Non-squamous Non-small Cell Lung Cancer Research Articles

POSC61 Cost-Effectiveness of ROS1-Testing Strategy Compared to a NO-ROS1-Testing Strategy in Advanced NSCLC in Spain

Determination of ROS1 rearrangements in non-small cell lung cancer (NSCLC) is recommended in guidelines but not yet fully widespread. The aim of this study is to determine the clinical and economic impact of sequentially testing ROS1 in addition to EGFR and ALK in Spain. A joint model combining a decision-tree with Markov models was developed to determine the cost-effectiveness of testing ROS1 strategy by comparison against a no-ROS1-testing strategy. We assumed that EGFR, ALK and PD-L1 were tested sequentially. Current distribution of ROS1 techniques, testing, positivity, and invalidity rates of biomarker determinations (EGFR, ALK, ROS1, PD-L1) were obtained from experts and Lungpath real-world database. Treatment allocation based on test results was defined by expert opinion. For each treatment, a 3-states partitioned-survival model was developed, where progression-free survival and overall survival curves were extrapolated to model transition of patients among health states at long-term. Only medical direct costs were included (€ 2021). A lifetime horizon was analyzed. Both deterministic and probabilistic sensitivity analyses were performed to address uncertainty. We estimated that 9,578 patients are diagnosed in Spain with advanced non-squamous NSCLC or never-smokers squamous NSCLC in a year. 8,755 of those patients finally tested were defined as the target population entering the model. Over a lifetime horizon, the ROS1-testing scenario produced additional 157.5 life years and 121.3 quality-adjusted life years (QALYs) compared with no-ROS1-testing scenario. Total direct costs were increased up to € 2,244,737 for ROS1-testing scenario for the target population. The incremental cost-effectiveness ratio (ICER) was 18,514 €/QALY. The sensitivity analyses carried out confirmed the robustness of the base-case Results: Despite the low prevalence of ROS1 rearrangements in NSCLC, which may discourage its determination in some centers, our study shows that ROS1 testing in addition to EGFR and ALK is cost-effective compared to no-ROS1-testing strategy.

Clinical outcomes of Atezolizumab Therapy for Previously-Treated Advanced-Stage Non-Small Cell Lung Cancer: A Real-World Study in Taiwan

Immune checkpoint inhibitors (ICIs) are the standard treatment for non-small-cell lung cancer (NSCLC). We assessed the clinical prognostic factors in NSCLC patients receiving atezolizumab as a second- or later-line (2L+) treatment. Data were retrospectively collected for NSCLC patients treated with atezolizumab from July 2017 to June 2019 at six medical centers in Taiwan. Clinical characteristics, treatment course and responses of patients were recorded. A total of 128 NSCLC patients received 2L+ atezolizumab, and the outcomes included a response rate of 10.2%, median progression-free survival (mPFS) of 3.5 months, and median overall survival (mOS) of 10.7 months. Eleven patients who had received osimertinib treatment before atezolizumab had a shorter mPFS (2.3 versus 3.5 months; p = 0.002) and mOS (4.8 versus 11.2 months; p < 0.001) than those without prior osimertinib treatment. Even for the subgroup of patients with EGFR-mutant non-squamous NSCLC, prior osimertinib was still associated with shorter PFS (2.3 versus 4.1 months; p = 0.006) and OS (4.8 versus 11.7 months; p < 0.001). Multivariate analysis revealed that prior osimertinib treatment correlated with not only shorter PFS (hazard ratio [HR]: 2.94; 95% confidence interval [CI], 1.34-6.47; p = 0.007) but also shorter OS (HR, 3.55; 95% CI, 1.57-8.03; p = 0.002). Patients with prior ICIs treatment (HR, 3.18; p = 0.002) or poor performance status (HR, 2.70; p = 0.001) had shorter OS. In conclusion, osimertinib treatment before atezolizumab therapy was associated with a shorter PFS and a poor prognosis in NSCLC patients in real-world settings. Further studies with larger sample sizes are needed to validate these observations.

The role of diagnostics and treatment — lung cancer with ALK rearrangement

Lung cancer is the most common cause of cancer-related deaths both in Poland and worldwide. Recently, the incidence of lung adenocarcinoma has been increasing and currently it accounts for about 45% of all diagnosed lung cancers. Patients diagnosed with non-squamous non-small cell lung cancer (NSCLC), especially with adenocarcinoma, cancer containing adenocarcinoma component, large cell carcinoma, as well as patients with not otherwise specified (NOS) cancer may benefit from targeted therapy if molecular tests confirm the presence of activating EGFR gene mutations, ALK, ROS1 or NTRK rearrangement, or BRAF gene mutations. The ALK gene rearrangement is a positive predictive marker of tyrosine kinase inhibitors (TKIs) effectiveness, which are more effective than standard chemotherapy in this population, are associated with improving the quality of life and also indicate a different, more tolerable toxicity profile. This study presents the diagnostic sequence and registered treatment options for patients with ALK-positive NSCLC.

Cost-Effectiveness Analysis of Camrelizumab Plus Chemotherapy vs. Chemotherapy Alone as the First-Line Treatment in Patients With IIIB-IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Without EGFR and ALK Alteration from a Perspective of Health - Care System in China.

Objective: The CAMEL clinical trial (412 patients were randomly assigned to either camrelizumab plus chemotherapy (n = 205) or chemotherapy alone (n = 207)) demonstrated that camrelizumab plus chemotherapy (CC) improved the overall survival time (OS) and progression-free survival time (PFS) of patients with metastatic nonsquamous non-small cell lung cancer (non-sq NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations (EGFRm and ALKm) vs. chemotherapy (C) alone. Our objective was to conduct a cost-effectiveness analysis of CC vs. C from a perspective of health - care system in China with a lifetime horizon to identify whether it will be cost-effective. Materials and Methods: A partitioned survival model (PSM) was applied for patients with IIIB–IV non-sq NSCLC without EGFRm and ALKm. Transition parameters and proportions of three health states were derived from the CAMEL trial. The model was designed using a lifetime horizon, a 21-day cycle, and a 5% discount rate of costs and outcomes. It was deemed cost-effective in China if the incremental cost-effectiveness ratio (ICER) value is less than $32,457 per quality adjusted life-year (QALY). Deterministic and probabilistic sensitivity analyses were performed to verify the influence of parameter uncertainty on the results. Results: In the base-case analysis, we found that the ICER of CC compared with C is $-7,382.72/QALY which meant that CC had lower costs and better outcomes. The results of the sensitivity analyses demonstrated that the result was robust for the ICERs never transcending the willingness-to-pay (WTP) threshold. Conclusion: Camrelizumab plus chemotherapy is an obviously cost-effective therapeutic regime for patients of IIIB–IV non-sq NSCLC without EGFRm and ALKm in China at a $32,457 WTP threshold.

Defining comprehensive biomarker-related testing and treatment practices for advanced non-small-cell lung cancer: Results of a survey of U.S. oncologists.

BackgroundAn ASCO taskforce comprised of representatives of oncology clinicians, the American Cancer Society National Lung Cancer Roundtable (NLCRT), LUNGevity, the GO2 Foundation for Lung Cancer, and the ROS1ders sought to: characterize U.S. oncologists’ biomarker ordering and treatment practices for advanced non‐small‐cell lung cancer (NSCLC); ascertain barriers to biomarker testing; and understand the impact of delays on treatment decisions.MethodsWe deployed a survey to 2374 ASCO members, targeting U.S. thoracic and general oncologists.ResultsWe analyzed 170 eligible responses. For non‐squamous NSCLC, 97% of respondents reported ordering tests for EGFR, ALK, ROS1, and BRAF. Testing for MET, RET, and NTRK was reported to be higher among academic versus community providers and higher among thoracic oncologists than generalists. Most respondents considered 1 (46%) or 2 weeks (52%) an acceptable turnaround time, yet 37% usually waited three or more weeks to receive results. Respondents who waited ≥3 weeks were more likely to defer treatment until results were reviewed (63%). Community and generalist respondents who waited ≥3 weeks were more likely to initiate non‐targeted treatment while awaiting results. Respondents <5 years out of training were more likely to cite their concerns about waiting for results as a reason for not ordering biomarker testing (42%, vs. 19% with ≥6 years of experience).ConclusionsRespondents reported high biomarker testing rates in patients with NSCLC. Treatment decisions were impacted by test turnaround time and associated with practice setting and physician specialization and experience.

A Real-World Study on the Effectiveness and Safety of Pembrolizumab Plus Chemotherapy for Nonsquamous NSCLC

IntroductionThe real-world effectiveness of combination treatment with cytotoxic chemotherapy and programmed cell death protein-1 or programmed death-ligand 1 inhibitor for NSCLC, especially for the elderly (aged ≥75 y) or those with poor performance status (≥2), has not been fully elucidated. We investigated the real-world effectiveness and safety of this combination therapy in these populations. MethodsThis multicenter retrospective study evaluated patients who are chemo-naïve with advanced NSCLC who received a combination of platinum, pemetrexed, and pembrolizumab between December 2018 and June 2019. This was an updated prespecified secondary analysis with the primary objective of investigating the safety and effectiveness in this cohort. ResultsOverall, 299 patients were included. Multivariate analysis identified performance status (0–1) and programmed death-ligand 1 tumor proportion score (≥50%) as significant independent predictors of progression-free survival (p = 0.007, and p = 0.003, respectively). The incidence of severe adverse events (AEs) was higher in the elderly and those with poor performance status than in their younger and good performance status counterparts. A total of 71 patients developed AEs that led to treatment discontinuation, and AE-related treatment discontinuation occurred at a significantly higher rate in older patients (median [range]) (70 [46–82] y) than in younger patients (68 [31–84] y) (p <0.001). ConclusionsCombination treatment with pembrolizumab plus chemotherapy had low real-world effectiveness for poor performance status patients. Severe AEs occurred at a higher rate in the elderly and poor performance status patients, and the AE-related treatment discontinuation rate increased with age. Physicians should be cautious about using this regimen, especially in the elderly and poor performance status patients.

MYL-1402O: A Bevacizumab Biosimilar.

MYL-1402O (Abevmy®, Lextemy®) is a biosimilar of the reference anti-vascular endothelial growth factor antibody bevacizumab. Abevmy® is approved for use in all indications for which reference bevacizumab is approved, including the treatment of non-small cell lung cancer (NSCLC) and other solid cancers. Lextemy® is approved for all indications as reference bevacizumab, except in recurrent ovarian cancer. MYL-1402O has similar physicochemical and pharmacodynamic properties to those of reference bevacizumab, and the pharmacokinetic similarity of the agents has been shown in healthy male subjects. MYL-1402O demonstrated clinical efficacy equivalent to that of reference bevacizumab in patients with non-squamous NSCLC. The tolerability, safety and immunogenicity profiles of MYL-1402O were consistent with those of reference bevacizumab. The role of reference bevacizumab in the management of solid cancers is well established and MYL-1402O provides an effective biosimilar alternative for patients requiring bevacizumab therapy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00858-7.

Prospective, Noninterventional Study of Nivolumab in Real-world Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer After Prior Chemotherapy (ENLARGE-Lung).

Nivolumab was the first immune checkpoint inhibitor approved for use in advanced non-small cell lung cancer (NSCLC). This noninterventional, prospective cohort study investigates real-world effectiveness of nivolumab in pretreated NSCLC patients in Germany (Enlarge-Lung/CA209-580). Patients with squamous (SQ) or nonsquamous (NSQ) NSCLC previously treated for locally advanced or metastatic (stage IIIB/IV) disease received nivolumab according to the current Summary of Product Characteristics. Overall survival (OS) was the primary endpoint. Of 907 patients enrolled, 660 patients who were followed for at least 12 months across 79 study centers in Germany, were analyzed. Median OS was 11.2 months [95% confidence interval (CI), 9.1-12.9]; outcomes for the 418 patients with NSQ histology [13.1 mo (95% CI, 10.6-15.6)] were more favorable than outcomes for the 242 patients with SQ histology [8.9 mo (95% CI, 6.4-11.3)]. Patients' age, presence of distant or brain metastases, or line of therapy did not affect outcomes; however, patients with poor performance status (ECOG-PS ≥2, n=80) had shorter median OS [4.7 mo (95% CI, 3.1-5.4)]. This study represents one of the largest real-world cohorts providing outcomes of nivolumab in pretreated NSCLC. The results match well with the published evidence from pivotal clinical trials and demonstrate clinical effectiveness of nivolumab in advanced NSCLC.

Economic Evaluation of First-Line Camrelizumab for Advanced Non-small-cell Lung Cancer in China.

Background: As the first domestic PD-1 antibody approved for lung cancer in China, camrelizumab has exhibited proven effectiveness for non-small-cell lung cancer (NSCLC) patients. However, the cost-effectiveness of this new regimen remains to be investigated.Objective: To evaluate the cost-effectiveness of camrelizumab combination therapy vs. chemotherapy for previously untreated patients with advanced, non-squamous NSCLC without Alk or Egfr genomic aberrations from the perspective of China's healthcare system.Methods: Based on the CameL trial, the study developed a three-health state Markov model to evaluate the cost-effectiveness of adding camrelizumab to chemotherapy compared to chemotherapy alone in NSCLC patients. The analysis models were conducted for patients unselected by PD-L1 tumor expression (the base case) and the patient subgroup with PD-L1-expressing tumors (≥1%). Primary model outcomes included the costs in US dollars and health outcomes in quality-adjusted life-years (QALYs) as well as the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of $31,500 per QALY. Additionally, a scenario analysis that adjusted within-trial crossover was employed to evaluate camrelizumab combination therapy compared to chemotherapy without subsequent use of PD1/PD-L1 antibodies.Results: Camrelizumab combination therapy was more costly and provided additional 0.11 QALYs over chemotherapy in the base case analysis (0.86 vs. 0.75 QALYs), 0.12 QALYs over chemotherapy in the subgroup analysis (0.99 vs. 0.88 QALYs), and 0.34 QALYs over chemotherapy in the scenario analysis (0.86 vs. 0.52 QALYs). Correspondingly, the ICER was $63,080 per QALY, $46,311 per QALY, and $30,591 per QALY, in the base case, the subgroup, and the scenario analysis, respectively. One-way sensitivity analyses revealed that ICERs of the base case and the subgroup analysis were most sensitive to the cost of camrelizumab, the cost of pemetrexed. Besides, the base case and subgroup analysis were more sensitive to the risk of neutrophil count decreased in the camrelizumab and the utility of stable disease, respectively.Conclusion: Although camrelizumab combination therapy is not cost-effective as first-line therapy for NSCLC patients in China in the base case, adjusting within-trial crossover would move the treatment regimen toward cost-effectiveness in the scenario analysis.

Randomized phase II trial of pemetrexed-cisplatin plus bevacizumab or thoracic radiotherapy followed by surgery for stage IIIA (N2) nonsquamous non–small cell lung cancer

BackgroundPersonalized Induction Therapy-1 is a multicenter, randomized phase II selection design trial of the efficacy and safety of platinum-doublet induction chemotherapy plus angiogenesis inhibitors/concurrent thoracic radiotherapy (TRT) followed by surgery for stage IIIA (N2) nonsquamous non–small cell lung cancer (NSCLC). MethodsPatients with pathologically proven stage IIIA (N2) nonsquamous NSCLC were assigned at random to 1 of 2 arms. Patients received (1:1) induction therapy with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 plus bevacizumab 15 mg/kg intravenously every 3 weeks for 3 cycles (bevacizumab arm) or concurrent TRT (45 Gy in 25 fractions; TRT arm) before surgery. The primary endpoint was the 2-year progression-free survival (PFS) rate. ResultsEighty-two patients were treated, including 42 in the bevacizumab arm and 40 in the TRT arm. Thirty-eight patients (90%) in the bevacizumab arm and 37 patients (93%) in the TRT arm underwent surgery. The objective response rates in the 2 groups were 50% and 60%, respectively (P = .36). The 2-year PFS and overall survival rates were 37% (95% confidence interval [CI], 22.4%-51.2%) and 50% (95% CI, 33.8%-64.2%) (hazard ratio [HR], 1.34; P = .28), respectively, and 81% (95% CI, 64.7%-89.7%) and 80% (95% CI, 64.0%-89.5%) (HR, 1.10; P = .83), respectively. Although grade 5 toxicity did not occur during induction therapy, 2 patients in the bevacizumab arm died due to bronchopleural fistula. ConclusionsAlthough not significant, the 2-year PFS rate was higher in the TRT arm than in the bevacizumab arm. Fatal surgical complications were observed only in the bevacizumab arm. Therefore, pemetrexed-cisplatin with concurrent TRT was chosen as the investigational induction treatment strategy for future phase III trials.

Multicenter real-world data of patients harboring rare mutations other than EGFR or ALK in advanced or metastatic non-small cell lung cancer.

BackgroundStudies on the application of targeted therapies for patients with non‐small cell lung cancer (NSCLC) who harbor rare genetic mutations are ongoing. In the present study, we investigated the real‐world data of NSCLC patients who harbor rare mutations.MethodsWe retrospectively analyzed patients with advanced or metastatic nonsquamous NSCLC aged >20 years with confirmed rare mutations (BRAF, ROS1, MET, RET, HER2, FGFR, and NTRK) from January 2015 to September 2020 at nine tertiary hospitals. In addition, we validated the lung cancer PCR panel kit in patients with confirmed mutations by NGS.ResultsAmong 118 patients included, 88 received platinum‐based chemotherapy as first‐line chemotherapy. The progression‐free survival of patients with BRAF, ERBB2, MET, RET, and ROS1 mutations was 10.9 months (95% confidence interval [CI]: 1.3–20.5), 5.3 months (95% CI: 3.0–7.5), 7.2 months (95% CI: 3.6–10.9), 11.4 months (95% CI: 9.2–13.6), and 10.0 months (95% CI: 3.7–16.4) respectively (p = 0.041). The median overall survival (OS) was not reached in patients with ROS1 mutations; however, in BRAF, ERBB2, MET, and RET mutant patients, median OS was 14.1 months (95% CI: 10.1–14.1), 34.5 months (95% CI: 13.2–36.9), 22.7 months (95% CI: 1.7–24.0), and 29.8 months (95% CI: 28.9–61.3), respectively (p = 0.006). Of the 27 tissue samples, 26 (96.3%) showed the same PCR panel kit result with NGS.ConclusionsFirst‐line platinum‐based chemotherapy showed durable benefit in patients with advanced or metastatic nonsquamous NSCLC harboring rare genetic mutation other than EGFR or ALK.

First-Line Pharmacotherapies and Survival among Patients Diagnosed with Non-Resectable NSCLC: A Real-Life Setting Study with Gender Prospective.

Simple SummaryWomen and men have a different biomolecular profile that could impact drug utilization and survival in non-small cell lung cancer (NSCLC) patients. The aim of the study was to describe first-line pharmacotherapy and overall survival in non-resectable (nr)NSCLC patients by gender. About 4400 incident cases of nrNSCLC were included. We reported a different use of target therapies on the basis of the known biomolecular profile between the two sexes. The survival improved in the last decade, and women and men also showed different survival if diagnosed with a squamous or non-squamous nrNSCLC.(1) Purpose: To describe first-line pharmacotherapy and overall survival in non-resectable non-small cell lung cancer (nrNSCLC) patients by gender. (2) Methods: Incident cases of nrNSCLC recorded between 2009 and 2019 (cohort entry) in the pathology registry of the regional administrative healthcare database of Tuscany were identified. Records of antineoplastic therapies delivered up to 4 months following cohort entry were classified as chemotherapy, target therapies, immunotherapies, and undefined monoclonal antibodies. First-line treatment and survival of patients receiving drug treatment was described. Analyses were stratified according to histology, gender, and cohort entry year. (3) Results: 4393 incident cases of nrNSCLC were included. Women with non-squamous-NSCLC received target-therapy more frequently than men (14.9% vs. 6.5%). Immunotherapy incidence of use varied between 3.8% (2017) and 9.1% (2019). The 2-year survival rate increased over time: for non-squamous-NSCLC, it was 22.3% (2009–2011) and 30.6% (2018–2019), while for squamous-NSCLC, it was 13.5% and 22.5%, respectively. After multivariate analysis, a low reduction in mortality risk in 2018–2019 vs. 2009–2011 was found (non-squamous: HR: 0.95 CI95%: 0.92–0.98; squamous: HR: 0.94 CI95%: 0.90–0.98). Among non-squamous NSCLC, median survival was longer in women than in men (389 vs. 276 days). (4) Conclusion: In light of sex-related biomolecular differences, among non-squamous NSCLC, women received target-therapy more frequently than men. Survival seemed to slightly improve over the study period for both histologies, despite a poor reduction in mortality risk was still observed.

19P Therapeutic targets in non-small cell lung cancer: Preclinical and human studies of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression and its associated molecular landscape

19P Therapeutic targets in non-small cell lung cancer: Preclinical and human studies of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression and its associated molecular landscape

Plasma Endoglin is Associated with Favorable Outcome for Pemetrexed-Based Therapy in Advanced Non-Small Cell Lung Cancer.

PurposePemetrexed-based chemotherapy (Pem-C) is the first-line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). However, limited tumor-associated proteins in blood are available to predict pemetrexed response and/or survival.Patients and MethodsPlasma samples from three responders and three nonresponders with stage IIIB–IV NSCLC were collected prior to Pem-C and analyzed using Proteome ProfilerTM Human XL Oncology Array to detect 84 oncology-related proteins. The plasma concentrations of cathepsin S, endoglin (ENG), and matrix metalloproteinases 3 and 9 in 71 patients with advanced NSCLC treated with Pem-C were further measured using enzyme-linked immunosorbent assay based on the remarkable differences in the four proteins between responders and nonresponders in the array results.ResultsPem-C responders had significantly higher ENG levels but not the other three markers than nonresponders (mean ENG level: 27.1 ± 7.4 vs 22.3 ± 6.9, p < 0.01). High ENG concentration was correlated with improved progression-free survival (hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.31–0.86, p < 0.01) and overall survival (HR: 0.55, 95% CI: 0.32–0.94, p < 0.05) in patients treated with Pem-C, and the ENG level was an independent factor in our cohort (HR: 0.54, 95% CI: 0.33–0.89, p < 0.05). ENG concentration in Pem-C responders also significantly increased at the time of best response (p < 0.05).ConclusionCumulatively, this study reveals that ENG is correlated with Pem-C responsiveness in patients, which indicates the potential use of plasma ENG levels as a non-invasive biomarker for pemetrexed-based treatment in patients with non-squamous NSCLC.

62P PD-1 inhibitor plus chemotherapy versus bevacizumab plus chemotherapy in patients with advanced non-squamous non-small cell lung cancer: A pooled analysis of three randomized trials

To date, none of randomized trials aim to compare the efficacy of programmed death 1 (PD-1) inhibitor plus chemotherapy and bevacizumab plus chemotherapy as first-line treatment for non-squamous non-small cell lung cancer (NSCLC). This analysis pooled prospective data to compare the survival benefits of the two regimens for advanced NSCLC without targetable genetic mutations.

Abstract P06-02: Discovery of TAS0953/HM06, a novel next generation RET-specific inhibitor capable of inhibiting RET solvent front mutations

Abstract RET gene fusions are oncogenic drivers in multiple tumor types and are estimated to be present in 1% to 2% of non-squamous non-small cell lung cancers (NSCLCs). Although the first-generation selective RET inhibitors selpercatinib and pralsetinib show clinical antitumor activity in NSCLCs, acquired resistances driven by RET solvent front mutation (G810R/S/C) have emerged. In such cases, no other treatment options are currently available for these patients after relapse with selpercatinib or pralsetinib. TAS0953/HM06, a novel adenosine triphosphate-competitive and highly selective RET inhibitor, is a next-generation RET inhibitor that may overcome solvent front mutant resistance. We performed a panel test of 254 kinases and found that 23-nM TAS0953/HM06 displayed only RET inhibition as plotted over 50% inhibited kinases. TAS0953/HM06 potently inhibits recombinant wild-type (WT) RET at sub-nanomolar concentrations that are similar to the IC50 values of selpercatinib and pralsetinib in WT RET. We investigated the cellular potencies against RET WT fusions and RET mutations, including the gatekeeper mutations V804L/M and selpercatinib- or pralsetinib-resistant mutations G810R/S, in engineered BA/F3 cells. TAS0953/HM06 inhibited the growth of the RET fusion overexpressed in Ba/F3 cells, including both the V804M/L and G810R/S RET mutations and WT RET. In addition, we examined the crystal structure of the RET kinase domain complexed with an analogue of TAS0953/HM06. X-ray crystal structures of the complex revealed that the analogue has unique binding mode to RET respect to selpercatinib and pralsetinib: it does not fill the space in the direction of the side chain of G810, suggesting that TAS0953/HM06 effectively circumvents steric hindrance from solvent front substitutions. This feature likely contributes to the ability of TAS0953/HM06 to maintain its biological potency in G810 mutations. Finally, we evaluated the antitumor activity of various doses of TAS0953/HM06 in xenograft tumor model derived from Ba/F3 cells from mice expressing WT or G810R KIF5B-RET (these mice show resistance to selpercatinib and pralsetinib). A Doses as low as of 10 mg/kg twice a day, TAS0953/HM06 were able to significantly inhibit tumor growth and phospho-RET. Taken together, the results show that, in addition to its selective high potency against WT RET, TAS0953/HM06 shows significant potency against G810R solvent front mutation which is highly resistant to selpercatinib and pralsetinib, in vitro and in vivo. Therefore, TAS0953/HM06 might represent a new therapeutic option for patients with RET mutations, including those resistant to 1st generation selective RET inhibitors. The safety and efficacy of TAS0953/HM06 are currently being investigated in a phase 1/2 clinical trials (NCT04683250). Citation Format: Isao Miyazaki, Keiji Ishida, Masanori Kato, Tatsuya Suzuki, Hidenori Fujita, Shuichi Ohkubo, Yoshikazu Iwasawa. Discovery of TAS0953/HM06, a novel next generation RET-specific inhibitor capable of inhibiting RET solvent front mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P06-02.

168TiP KEYNOTE-A86: Phase III, randomized, open-label study of first-line subcutaneous (SC) vs intravenous (IV) pembrolizumab with platinum doublet chemotherapy in metastatic squamous or nonsquamous non-small cell lung cancer (NSCLC)

IV pembrolizumab is approved for several tumor types, including squamous and nonsquamous NSCLC. Because most patients prefer SC vs IV dosing, a SC formulation of pembrolizumab was developed, and was found to have similar pharmacokinetics (PK) to the IV formulation in the phase 1 KEYNOTE-555 study. The phase 3, randomized, multicenter, open-label KEYNOTE-A86 study (NCT04956692) evaluates the PK, safety, and efficacy of first-line SC vs IV pembrolizumab plus chemotherapy in metastatic squamous or nonsquamous NSCLC.

Using a convolutional neural network for classification of squamous and non-squamous non-small cell lung cancer based on diagnostic histopathology HES images

Histological stratification in metastatic non-small cell lung cancer (NSCLC) is essential to properly guide therapy. Morphological evaluation remains the basis for subtyping and is completed by additional immunohistochemistry labelling to confirm the diagnosis, which delays molecular analysis and utilises precious sample. Therefore, we tested the capacity of convolutional neural networks (CNNs) to classify NSCLC based on pathologic HES diagnostic biopsies. The model was estimated with a learning cohort of 132 NSCLC patients and validated on an external validation cohort of 65 NSCLC patients. Based on image patches, a CNN using InceptionV3 architecture was trained and optimized to classify NSCLC between squamous and non-squamous subtypes. Accuracies of 0.99, 0.87, 0.85, 0.85 was reached in the training, validation and test sets and in the external validation cohort. At the patient level, the CNN model showed a capacity to predict the tumour histology with accuracy of 0.73 and 0.78 in the learning and external validation cohorts respectively. Selecting tumour area using virtual tissue micro-array improved prediction, with accuracy of 0.82 in the external validation cohort. This study underlines the capacity of CNN to predict NSCLC subtype with good accuracy and to be applied to small pathologic samples without annotation.

105P US real-world treatment patterns and outcomes of metastatic nonsquamous non-small cell lung cancer (mNSQ NSCLC) patients (pts) after progression on standard of care (SOC)

The SOC for mNSQ NSCLC pts with no targetable genetic alterations is immunotherapy (IO) or platinum-based chemotherapy (CT) alone in 1L followed by the other in 2L or platinum-based CT and IO in 1L. SOC for pts with targetable genetic alterations (EGFR, ALK, ROS1) is one or more lines of tyrosine kinase inhibitors (TKIs). Data on optimal subsequent treatment after progression(s) on SOC are scarce.

4O Nivolumab (NIVO) + ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced NSCLC (aNSCLC) in CheckMate 227 part 1: Efficacy by KRAS, STK11, and KEAP1 mutation status

4O Nivolumab (NIVO) + ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced NSCLC (aNSCLC) in CheckMate 227 part 1: Efficacy by KRAS, STK11, and KEAP1 mutation status