The impact of decision tools during oncological consultation with lung cancer patients: A systematic review within the I3LUNG project.

INTRODUCTION: To date, lung cancer is one of the most lethal diagnoses worldwide. A variety of lung cancer treatments and modalities are available, which are generally presented during the patient and doctor consultation. The implementation of decision tools to facilitate patient's decision-making and the management of their healthcare process during medical consultation is fundamental. Studies have demonstrated that decision tools are helpful to promote health management and decision-making of lung cancer patients during consultations. The main aim of the present work within the I3LUNG project is to systematically review the implementation of decision tools to facilitate medical consultation about oncological treatments for lung cancer patients. METHODS: In the present study, we conducted a systematic review following the PRISMA guidelines. We used an electronic computer-based search involving three databases, as follows: Embase, PubMed, and Scopus. 10 articles met the inclusion criteria and were included. They explicitly refer to decision tools in the oncological context, with lung cancer patients. RESULTS: The discussion highlights the most encouraging results about the positive role of decision aids during medical consultations about oncological treatments, especially regarding anxiety, decision-making, and patient knowledge. However, no one main decision aid tool emerged as essential. Opting for a more recent timeframe to select eligible articles might shed light on the current array of decision aid tools available. CONCLUSION: Future review efforts could utilize alternative search strategies to explore other lung cancer-specific outcomes during medical consultations for treatment decisions and the implementation of decision aid tools. Engaging with experts in the fields of oncology, patient decision-making, or health communication could provide valuable insights and recommendations for relevant literature or research directions that may not be readily accessible through traditional search methods. The development of guidelines for future research were provided with the aim to promote decision aids focused on patients' needs.

Evaluation of Major Pathologic Response and Pathologic Complete Response as Surrogate End Points for Survival in Randomized Controlled Trials of Neoadjuvant Immune Checkpoint Blockade in Resectable in NSCLC.

INTRODUCTION: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC. METHODS: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R2 with 95% confidence interval were calculated by the bootstrapping approach. RESULTS: Seven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R2 of pCR and MPR with 2-year EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07-0.19) and 0.11 (0.05-0.22), respectively. For the 2-year OS, the R2 of pCR and MPR were 0.55 (0.09-0.98) and 0.52 (0.10-0.96), respectively. At the trial level, the R2 for the association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97), respectively. CONCLUSIONS: Our analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed.

Cost of genetic testing, delayed care, and suboptimal treatment associated with polymerase chain reaction versus next-generation sequencing biomarker testing for genomic alterations in metastatic non-small cell lung cancer.

AIMS: To assess US payers' per-patient cost of testing associated with next-generation sequencing (NGS) versus polymerase chain reaction (PCR) biomarker testing strategies among patients with metastatic non-small cell lung cancer (mNSCLC), including costs of testing, delayed care, and suboptimal treatment initiation. METHODS: A decision tree model considered biomarker testing for genomic alterations using either NGS, sequential PCR testing, or hotspot panel PCR testing. Literature-based model inputs included time-to-test results, costs for testing/medical care, costs of delaying care, costs of immunotherapy [IO]/chemotherapy [CTX] initiation prior to receiving test results, and costs of suboptimal treatment initiation after test results (i.e. costs of first-line IO/CTX in patients with actionable mutations that were undetected by PCR that would have been identified with NGS). The proportion of patients testing positive for a targetable alteration, time to appropriate therapy initiation, and per-patient costs were estimated for NGS and PCR strategies combined. RESULTS: In a modeled cohort of 1,000,000 members (25% Medicare, 75% commercial), an estimated 1,119 had mNSCLC and received testing. The proportion of patients testing positive for a targetable alteration was 45.9% for NGS and 40.0% for PCR testing. Mean per-patient costs were lowest for NGS ($8,866) compared to PCR ($18,246), with lower delayed care costs of $1,301 for NGS compared to $3,228 for PCR, and lower costs of IO/CTX initiation prior to receiving test results (NGS: $2,298; PCR:$5,991). Cost savings, reaching $10,496,220 at the 1,000,000-member plan level, were driven by more rapid treatment with appropriate therapy for patients tested with NGS (2.1 weeks) compared to PCR strategies (5.2 weeks). LIMITATIONS: Model inputs/assumptions were based on published literature or expert opinion. CONCLUSIONS: NGS testing was associated with greater cost savings versus PCR, driven by more rapid results, shorter time to appropriate therapy initiation, and minimized use of inappropriate therapies while awaiting and after test results.

A Phase 1/2 Study to Evaluate the Safety and Activity of Nivolumab in Combination With Vorolanib, a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor, in Patients With Refractory Thoracic Tumors.

Introduction: Targeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies. Methods: This single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance). The primary objective of phase 1 was to determine the maximum tolerated dose, and the primary end point for each dose-expansion cohort was the objective response rate. Results: A total of 88 patients were enrolled in phase 1 (n = 11) and dose expansion (n = 77) cohorts. Transaminitis was dose-limiting and expansion proceeded with oral vorolanib 200 mg daily combined with intravenous nivolumab 240 mg every 2 weeks. The objective response rate per cohort were as follows: NSCLC naive 33% (five of 15, 95% confidence interval [CI]: 13%-60%), NSCLC primary refractory 5.9% (one of 17, 95% CI: 0%-17.6%), NSCLC acquired resistance 11.1% (two of 18, 95% CI: 0%-27.8%); SCLC 0% (zero of 18), and thymic carcinoma 11% (one of nine, 95% CI: 0%-33%). Disease control rate ranged from 11.1% in SCLC (two of 18, 0%-27.8%) to 66.7 % in thymic carcinoma (six of nine, 95% CI: 33.3%-100%). The most common adverse events were fatigue (32%), aspartate transaminase (27%) and alanine transaminase elevation (25%), and diarrhea (19%). Transaminitis was more common in patients with thymic carcinoma than other tumors. Conclusions: Vorolanib plus nivolumab had a manageable safety profile and may have clinical benefits in various thoracic malignancies. The disease control rate in thymic malignancies warrants further assessment.

Combined Stereotactic Body Radiation Therapy and Immune Checkpoint Inhibition for Liver Metastases: Safety and Outcomes in a Pooled Analysis of 3 Phase 1 Trials.

PURPOSE: Stereotactic body radiation therapy (SBRT) safely and effectively controls liver metastases (LMs), but its safety and efficacy when combined with immune checkpoint inhibitors (ICIs) are not well characterized. This analysis of 3 phase 1 trials of combination SBRT and ICI evaluates whether LM-SBRT increases the risk for hepatotoxicity when combined with ICI and explores efficacy endpoints. METHODS AND MATERIALS: Data were analyzed from 3 phase 1 trials of combination SBRT and ICI for patients with metastatic solid tumors conducted between 2016 and 2020. ICI was administered per trial protocol with LM-SBRT delivered to 45 Gy in 3 fractions with mean liver dose <16 Gy and ≥700 cc of normal liver spared 17.1 Gy. Hepatic adverse events (HAEs) were defined as hepatic failure, autoimmune hepatitis, or elevation of aspartate transaminase, alanine transaminase, bilirubin, or alkaline phosphatase using Common Terminology Criteria for Adverse Events version 4.0. Cumulative incidence of HAEs and local failure were modeled with death as a competing risk. Competing risk regression was performed using Fine-Gray modeling. Survival was estimated via the Kaplan-Meier method. RESULTS: Two hundred patients were analyzed, including 81 patients with LM, 57 of whom received LM-SBRT. The 12-month rate of any grade ≥2 HAE was 11% and 10% in LM-SBRT and non-LM-SBRT patients, respectively non-significant (NS). Radiographic evidence for liver disease and dual-agent ICI was significantly associated with HAEs on univariable and multivariable analysis, but liver dose metrics were not. Patients with LM had significantly worse progression-free and overall survival compared with those without, and local failure of treated LM was significantly higher than for treated extrahepatic metastases (28% vs 4% at 12 months, P < .001). CONCLUSIONS: Combination LM-SBRT and ICI did not significantly increase the risk for HAEs compared with ICI without LM-SBRT, suggesting hepatotoxicity is largely driven by factors other than liver radiation therapy, such as choice of ICI. LM is associated with worse overall survival and local control outcomes.

Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial.

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .

Disparities in outcomes between Black and White patients in North America with thoracic malignancies and COVID-19 infection (TERAVOLT).

BACKGROUND: Patients with thoracic malignancies who develop COVID-19 infection have a higher hospitalization rate compared to the general population and to those with other cancer types, but how this outcome differs by race and ethnicity is relatively understudied. METHODS: The TERAVOLT database is an international, multi-center repository of cross-sectional and longitudinal data studying the impact of COVID-19 on individuals with thoracic malignancies. Patients from North America with thoracic malignancies and confirmed COVID-19 infection were included for this analysis of racial and ethnic disparities. Patients with missing race data or races and ethnicities with fewer than 50 patients were excluded from analysis. Multivariable analyses for endpoints of hospitalization and death were performed on these 471 patients. RESULTS: Of the 471 patients, 73% were White and 27% were Black. The majority (90%) were non-Hispanic ethnicity, 5% were Hispanic, and 4% were missing ethnicity data. Black patients were more likely to have an Eastern Cooperative Oncology Group (ECOG) Performance Status ≥ 2 (p-value = 0.04). On multivariable analysis, Black patients were more likely than White patients to require hospitalization (Odds Ratio (OR): 1.69, 95% CI: 1.01-2.83, p-value = 0.044). These differences remained across different waves of the pandemic. However, no statistically significant difference in mortality was found between Black and White patients (OR 1.29, 95% CI: 0.69-2.40, p-value = 0.408). CONCLUSIONS: Black patients with thoracic malignancies who acquire COVID-19 infection are at a significantly higher risk of hospitalization compared to White patients, but there is no significant difference in mortality. The underlying drivers of racial disparity among patients with thoracic malignancies and COVID-19 infection require ongoing investigation.

What is the ideal endpoint in early-stage immunotherapy neoadjuvant trials in lung cancer?

Numerous clinical trials investigating neoadjuvant immune checkpoint inhibitors (ICI) have been performed over the last 5 years. As the number of neoadjuvant trials increases, attention must be paid to identifying informative trial endpoints. Complete pathologic response has been shown to be an appropriate surrogate endpoint for clinical outcomes, such as event-free survival or overall survival, in breast cancer and bladder cancer, but it is less established for non-small-cell lung cancer (NSCLC). The simultaneous advances reported with adjuvant ICI make the optimal strategy for early-stage disease debatable. Considering the long time required to conduct trials, it is important to identify optimal endpoints and discover surrogate endpoints for survival that can help guide ongoing clinical research. Endpoints can be grouped into two categories: medical and surgical. Medical endpoints are measures of survival and drug activity; surgical endpoints describe the feasibility of neoadjuvant approaches at a surgical level as well as perioperative attrition and complications. There are also several exploratory endpoints, including circulating tumor DNA clearance and radiomics. In this review, we outline the advantages and disadvantages of commonly reported endpoints for clinical trials of neoadjuvant regimens in NSCLC.

Abnormalities on baseline chest imaging are risk factors for immune checkpoint inhibitor associated pneumonitis.

BACKGROUND: Chronic lung disease is a proposed risk factor for immune checkpoint inhibitor pneumonitis (ICI-pneumonitis); however, data is sparse regarding the impact of pre-existing lung disease and baseline chest imaging abnormalities on the risk of developing ICI-pneumonitis. METHODS: We conducted a retrospective cohort study of patients with ICI treatment for cancer from 2015 to 2019. ICI-pneumonitis was determined by the treating physician with corroboration via an independent physician review and exclusion of alternative etiologies. Controls were patients treated with ICI without a diagnosis of ICI-pneumonitis. Fisher's exact tests, Student's t-tests, and logistic regression were used for statistical analysis. RESULTS: We analyzed 45 cases of ICI-pneumonitis and 135 controls. Patients with abnormal baseline chest CT imaging (emphysema; bronchiectasis; reticular, ground glass and/or consolidative opacities) had increased risk for ICI-pneumonitis (OR 3.41, 95%CI: 1.68-6.87, p = 0.001). Patients with gastroesophageal reflux disease (GERD) (OR 3.83, 95%CI: 1.90-7.70, p = < 0.0001) also had increased risk for ICI-pneumonitis. On multivariable logistic regression, patients with abnormal baseline chest imaging and/or GERD remained at increased risk for ICI-pneumonitis. Eighteen percent of all patients (32/180) had abnormal baseline chest CT consistent with chronic lung disease without a documented diagnosis. CONCLUSION: Patients with baseline chest CT abnormalities and GERD were at increased risk for developing ICI-pneumonitis. The large proportion of patients with baseline radiographic abnormalities without a clinical diagnosis of chronic lung disease highlights the importance of multidisciplinary evaluation prior to ICI initiation.

The Role of MET in Resistance to EGFR Inhibition in NSCLC: A Review of Mechanisms and Treatment Implications.

Utilizing targeted therapy against activating mutations has opened a new era of treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). For patients with epidermal growth factor (EGFR)-mutated cancers, EGFR inhibitors, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib, significantly prolong progression-free survival and overall survival, and are the current standard of care. However, progression after EGFR inhibition invariably occurs, and further study has helped elucidate mechanisms of resistance. Abnormalities in the mesenchymal-epithelial transition (MET) oncogenic pathway have been implicated as common alterations after progression, with MET amplification as one of the most frequent mechanisms. Multiple drugs with inhibitory activity against MET, including TKIs, antibodies, and antibody-drug conjugates, have been developed and studied in advanced NSCLC. Combining MET and EGFR is a promising treatment strategy for patients found to have a MET-driven resistance mechanism. Combination TKI therapy and EGFR-MET bispecific antibodies have shown promising anti-tumor activity in early clinical trials. Future study including ongoing large-scale trials of combination EGFR-MET inhibition will help clarify if targeting this mechanism behind EGFR resistance will have meaningful clinical benefit for patients with advanced EGFR-mutated NSCLC.

Targeted Toxicities: Protocols for Monitoring the Adverse Events of Targeted Therapies Used in the Treatment of Non-Small Cell Lung Cancer.

Targeted therapies have revolutionized the treatment for many patients with non-small cell lung cancer (NSCLC). Multiple new oral targeted therapies have been approved in the last decade; however, their overall efficacy may be reduced by poor adherence, treatment interruptions, or dose reductions due to adverse events. Most institutions lack standard monitoring protocols for toxicities from these targeted agents. This review describes important adverse events observed in clinical trials and reported by the U.S. Food and Drug Administration for both currently approved and upcoming promising therapies in the treatment of NSCLC. These agents cause a range of toxicities, including dermatologic, gastroenteric, pulmonary, and cardiac toxicities. This review proposes protocols for routine monitoring of these adverse events, both prior to initiation of therapy and while on treatment.

Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC.

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.

Phase I study of anti-epidermal growth factor receptor antibody-drug conjugate serclutamab talirine: Safety, pharmacokinetics, and antitumor activity in advanced glioblastoma.

Background: Serclutamab talirine (Ser-T, formerly ABBV-321) is an antibody-drug conjugate consisting of an antibody (AM-1-ABT-806) directed against activated epidermal growth factor receptor (EGFR) and a pyrrolobenzodiazepine dimer. We investigated Ser-T monotherapy in a phase I, first-in-human, dose-escalation, and dose-expansion study in patients with advanced solid tumors associated with EGFR overexpression. Methods: Eligible patients (≥18 years) had advanced, histologically confirmed solid tumors associated with EGFR overexpression (centralized testing). Patients received Ser-T intravenously once every 4 weeks (Q4W; 5-50 µg/kg) in the dose-escalation phase. Herein, preliminary antitumor activity at the recommended phase II dose (RP2D) is reported only for patients with glioblastoma (n = 24); additional assessments included all treated patients. Results: Sixty-two patients (median age: 58 years) were enrolled within the dose-escalation (n = 43) and dose-expansion (n = 19) phases. One dose-limiting toxicity, grade 3 aspartate aminotransferase and alanine aminotransferase elevation, occurred at 20 µg/kg during dose escalation. The Ser-T RP2D regimen of 50 µg/kg × 1 (loading dose) followed by 25 µg/kg Q4W (maintenance dose) was administered during dose expansion. Fatigue (37%) was the only treatment-emergent adverse event (AE) occurring in >25% of patients. Two patients (3%) reported mild treatment-related ocular AEs (eye pruritus). Responses in patients with glioblastoma included 1 partial response (~33 months), 6 stable disease, and 14 progressive disease (not evaluable: n = 3). Conclusions: Ser-T monotherapy at doses up to 50 µg/kg initial dose, followed by 25 µg/kg Q4W demonstrated a tolerable safety profile with minimal antitumor activity observed in patients with glioblastoma. The glioblastoma dose-expansion cohort was closed due to a lack of efficacy (NCT03234712).

A Multicenter Retrospective Chart Review of Clinical Outcomes Among Patients With KRAS G12C Mutant Non-Small Cell Lung Cancer.

BACKGROUND: On May 28, 2021, the United States Food and Drug Administration (FDA) granted accelerated approval to sotorasib for second-line or later treatment of patients with locally advanced or metastatic KRAS G12C mutant non-small cell lung cancer (NSCLC). This was the first FDA-approved targeted therapy for this patient population. Due to a paucity of real world data describing clinical outcomes in patients with locally advanced or metastatic KRAS G12C mutated NSCLC in the second-line or later, we sought to compile a large, academic medical center-based historical dataset to clarify clinical outcomes in this patient population. MATERIALS AND METHODS: The clinical outcomes of 396 patients with stage IV (n = 268, 68%) or recurrent, metastatic (n = 128, 32%) KRAS G12C mutant NSCLC were evaluated in this multicenter retrospective chart review conducted through the Academic Thoracic Oncology Medical Investigator's Consortium (ATOMIC). Patients treated at 13 sites in the United States and Canada and diagnosed between 2006 and 2020 (30% 2006-2015, 70% 2016-2020) were included. Primary outcomes included real-world PFS (rwPFS) and overall survival (OS) from time of stage IV or metastatic diagnosis, with particular interest in patients treated with second-line docetaxel-containing regimens, as well as clinical outcomes in the known presence or absence of STK11 or KEAP1 comutations. RESULTS: Among all patients with stage IV or recurrent, metastatic KRAS G12C mutant NSCLC (n = 201 with KRAS G12C confirmed prior to first line systemic therapy), the median first-line rwPFS was 9.3 months (95% CI, 7.3-11.8 months) and median OS was 16.8 months (95% CI, 12.7-22.3 months). In this historical dataset, first line systemic therapy among these 201 patients included platinum doublet alone (44%), PD-(L)1 inhibitor monotherapy (30%), platinum doublet chemotherapy plus PD-(L)1 inhibitor (18%), and other regimens (8%). Among patients with documented second-line systemic therapy (n = 123), the second-line median rwPFS was 8.3 months (95% CI, 6.1-11.9 months), with median rwPFS 4.6 months (95% CI, 1.4-NA) among 10 docetaxel-treated patients (9 received docetaxel and 1 received docetaxel plus ramucirumab). Within the total study population, 49 patients (12%) had a co-occurring STK11 mutation and 3 (1%) had a co-occurring KEAP1 mutation. Among the 49 patients with a co-occurring KRAS G12C and STK11 mutation, median rwPFS on first-line systemic therapy (n = 23) was 6.0 months (95% CI, 4.7-NA), and median OS was 14.0 months (95% CI, 10.8-35.3 months). CONCLUSION: In this large, multicenter retrospective chart review of patients with KRAS G12C mutant NSCLC we observed a relatively short median rwPFS of 4.6 months among 10 patients with KRAS G12C mutant NSCLC treated with docetaxel with or without ramucirumab in the second-line setting, which aligns with the recently reported CodeBreak 200 dataset.

STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer.

PURPOSE: Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC. MATERIALS AND METHODS: This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62). RESULTS: Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local. CONCLUSION: In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

Meeting an un-MET need: Targeting MET in non-small cell lung cancer.

The MET pathway can be activated by MET exon 14 skipping mutations, gene amplification, or overexpression. Mutations within this pathway carry a poor prognosis for patients with non-small cell lung cancer (NSCLC). MET exon 14 skipping mutations occur in 3-4% of patients with NSCLC, while MET amplifications are found in 1-6% of patients. The most effective method for detection of MET amplification is fluorescent in situ hybridization (FISH) and of MET exon 14 skipping mutations is RNA-based next generation sequencing (NGS). Immunohistochemistry (IHC) is an alternative method of diagnosis but is not as reliable. Early studies of MET tyrosine kinase inhibitors (TKIs) demonstrated limited clinical benefit. However, newer selective MET TKIs, such as capmatinib and tepotinib, have improved efficacy. Both drugs have an acceptable safety profile with the most common treatment-related adverse event being peripheral edema. One of the most frequent resistance mechanisms to EGFR inhibition with osimertinib is MET amplification. There is interest in combining EGFR inhibition plus MET inhibition in an attempt to target this resistance mechanism. Additional ways of targeting MET alterations are currently under investigation, including the bi-specific antibody amivantamab. Additional research is needed to further understand resistance mechanisms to MET inhibition. There is limited research into the efficacy of immune checkpoint inhibition for MET-altered NSCLC, though some data suggests decreased efficacy compared with wild-type patients and increased toxicity associated with the combination of immunotherapy and MET TKIs. Future directions for research will include combination clinical trials and understanding rational combinations for MET alterations.