunotherapy for R/M HNSCC from 2015 to 2023. Data cutoff was August 31, 2023; data analysis was conducted from December 2023 to February 2024. Exposures: Treatment continuation vs discontinuation at 1 and 2 years; rechallenge with ICI after at least a 60-day period off ICI therapy without intervening systemic treatment (immediate rechallenge), or with intervening systemic treatment (delayed rechallenge). Main Outcomes and Measures: Overall survival (OS) from ICI initiation was analyzed using the Kaplan-Meier method. Cox multivariable regression was used to examine associations of key variables (line of therapy, human papillomavirus [HPV] status, Eastern Cooperative Oncology Group [ECOG] performance status) with survival. Results: The cohort included 4549 patients with R/M HNSCC who received ICI-containing therapy (median [IQR] age, 66 [59-72] years; 3551 [78.1%] male; 56 [1.2%] Asian, 260 [5.7%] Black or African American, 3020 [66.4%] White, 1213 [26.7%] other or unknown race; 3226 [70.9%] ECOG performance status 0 or 1). There were 3000 patients (65.9%) who received ICI in frontline and 1207 (26.5%) in second line; 3478 patients (76.5%) received ICI monotherapy. Median (IQR) OS was 10.9 (4.1-29.1) months and was longer in patients who received ICI in frontline therapy (12.2 [4.8-32.0] vs 8.7 [3.2-22.4] months), had HPV-positive cancer (16.6 [6.5-43.9] vs 8.8 [3.5-24.0] months), and had ECOG performance status 0 or 1 (13.5 [5.2-33.9] vs 5.5 [2.0-13.7] months). There were no survival differences on adjusted analysis between patients who stopped vs those who continued ICI at 1 or 2 years. Median (IQR) OS after ICI rechallenge was 15.7 (13.7-21.9) months in the immediate rechallenge group and 9.9 (3.7-18.1) months in the delayed rechallenge group. Conclusions and Relevance: In this large cohort study of patients with R/M HNSCC receiving ICI-based therapy, survival estimates closely mirrored clinical trial results, both in frontline and later-line settings. Discontinuation of ICI in long-term responders at 1 or 2 years may be a reasonable strategy that does not appear to compromise survival. ICI rechallenge was associated with clinical benefit in a subset of patients.

Patterns of Failure in Metastatic NSCLC Treated With First Line Pembrolizumab and Use of Local Therapy in Patients With Oligoprogression.

INTRODUCTION: The patterns of failure (POF) for metastatic non-small-cell lung cancer (mNSCLC) treated with immunotherapy are not well established. METHODS: We conducted a retrospective cohort study of mNSCLC that received first-line pembrolizumab with or without chemotherapy at a single academic center from 2015 to 2021. We defined POF with 2 classifications: 1) local, regional, or distant failure, or 2) failure in existing lesions, new lesions, or a combination. Oligoprogression was defined as disease progression (PD) in ≤3 sites of failure. Overall survival (OS) was measured via Kaplan-Meier and modelled with Cox regression. RESULTS: Of 298 patients identified, 198 had PD. Using POF classification 1, most failures were distant (43.9%) or a combination of locoregional and distant (34.4%). For POF classification 2, failures occurred in a combination of new and existing lesions (45.0%), existing lesions alone (33.3%), or in new lesions only (21.7%). Oligoprogression occurred in 39.9% (n = 79) cases. Median OS was higher in the following: PD in existing lesions vs. new or new + existing lesions (28.7 vs. 20.2 vs. 13.9 months, P < .001) and oligoprogression vs. polyprogression (35.1 vs. 12.2 months, P < .001). In oligoprogression, median OS was better for those who received radiation to all sites of PD (62.2 months) than for those who changed systemic therapy (22.9 months, P = .007). On multivariable analysis, radiation for oligoprogression (HR 0.35, 95% CI: 0.20-0.62, P < .001) was associated with improved OS. CONCLUSIONS: In mNSCLC treated with pembrolizumab, oligoprogression is relatively common. Randomized data are needed to define the benefits of radiation in oligoprogressive mNSCLC.

Plunging Into the PACIFIC: Outcomes of Patients With Unresectable KRAS-Mutated Non-Small Cell Lung Cancer Following Definitive Chemoradiation and Durvalumab Consolidation.

BACKGROUND: Immune checkpoint inhibitor (ICI) consolidation following concurrent chemoradiotherapy (CRT) substantially improved progression free survival (PFS) and overall survival (OS) in the PACIFIC trial becoming the standard of care in locally-advanced, unresectable NSCLC. KRAS mutation may influence response to ICI. METHODS: In this single-institution, retrospective analysis, we compared treatment outcomes for patients with unresectable KRAS mutated (KRAS-mt) and wild-type (KRAS-wt) NSCLC treated with CRT between October 2017 and December 2021. Kaplan-Meier analysis was conducted comparing median progression free survival and median overall survival from completion of radiotherapy in all KRAS-mt patients and KRAS-G12C-mutated patients. Outcomes were also compared with and without ICI consolidation. RESULTS: Of 156 patients, 42 (26.9%) were KRAS-mt and 114 (73.1%) were KRAS-wt. Baseline characteristics differed only in histology; KRAS-mt NSCLC more likely to be adenocarcinoma. KRAS-mt patients had worse PFS (median 6.3 vs. 10.7 months, P = .041) but similar OS (median 23.1 vs. 27.3 months, P = .237). KRAS-mt patients were more likely to not receive ICI due to rapid disease progression post-CRT (23.8% vs. 4.4%, P = .007). Among patients who received ICI (n = 114), KRAS-mt was not associated with inferior PFS (8.1 vs. 11.9 months, P = .355) or OS (30.5 vs. 31.7 months, P = .692). KRAS-G12C patients (n = 22) had similar PFS and OS to other KRAS-mt. CONCLUSION: In one of the largest post-CRT KRAS-mt cohort published, KRAS-mt was associated with inferior PFS, largely due to rapid progression prior to ICI consolidation, but did not affect OS. Among those who received ICI consolidation, outcomes were comparable regardless of KRAS-mt status.

Brief Report: Second-line treatment outcomes in patients with advanced NSCLC previously treated with first-line immunotherapy regimens.

CLINICAL PRACTICE POINTS: In the United States of America, nearly all patients with advanced NSCLC, absent oncogenic drivers, receive some form of immunotherapy (IO) as part of initial treatment. Current national guidelines currently recommend against IO re-challenge if there is disease progression on IO in the first line, but re-treatment with IO is attractive given its favorable toxicity profile and descriptions of durable clinical benefit in a subset of patients treated beyond disease progression on initial IO (Gandara, J Thorac Oncol, 2018). Data in the non-clinical trial setting on the efficacy of IO in sequential lines of treatment after initial IO are lacking. In our large cohort study of patients with advanced NSCLC treated with immunotherapy regimens in the first-line setting, we find that outcomes after second-line treatment did not differ statistically by type of treatment used in the second line. While current prospective clinical trials are investigating several aspects of the utility of continuing immunotherapy and adding novel agents, our study offers data outside of a clinical trial. In addition, with the increased prevalence of adjuvant immunotherapy we urgently need to wrestle with whether to continue immunotherapy in the first-line metastatic setting if a patient experiences disease progression on adjuvant immunotherapy. While this analysis does not directly investigate that question, it does provide hypothesis-generating evidence for further evaluations.

Utilization and Factors Precluding Receipt of Checkpoint Inhibitor Consolidation for Stage III NSCLC in a Large US Academic Health System.

OBJECTIVES: We sought to determine the proportion of patients with stage III non-small cell lung cancer (NSCLC) who initiate consolidation durvalumab or other immune checkpoint inhibitors (ICIs) after concurrent chemoradiotherapy (cCRT), as well as reasons for nonreceipt and prognostic implications. MATERIALS AND METHODS: We retrospectively identified consecutive patients with unresectable stage III NSCLC treated with definitive cCRT between October 2017 and December 2021 within a large US academic health system. Patients either received consolidation ICIs (ICI group) or did not (no-ICI group). Baseline characteristics and overall survival (OS) of the groups were assessed. Factors predictive of ICI nonreceipt were evaluated using logistic regression. RESULTS: Of 333 patients who completed cCRT, 229 (69%) initiated consolidation ICIs; 104 (31%) did not. Reasons for ICI nonreceipt included progressive disease post-cCRT (N = 31, 9%), comorbidity or intercurrent illness (N = 25, 8%), cCRT toxicity (N = 23, 7%; 19/23 pneumonitis), and EGFR/ALK alteration (N = 14, 4%). The no-ICI group had worse performance status and a higher rate of baseline pulmonary comorbidity. Larger planning target volume was associated with post-cCRT progressive disease, and higher lung radiation dose with cCRT toxicity. Median OS was 16 months in the no-ICI group and 34.4 months in the ICI group. In the no-ICI group, OS was superior among those with EGFR/ALK alterations (median 44.5 months) and worst among those with progressive disease (median 5.9 months, P < 0.001). CONCLUSION: 31% of patients who completed cCRT for stage III NSCLC did not receive consolidation ICIs. Survival amongst these patients is poor, especially for those with progressive disease post-cCRT.

Outcomes Among Patients With Mucosal Head and Neck Squamous Cell Carcinoma Treated With Checkpoint Inhibitors.

Importance: Immune checkpoint inhibitors (CPIs) are now part of standard therapy for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) because of improved outcomes compared with chemotherapy in clinical trials. However, data on outcomes in patients with HNSCC in the general population who are treated with CPIs remain limited. Objective: To assess response rates, survival outcomes, and associations with key clinical covariates in a large, contemporary cohort of patients with recurrent or metastatic mucosal HNSCC who were treated with CPIs with or without chemotherapy. Design, Setting, and Participants: This retrospective cohort study included patients older than 18 years who received CPI-based therapy for recurrent or metastatic HNSCC at the University of Pennsylvania from January 1, 2015, through August 15, 2021. Clinical and survival data were abstracted through medical record review. Exposures: Treatment with CPIs with or without chemotherapy for a diagnosis of HNSCC. Main Outcomes and Measures: The main outcomes were overall survival, progression-free survival, and response rates. Overall survival and progression-free survival were estimated by Kaplan-Meier methods. Multivariable Cox proportional hazards regression was used to examine associations of key clinical variables with survival; a χ2 test and logistic regression were used to assess associations with response rate. Results: The study cohort consisted of 212 patients, of whom 165 (77.8%) were male, 148 (69.8%) were former or current smokers, and 66 (31.1%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater; median age was 63.2 years (IQR, 57.2-71.2 years). Primary tumor sites included the oropharynx (99 [46.7%]), oral cavity (61 [28.8%]), and larynx or hypopharynx (52 [24.5%]). Most (126 [59.4%]) received CPI as first-line systemic therapy, and 23 (10.8%) received combination CPI with chemotherapy. The overall response rate was 30.1%. Estimated 1-year overall survival was 51.8% (95% CI, 44.5%-58.8%), and estimated 1-year progression-free survival was 9.4% (95% CI, 5.0%-15.5%). Median overall survival was 12.9 months (IQR, 4.1-36.5 months), and median progression-free survival was 3.9 months (IQR, 1.9-17.8 months). Non-oral cavity primary site (vs oral cavity) was associated with improved overall survival (human papillomavirus-positive oropharynx: hazard ratio [HR], 0.567 [95% CI, 0.335-0.960]; all other sites: HR, 0.491 [95% CI, 0.298-0.810]), and T category of 4 at presentation (HR, 1.594; 95% CI, 1.062-2.394) and an ECOG performance status greater than 1 (HR, 2.720; 95% CI, 1.866-3.964) were associated with worse overall survival. Conclusions and Relevance: In this cohort study of patients with recurrent or metastatic HNSCC who received CPI therapy, the overall response rate was 30.1%. Patients with oral cavity cancer had worse overall survival compared with patients with HNSCC of other subsites. These findings support the use of CPI therapies for first- or second-line treatment of recurrent or metastatic HNSCC.

Cetuximab-Based vs Carboplatin-Based Chemoradiotherapy for Patients With Head and Neck Cancer.

Importance: Cetuximab-based and carboplatin-based chemoradiotherapy (CRT) are often used for patients with locally advanced head and neck cancer who are ineligible for cisplatin. There are no prospective head-to-head data comparing cetuximab-based and carboplatin-based regimens for radiosensitization. Objective: To compare survival with cetuximab-based and carboplatin-based CRT in locally advanced head and neck squamous cell carcinoma (HNSCC). Design, Setting, and Participants: This cohort study included US veterans who received a diagnosis of HNSCC between January 2006 and December 2020 and were treated with systemic therapy and radiation. Data cutoff was March 1, 2022 and data analysis was conducted from April-May 2022. Exposures: Cisplatin, cetuximab, or carboplatin-based systemic therapy as captured in VA medication data and cancer registry. Main Outcomes and Measures: Overall survival by systemic therapy was estimated using Kaplan-Meier methods. We used propensity score and inverse probability weighting to achieve covariate balance between cetuximab-treated and carboplatin-treated patients and used Cox regression to estimate cause-specific hazard ratios of death associated with carboplatin vs cetuximab. We also performed subgroup analyses of patients with oropharynx vs nonoropharynx primary sites. Results: A total of 8290 patients (median [IQR] age, 63 [58-68] years; 8201 men [98.9%]; 1225 [15.8%] Black or African American and 6424 [82.6%] White individuals) with nonmetastatic HNSCC were treated with CRT with cisplatin (5566 [67%]), carboplatin (1231 [15%]), or cetuximab (1493 [18%]). Compared with cisplatin-treated patients, patients treated with carboplatin and cetuximab were older with worse performance status scores and higher comorbidity burden. Median (IQR) overall survival was 74.4 (22.3-162.2) months in patients treated with cisplatin radiotherapy (RT), 43.4 (15.3-123.8) months in patients treated with carboplatin RT, and 31.1 (12.4-87.8) months in patients treated with cetuximab RT. After propensity score and inverse probability weighting, carboplatin was associated with improved overall survival compared with cetuximab (cause-specific hazard ratio, 0.85; 95% CI, 0.78-0.93; P = .001). This difference was prominent in the oropharynx subgroup. Conclusions and Relevance: In this cohort study of a US veteran population with HNSCC undergoing treatment with CRT, almost a third of patients were ineligible to receive treatment with cisplatin and received cetuximab-based or carboplatin-based radiosensitization. After propensity score matching, carboplatin-based systemic therapy was associated with 15% improvement in overall survival compared with cetuximab, suggesting that carboplatin may be the preferred radiosensitizer, particularly in oropharynx cancers.

Phase II Trial of Combination Nab-paclitaxel and Gemcitabine in Non-squamous Non-small Cell Lung Cancer After Progression on Platinum and Pemetrexed.

BACKGROUND: Better therapies are needed to improve survival in metastatic non-small cell lung cancer (NSCLC). Given the synergy of combination nab-paclitaxel and gemcitabine in metastatic pancreatic cancer and their individual activity in advanced NSCLC, we sought to determine whether the same combination would confer a therapeutic benefit in the second-line therapy of recurrent or metastatic non-squamous (NSQ) NSCLC. MATERIALS AND METHODS: This single-arm phase II trial of nab-paclitaxel and gemcitabine was performed from June 2015 to April 2020 at an academic referral cancer center. Patients with advanced NSQ-NSCLC whose disease progressed on first-line pemetrexed plus platinum +/- immunotherapy were enrolled. Patients received intravenous nab-paclitaxel 100 mg/m2 and gemcitabine 1000 mg/m2 on days 1 and 8 of each 21-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety and tolerability were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Thirty-seven patients (15 men [41%] and 22 women [59%]; median age, 66 years [range, 41-81 years]) were accrued. ORR was 13.5% (95% CI, 2.5-24.5%). DCR was 59.5% (95% CI, 43.5-75.5%). Median PFS was 2.6 months (95% CI, 1.4-3.8 months). Median OS was 6.2 months (95% CI, 4.2-8.2 months). 1-year OS was 24% (95% CI, 10-38%). Safety and tolerability were similar to other second-line chemotherapies, although there was an 11% incidence of grade 2-3 pneumonitis. CONCLUSION: Combination nab-paclitaxel and gemcitabine after platinum and pemetrexed for NSQ-NSCLC was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting. The higher-than-expected risk of pneumonitis was also concerning. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02303977 MICRO-ABSTRACT: In this phase II trial, 37 patients with metastatic non-squamous non-small cell lung cancer were treated with nab-paclitaxel/gemcitabine in second-line. ORR = 13.5% (95% CI, 2.5%-24.5%). Median PFS = 2.6 months (95% CI, 1.4-3.8 months). Median OS = 6.2 months (95% CI, 4.2-8.2 months). Nab-paclitaxel and gemcitabine was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting.

Plasma Genotyping at the Time of Diagnostic Tissue Biopsy Decreases Time-to-Treatment in Patients With Advanced NSCLC-Results From a Prospective Pilot Study.

Introduction: The availability of targeted therapies has transformed the management of advanced NSCLC; however, most patients do not undergo guideline-recommended tumor genotyping. The impact of plasma-based next-generation sequencing (NGS) performed simultaneously with diagnostic biopsy in suspected advanced NSCLC has largely been unexplored. Methods: We performed a prospective cohort study of patients with suspected advanced lung cancer on the basis of cross-sectional imaging results. Blood from the time of biopsy was sequenced using a commercially available 74-gene panel. The primary outcome measure was time to first-line systemic treatment compared with a retrospective cohort of consecutive patients with advanced NSCLC with reflex tissue NGS. Results: We analyzed the NGS results from 110 patients with newly diagnosed advanced NSCLC: cohorts 1 and 2 included 55 patients each and were well balanced regarding baseline demographics. In cohort 1, plasma NGS identified therapeutically informative driver mutations in 32 patients (58%) (13 KRAS [five KRAS G12C], 13 EGFR, two ERRB2, two MET, one BRAF, one RET). The NGS results were available before the first oncology visit in 85% of cohort 1 versus 9% in cohort 2 (p < 0.0001), with more cohort 1 patients receiving a guideline-concordant treatment recommendation at this visit (74% versus 46%, p = 0.005). Time-to-treatment was significantly shorter in cohort 1 compared with cohort 2 (12 versus 20 d, p = 0.003), with a shorter time-to-treatment in patients with specific driver mutations (10 versus 19 d, p = 0.001). Conclusions: Plasma-based NGS performed at the time of diagnostic biopsy in patients with suspected advanced NSCLC is associated with decreased time-to-treatment compared with usual care.

Mutations in renal cell carcinoma.

Renal cell carcinoma (RCC) is a commonly diagnosed and histologically diverse urologic malignancy. Clear cell RCC (ccRCC) is by far the most common, followed by the papillary and chromophobe subtypes. Sarcomatoid differentiation is a morphologic change that can be seen in all subtypes that typically portends a poor prognosis. In the past, treatment options for RCC were limited to cytokine-based therapy with a high-toxicity profile and low response rate. An increased understanding of the molecular basis of RCC has led to substantial improvement in treatment options in the form of targeted therapy and immunotherapy. A significant early discovery in RCC was frequent inactivation of the Von Hippel Lindau gene in ccRCC, which ultimately led to the development of vascular endothelial growth factor and mammalian target of rapamycin inhibitors. Further genomic sequencing of ccRCC tumors has identified other common mutations including BAP-1, PBRM1, SETD2, and PIK3CA. Many recent studies have explored how these mutations can affect prognosis and response to treatment. Likewise, papillary RCC has also been studied at the molecular level, which has shown a high level of mutations in the MET gene; early clinical data suggest the utility of MET targeted therapy. Finally, regarding the rarer sarcomatoid tumors, mutations in TP53 and NF2 may be important to their development. As we continue to learn more about what drives RCC at the molecular level, treatment options for RCC patients are diversifying.