Faculty Bibliography

INTRODUCTION:Determining lines of therapy (LOT) using real-world data is crucial to inform clinical decisions and support clinical research. Existing rules for determining LOT in patients with metastatic non-small cell lung cancer (mNSCLC) do not incorporate the growing number of targeted therapies used in treatment today. Therefore, we propose rules for determining LOT from real-world data of patients with mNSCLC treated with targeted therapies. METHODS:LOT rules were developed through expert consensus using a real-world cohort of 550 patients with ALK+ or ROS1+ mNSCLC in the multi-institutional, electronic medical record-based Academic Thoracic Oncology Medical Investigators Consortium's (ATOMIC) Driver Mutation Registry. Rules were subsequently modified based on a review of appropriate LOT determination. These resulting rules were then applied to an independent cohort of patients with EGFR+ mNSCLC to illustrate their use. RESULTS:Six rules for determining LOTs were developed. Among 1133 patients with EGFR mutations and mNSCLC, a total of 3168 regimens were recorded with a median of 2 regimens per patient (IQR, 1-4; range, 1-13). After applying our rules, there were 2834 total LOTs with a median of 2 LOTs per patient (IQR, 1-3; range, 1-11). Rules 1-3 kept 11% of regimen changes from advancing the LOT. When compared to previously published rules, LOT assignments differed 5.7% of the time, mostly in LOTs with targeted therapy. CONCLUSION:These rules provide an updated framework to evaluate current treatment patterns, accounting for the increased use of targeted therapies in patients with mNSCLC, and promote standardization of methods for determining LOT from real-world data.

BACKGROUND:T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors. METHODS:This was a three-part, open-label, phase 1/2 study: part A, dose-escalation monotherapy, part B, dose-expansion monotherapy, and part C, combination therapy with pembrolizumab. The study was conducted at 32 sites in 7 countries. Adult patients with advanced solid tumors were enrolled and received intravenous nemvaleukin once daily on days 1-5 (21-day cycle) at 0.1-10 µg/kg/day (part A), or at the RP2D (part B), or with pembrolizumab (part C). Primary endpoints were RP2D selection and dose-limiting toxicities (part A), and overall response rate (ORR) and safety (parts B and C). RESULTS:T and natural killer cell expansion, and minimal regulatory T cell expansion were observed following nemvaleukin treatment. ORR with nemvaleukin plus pembrolizumab was 13% (19/144; 95% CI 8 to 20), with 5 complete and 14 partial responses; 6 responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types. Three responses were in patients with platinum-resistant ovarian cancer. The most common grade 3-4 treatment-related adverse events (TRAEs) in parts B and C, respectively, were neutropenia (49%, 21%) and anemia (10%, 11%); 4% of patients in each part discontinued due to TRAEs. CONCLUSIONS:Nemvaleukin was well tolerated and demonstrated promising antitumor activity across heavily pretreated advanced solid tumors. Phase 2/3 studies of nemvaleukin are ongoing. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT02799095.

BACKGROUND:Brain metastases (BM) are a common, severe complication in patients with non-small cell lung cancer (NSCLC) and are difficult to treat due to their complex tumor biology and the intricate microenvironment of the brain. OBJECTIVES/OBJECTIVE:This review examines the current role of immune checkpoint inhibitors (ICIs) in treating NSCLC with BM, focusing on the latest clinical trials, emerging strategies, current guidelines, and future directions. We highlight the efficacy of ICIs as monotherapy and in combination with other treatments such as radiotherapy, stereotactic radiosurgery, chemotherapy, and anti-VEGF agents. RESULTS:While no single treatment sequence is universally accepted, combining ICIs with traditional therapies forms the core of the current treatment protocols. ICIs targeting the PD-1/PD-L1 pathway have significantly advanced NSCLC treatment, demonstrated by improved overall and progression-free survival in various settings. However, optimizing these benefits requires careful consideration of potential side effects, including cognitive decline and radiation necrosis, and the impact of steroid use on ICI efficacy. CONCLUSION/CONCLUSIONS:The review underscores the necessity for a personalized, integrated multidisciplinary treatment approach. Future research should focus on refining combination therapies and understanding the optimal sequence and timing of treatment.

BACKGROUND:In clinical trials, frontline pembrolizumab for advanced NSCLC has demonstrated durable, clinically meaningful, long-term survival benefits over chemotherapy. Our objective was to evaluate 5-year survival rates outside the idealized setting of clinical trials for advanced/metastatic NSCLC treated with frontline pembrolizumab monotherapy. METHODS:Using a nationwide, electronic health record-derived, deidentified database in the United States, we studied adult patients with advanced/metastatic NSCLC (unresectable stage IIIB/IIIC, or stage IV), with PD-L1 expression ≥ 50%, no documented EGFR, ALK, or ROS1 genomic alteration, and ECOG performance status of 0-1 initiating frontline pembrolizumab monotherapy from November 1, 2016, through March 31, 2020, excluding those in clinical trials. Kaplan-Meier was used to determine overall survival (OS). Data cutoff was May 31, 2023. RESULTS:A total of 804 patients were eligible for the study, including 404 women (50%); median age was 72 years (range, 38-85 years), with 310 patients (39%) ≥ 75 years old. Median follow-up time from pembrolizumab initiation to data cutoff was 60.5 months (range, 38.0-78.7). At data cutoff, 549 patients (68%) had died. Median OS was 19.2 months (95% CI, 16.6-21.4), and survival rate at 5 years was 25.1% (95% CI, 21.7-28.7). Overall, 266 patients (33%) received 1 or more subsequent regimens, most commonly an anti-PD-(L)1 agent (as monotherapy or combination therapy) or platinum-based chemotherapy. CONCLUSIONS:With 5-year follow-up in a real-world population, frontline pembrolizumab monotherapy continues to demonstrate long-term effectiveness, with survival outcomes consistent with those of pivotal clinical trials, for treating patients with advanced NSCLC with PD-L1 expression of ≥ 50% and no EGFR, ALK, or ROS1 genomic alteration.

INTRODUCTION/UNASSIGNED:Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors. METHODS/UNASSIGNED:Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively. RESULTS/UNASSIGNED:< 0.001, respectively). CONCLUSIONS/UNASSIGNED:Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy.

Up to 71% of lung cancer patients admitted to the ICU are newly diagnosed. The decision to initiate cancer directed treatments in lung cancer patients admitted to the ICU remains complex. For those with identified oncogene driver mutations, targeted therapies with rapid and high response rates are attractive treatment options. However, mechanically ventilated patients face additional barriers in which enteral tube administration of oral therapies may require tablets or capsules to be crushed or opened and diluted. Data on the pharmacodynamics and pharmacokinetics of this alternative route of administration are often very limited. Here we describe the first case report of an intubated patient with newly diagnosed NSCLC who was successfully treated with opened dabrafenib capsules and crushed trametinib tablets administered through a nasogastric tube. We also provide a review of the existing literature on feeding tube administration of commonly used tyrosine kinase inhibitors in lung cancer. Tyrosine kinase inhibitors administered through feeding tubes can lead to a clinically meaningful recovery in critically ill patients.

KRAS^G12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRAS^G12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRAS^G12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRAS^G12C and Kras^G12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

PURPOSE:The spatial arrangement of lymphocytes in the tumor bed (e.g., immune infiltrated, immune excluded, immune desert) is expected to reflect distinct immune evasion mechanisms and to associate with immunotherapy outcomes. However, data supporting these associations are scant and limited by the lack of a clear definition for lymphocyte infiltration patterns and the subjective nature of pathology-based approaches. EXPERIMENTAL DESIGN:We used multiplexed immunofluorescence to study major tumor-infiltrating lymphocyte (TIL) subsets with single-cell resolution in baseline whole-tissue section samples from NSCLC patients treated with immune checkpoint inhibitors (ICI). The spatial TIL patterns were analyzed using a qualitative pathologist-based approach, and an objective analysis of TIL density ratios in tumor/stromal tissues. The association of spatial patterns with outcomes was studied for different TIL markers. RESULTS:The analysis of CD8+ TIL patterns using qualitative assessment identified prominent limitations including the presence of a broad spectrum of phenotypes within most tumors and limited association with outcomes. The utilization of an objective method to classify NSCLCs showed the existence of at least three subgroups with partial overlap with those defined using visual patterns. Using this strategy, a subset of cases with "immune excluded-like" tumors showed prominently worse outcomes, suggesting reduced sensitivity to ICI; however, these results need to be validated. The analysis for other TIL subsets showed different results, underscoring the relevance of the marker selected for spatial TIL pattern evaluation and opportunities for market integration. CONCLUSIONS:Our results identified major challenges associated with the qualitative spatial TIL pattern evaluation. We devised a novel objective strategy to overcome some of these limitations that has strong biomarker potential.

BACKGROUND:G2032R. METHODS:fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2. RESULTS:G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events. CONCLUSIONS:fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).

WHAT IS THIS SUMMARY ABOUT?/UNASSIGNED:G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?/UNASSIGNED:were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?/UNASSIGNED:: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).