non-Sq Non-small Cell Lung Cancer Research Articles

EGFR mutation testing trends for patients with metastatic, non-squamous non-small cell lung cancer (non-SQ NSCLC) in Queensland, Australia from 2014-2021.

e13505 Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Epidermal growth factor receptor (EGFR) is the most common actionable mutation in non-small cell lung cancer (NSCLC) with routine testing recommended globally. In late 2013, screening for EGFR mutations was publicly funded in Australia for metastatic non-SQ-NSCLC. However, timely EGFR results are not universally available, often limited by tissue quantity/quality or prolonged turnaround times. This in turn affects access to treatment and thus survival. Methods: We aimed to examine the rates of EGFR testing over time and explore factors impacting results. Cases were identified from the Queensland Oncology Repository, a clinical database consolidating diagnostic, treatment and outcome data for all Queenslanders with cancer through the Queensland Cancer Registry. Cases were included if they had metastatic non-SQ-NSCLC, EGFR testing available via Pathology Queensland, and no other metastatic solid organ cancer within 1 year. Primary outcomes were EGFR mutation testing rates and time from first biopsy to EGFR mutation result, stratified by year of diagnosis and rurality. Results: A total of 3369 cases were included, of which 2871 had EGFR testing. The EGFR mutant (mt) rate was 12.6%, while 16.1% of cases had no EGFR results. Of cases without a conclusive EGFR result, reasons included: 179 transitioned to best supportive care before testing, 208 with insufficient tissue for a conclusive result, and 155 without testing for unclear reasons. The average time from biopsy to EGFR result improved from 29.9 days in 2014 to 21.5 days in 2021, with no significant difference in time to result between major cities, regional or remote areas. Cases with no EGFR results were more prevalent in rural areas. The proportion of patients living in outer regional/remote areas with no EGFR result was 21.1% compared to 15.5% in those living in major cities/inner regional sites. This was a relative increase of 36.2% (95% CI: 10.1% - 68.6%), a significant result (χ2 = 7.7483, p=0.005). Cases with no EGFR results in outer regional and remote sites declined from 30.1% in 2014-2015 to 15.3% in 2020-2021. Conclusions: EGFR mutation testing and result time has improved since 2014. Though time to result was not affected by rurality, significantly more rural patients lacked conclusive EGFR data, highlighting a gap in access to care. The cumulative EGFR no result rate of 16% and result time of 24 days indicates health systems need to more rapidly adapt to new treatment paradigms, particularly in the era of targeted therapies. [Table: see text]

KN046, a bispecific antibody against PD-L1 and CTLA-4, plus chemotherapy as first-line treatment for metastatic NSCLC: A multicenter phase 2 trial

KN046, a bispecific antibody targeting PD-L1 and CTLA-4, presents a promising therapeutic option for metastatic non-small cell lung cancer (NSCLC). In this multicenter phase 2 trial, patients with nonsquamous (non-sq) NSCLC receive pemetrexed, whereas those with sq-NSCLC receive paclitaxel, plus KN046 and carboplatin. Following four cycles, maintenance therapy includes KN046 with pemetrexed for non-sq-NSCLC and KN046 for sq-NSCLC. The objective response rate is 46.0%, and the median duration of response is 8.1months. The median progression-free and overall survival are 5.8 and 26.6months, respectively. The common adverse events include anemia (87.4%), loss of appetite (72.4%), and neutropenia (70.1%). The most prevalent immune-related adverse event is pruritus (28.7%). These findings indicate that first-line treatment with KN046 and chemotherapy is effective and tolerable in metastatic NSCLC patients, warranting further investigation in a larger phase 3 trial. The trial is registered at ClinicalTrials.gov (NCT04054531).

ECOG-ACRIN LUNG-MAP S1900E substudy: A phase II study of sotorasib in participants (Pts) with previously treated stage IV or recurrent KRAS G12C mutant non-squamous (Non-sq) non-small cell lung cancer (NSCLC).

TPS9143 Background: KRAS mutant NSCLC is further defined molecularly by specific mutation subtypes and co-mutations in tumor suppressor genes. Two targeted therapeutics, sotorasib and adagrasib, are currently approved for the treatment of previously treated advanced KRAS G12C mutant NSCLC. Sotorasib has also demonstrated superiority to docetaxel in the randomized phase III CodeBreaK 200 study ( de Langen et al Lancet. 2023 Feb 7 Epub). The impact of co-mutations in tumor suppressors, including TP53 and STK11, on the efficacy of first generation KRAS G12C inhibitors has been inconclusive. The S1900E substudy aims to prospectively understand, using rigorous biomarker testing/definitions, the impact of co-mutations on the clinical activity of sotorasib in pts with KRAS G12C mutant NSCLC. Methods: S1900E is a phase 2 open-label study of sotorasib in biomarker-defined cohorts for pts who have KRAS G12C stage IV/recurrent non-sq NSCLC, received at least one line of systemic treatment, and are naïve to KRAS G12C inhibitors. Pts are assigned to S1900E under the Lung-MAP screening protocol (NCT03851445) using FoundationOne F1CDx next generation sequencing assay on tissue (Foundation Medicine, Cambridge, MA). S1900E cohorts include: #1) Presence of TP53 co-mutation AND Wild Type STK11, KEAP1, NFE2L2, CUL3; #2) Presence of STK11 co-mutation AND Wild Type TP53, KEAP1, NFE2L2, CUL3; 3) All pts not eligible for Cohorts 1 and 2 (e.g. dual co-mutations in STK11 and TP53; co-mutations in KEAP1, NFE2L2, CUL3, or others; or lack of any co-mutations). Pts with treated, clinically controlled, and asymptomatic brain metastases are eligible and with amendment 3 (Mar 20 2022), eligibility expanded to pts with asymptomatic untreated brain metastases. Sotorasib is dosed 960 mg oral daily. The primary objective is to evaluate the RECIST 1.1 response rate (ORR) per cohort. For cohorts 1 and 3, the target sample size is 40 eligible pts based on a design with 92% exact power to rule out a 14% ORR at the 1-sided 5% level, if the true ORR were 34%; ≥10 responses would rule out a 14% ORR. Cohort 2 has a target sample size of 25 eligible pts with 93% exact power to rule out a 14% ORR at the 1-sided 5% level, if the true ORR were 40%; ≥7 responses would rule out a 14% ORR. Secondary endpoints include PFS, OS, duration of response, and toxicity. Circulating tumor DNA is being collected at day 1 of cycle 1, 2, and 3 and at progression. Enrollment started April 2 2021 with conservative accrual targets met, currently with 72% enrolled (84/116) as of Feb 14 2023, including 37, 16, and 31 pts, in cohorts 1, 2, and 3, respectively. Clinical trial information: NCT04625647 .

Abstract CT553: Tislelizumab (TIS) versus docetaxel (D) in patients with previously treated advanced non-squamous (non-sq) non-small-cell lung cancer (NSCLC): Subanalysis from the RATIONALE-303 phase 3 randomized clinical study

Abstract Background: At a predefined interim analysis (IA), RATIONALE-303 (NCT03358875) demonstrated improved overall survival (OS) for TIS vs D in the intent-to-treat (ITT), with a manageable safety profile. Disease characteristics, standard of care and treatment/prognosis differ between histologic types of NSCLC. Here, we report on the non-sq population. Methods: 805 patients with histologically confirmed, advanced NSCLC with progressive disease during or after ≥ 1 platinum (Pt)-containing chemotherapy regimen were randomized (2:1) to TIS 200 mg or D 75 mg/m2 every 3 weeks until disease progression, intolerable toxicity, or withdrawal. Histology (sq vs non-sq) was a randomization stratification factor. Dual primary endpoints were OS in the ITT and PD-L1 ≥ 25% populations. A prespecified IA was conducted after ~426 deaths (76% of planned events). Efficacy and safety were assessed in 435 randomized patients with non-sq histology. Results: Baseline characteristics of non-sq patients were balanced between treatment arms and similar to the ITT population. As of August 10, 2020, at median follow-up of 20 and 17 months (mo), respectively, median (95% CI) OS was longer with TIS (18.6 mo [15.41, 23.16]) vs D (13.8 mo [9.43, 17.94]) in the non-sq ITT population, and objective response rate (ORR) and duration of response (DoR) were also improved for TIS vs D (Table). 95.5% (TIS) and 97.9% (D) of patients had ≥ 1 treatment-emergent adverse event (TEAE) and 39.0% (TIS) and 70.9% (D) of patients had ≥ Grade 3 TEAEs. The most common TEAEs were anemia, aspartate aminotransferase increased and alanine aminotransferase increased (TIS arm), and alopecia, anemia and neutrophil count decreased (D arm). Conclusions: TIS prolonged OS, consistent with the overall ITT population, with a favorable safety profile in patients with advanced non-sq NSCLC who progressed after a Pt-containing regimen. Table Efficacy* TIS (n=287) D (n=148) Median OS, mo (95% CI) 18.6 (15.41, 23.16) 13.8 (9.43, 17.94) OS HR (95% CI)† 0.71 (0.538, 0.929) P=0.0064‡,§ Median PFS, mo (95% CI) 2.5 (2.14, 4.01) 3.6 (2.17, 4.14) PFS HR (95% CI)† 0.84 (0.660, 1.062) P=0.0686‡,§ ORR, n (%) 60 (20.9) 14 (9.5) Median DoR, mo (95% CI) 11.7 (6.80, 14.65) 6.2 (2.10, 7.16) Safety** TIS (n=287) D (n=141) TEAEs ≥ 15% of patients in either arm, n (%) All grades ≥ Grade 3 All grades ≥ Grade 3 Anemia 76 (26.5) 11 (3.8) 56 (39.7) 6 (4.3) AST increased 64 (22.3) 5 (1.7) 18 (12.8) 0 (0.0) ALT increased 63 (22.0) 4 (1.4) 24 (17.0) 0 (0.0) Cough 59 (20.6) 4 (1.4) 25 (17.7) 0 (0.0) Weight decreased 44 (15.3) 2 (0.7) 13 (9.2) 0 (0.0) Decreased appetite 41 (14.3) 3 (1.0) 26 (18.4) 0 (0.0) Hypoalbuminemia 37 (12.9) 0 (0.0) 23 (16.3) 0 (0.0) Nausea 37 (12.9) 0 (0.0) 22 (15.6) 0 (0.0) Constipation 31 (10.8) 0 (0.0) 22 (15.6) 0 (0.0) Asthenia 29 (10.1) 1 (0.3) 29 (20.6) 8 (5.7) Neutrophil count decreased 8 (2.8) 1 (0.3) 53 (37.6) 36 (25.5) White blood cell count decreased 8 (2.8) 0 (0.0) 42 (29.8) 26 (18.4) Neutropenia 7 (2.4) 3 (1.0) 44 (31.2) 38 (27.0) Leukopenia 6 (2.1) 0 (0.0) 38 (27.0) 22 (15.6) Alopecia 0 (0.0) 0 (0.0) 70 (49.6) 2 (1.4) *Efficacy analysis set - non-sq patients; †Stratified; ‡One-sided stratified log-rank test; §Descriptive P-value; **Safety analysis set - non-squamous patients ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI; confidence interval; DoR, duration of response; HR, hazard ratio; mo, months; NE, not evaluable; ORR, objective response rate; PFS, progression-free survival; TEAE, treatment-emergent adverse event Data cut-off: August 10, 2020 Citation Format: Ying Cheng, Dingzhi Huang, Zhiyong Ma, Yun Fan, Jie Wang, Xinmin Yu, Mikhail Dvorkin, Gareth Rivalland, Yiyuan Ma, Yan Wang, Yan Ma, Caicun Zhou. Tislelizumab (TIS) versus docetaxel (D) in patients with previously treated advanced non-squamous (non-sq) non-small-cell lung cancer (NSCLC): Subanalysis from the RATIONALE-303 phase 3 randomized clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT553.

1290P RATIONALE 304: Tislelizumab (TIS) plus chemotherapy (chemo) vs chemo alone as first-line (1L) treatment for non-squamous (non-sq) non-small cell lung cancer (NSCLC) in patients (pts) who are smokers vs non-smokers

Primary results from the phase III RATIONALE-304 study (NCT03663205) showed efficacy and a manageable safety/tolerability profile for TIS, an anti-programmed cell death protein 1 monoclonal antibody, plus chemo, as 1L treatment for advanced or metastatic non-sq NSCLC. Here, we report results based on smoking status.

Efficacy of S-1 after pemetrexed in patients with non-small cell lung cancer: A retrospective multi-institutional analysis.

BackgroundS‐1 and pemetrexed (PEM) are key treatments for non‐small cell lung cancer (NSCLC). However, the mechanism of anticancer activity of S‐1 and PEM is similar. Cross‐resistance between S‐1 and PEM is of concern. This exploratory study was designed to evaluate the treatment effect of S‐1 following PEM‐containing treatment.MethodsThis retrospective study included patients with advanced (c‐stage III or IV, UICC seventh edition) or recurrent NSCLC who received S‐1 monotherapy following the failure of previous PEM‐containing chemotherapy at six hospitals in Japan. The primary endpoint of the study was the overall response rate (ORR). The secondary endpoint was the disease control rate (DCR), time to treatment failure (TTF), progression‐free survival (PFS), and overall survival (OS).ResultsA total of 53 NSCLC patients met the criteria for inclusion in the study. Forty‐six patients had adenocarcinoma (88.7%) and no patients had squamous cell carcinoma. Thirty‐one patients (58.5%) received the standard S‐1 regimen and 18 patients (34.0%) received the modified S‐1 regimen. ORR was 1.9% (95% confidence interval [CI]: 0.00%–10.1%). Median TTF, PFS, and OS were 65, 84, and 385 days, respectively.ConclusionsAlthough there were several limitations in this study, the ORR of S‐1 after PEM in patients with nonsquamous (non‐SQ) NSCLC was low compared to the historical control. One of the options in the future might be to avoid S‐1 treatment in PEM‐treated patients who need tumor shrinkage.

177P Efficacy of S-1 after pemetrexed in patients with non-small cell lung cancer: A retrospective multi-institutional analysis

Background: S-1 and pemetrexed (PEM) are key treatments for non-small cell lung cancer (NSCLC). PEM and cisplatin (CDDP), showed superior overall survival (OS) compared with gemcitabine and CDDP in treating non-squamous (non-Sq) NSCLC patients, and PEM and platinum treatment is usually used for this population (1). S-1 monotherapy showed non-inferior OS compared with docetaxel in treated NSCLC patients, and is also used for NSCLC as a standard therapy after first line treatment (2). However, the mechanism of anticancer activity of S-1 and PEM is similar.

The utility of transbronchial rebiopsy for peripheral pulmonary lesions in patients with advanced non-squamous non-small cell lung cancer

BackgroundPatients treated for non-squamous (non-Sq) non-small cell lung cancer (NSCLC) often require repeat biopsies to determine the optimal subsequent treatment. However, the differences between rebiopsy and initial biopsy in terms of their diagnostic yields and their ability to test the molecular profiles using bronchoscopy with radial endobronchial ultrasound guidance in patients with advanced NSCLC remain unclear. Hence, we aimed to compare the diagnostic yields and ability for molecular analyses of rebiopsies with those of initial biopsies.MethodsWe investigated 301 patients with advanced non-Sq NSCLC who underwent radial endobronchial ultrasound-guided transbronchial biopsy (TBB) for peripheral pulmonary lesions (PPLs) between August 2014 and July 2017. Patients were divided into the rebiopsy and initial biopsy groups: the latter referred to the biopsy that determined the definitive diagnosis. The diagnostic yields and ability for molecular analyses were compared between the two groups, and the factors affecting the TBB diagnostic yield were identified using univariate and multivariate analyses.ResultsThe diagnostic yields of the rebiopsy and initial biopsy groups were comparable (86.8 and 90.8%, respectively; p = 0.287). Furthermore, 93.0 and 94.0% of the patients in the rebiopsy and initial biopsy groups, respectively, had adequate specimens for gene profiling and mutational analysis (p = 0.765). The factors that increased the diagnostic yield were a positive bronchus sign (p < 0.001) and tumour location within the internal two-thirds of the lungs (p = 0.026).ConclusionsThe PPL diagnostic yield of the rebiopsy group was as high as that of the initial biopsy group. Hence, TBB for PPLs is feasible for patients requiring rebiopsy as well as for those with initial diagnoses. Adequate, high-quality biopsy specimens can be obtained by transbronchial rebiopsy for molecular testing.

Therapeutic impact of mutation subtypes and concomitant STK11 mutations in KRAS–mutated non-small cell lung cancer (NSCLC): A result of nationwide genomic screening project (LC-SCRUM-Japan).

9589 Background: KRAS mutations are one of the common oncogene drivers in non-small cell lung cancer (NSCLC), and the development of several targeted drugs for KRAS-mutated NSCLC is now ongoing. However, the clinical impact of KRAS mutation subtypes or concomitant other gene mutations in NSCLC patients (pts) remains unclear. Methods: In a nationwide genomic screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer pts for genetic alterations and tumor mutation burden (TMB) by next-generation sequencing system, and for PD-L1 expression by immunohistochemistry (22C3 antibody). The therapeutic efficacy and survival of KRAS-mutated non-squamous (non-sq) NSCLC pts were evaluated using a clinico-genomic database of the LC-SCRUM-Japan. Results: A total of 5166 non-sq NSCLC pts enrolled from 2015 to 2019. KRAS mutations were detected in 794 pts (15%; G12C/G12D/G12V/G12A/G13X/others = 232/186/165/66/61/84). Among the 794 pts, TMB and PD-L1 expression were analyzed in 128 and 79, respectively, and 218 received PD-1/PD-L1 inhibitors (IO) after 1st-line chemotherapy. The median age was 66 years (range, 29-89). 142 pts (65%) were male and 172 (78%) were smokers. Concomitant STK11 mutations were detected in 33 pts (15%) with no difference in the mutation frequency among KRAS mutation subtypes. KRAS G12C was significantly associated with high TMB (≥ 10 mut/Mb) (p = 0.03), and KRAS G12C or G12V with high PD-L1 expression (≥ 50%) (p = 0.02). In pts who received IO, median progression-free survival (mPFS) was significantly longer in pts with KRAS G12C or G12V than in those with other KRAS mutations (4.7 vs 2.0 months, hazard ratio (HR) 0.58 [95%CI 0.43-0.78], p &lt; 0.01). Among pts with KRAS G12C or G12V, mPFS of IO was significantly shorter in pts with concomitant STK11 mutations than in those without (1.8 vs. 5.7 months, HR 1.97 [95%CI 1.06-3.41], p = 0.02). These correlations were not observed in platinum-containing chemotherapy (Plt-CTx). There were also no significant differences in IO and Plt-CTx efficacies between with and without other concomitant mutations, such as TP53, RB1, CDKN2A and PTEN mutations. Conclusions: Non-sq NSCLC pts with KRAS G12C/V were more sensitive to IO therapies than those with other KRAS mutations, but KRAS G12C/V-positive pts with concomitant STK11 mutations were less sensitive than those without. These results could be highly informative in the development of novel targeted therapies for KRAS-mutated NSCLC.

1498P - Real-world effectiveness of nivolumab monotherapy after prior systemic therapy in advanced non-small cell lung cancer (NSCLC) in the United States

BackgroundNivolumab demonstrated overall survival (OS) benefit over docetaxel in patients (pts) with pre-treated squamous (SQ) and non-SQ (NSQ) NSCLC in 3 phase III clinical trials. We investigated US real-world outcomes of pts treated with nivolumab after ≥1 prior systemic therapy in predominantly community-based clinical practice. MethodsThis retrospective analysis of clinical electronic health record data in the Flatiron Health database included adult pts with advanced NSCLC receiving nivolumab monotherapy in second or later line (2L+) treatment between Mar 1, 2015 and Dec 31, 2018 (SQ) or Oct 1, 2015 and Dec 31, 2018 (NSQ). The index date was the start date of nivolumab. Prior treatment with ≥1 platinum-based and, if indicated, targeted therapy was required for inclusion. Pts with primary cancers other than NSCLC or who had received prior immunotherapy were excluded. Median (95% confidence interval [CI]) OS and progression-free survival (PFS) from index were estimated using Kaplan–Meier methodology in pt subgroups by histology. ResultsOf 3023 pts included in the analysis, 65.2% and 34.8% had NSQ and SQ histology, respectively. In the 2 groups at index, median age (range) was 68 (21–84) yrs and 70 (36–84) yrs, 51% and 63% were male, 11.3% and 5.9% had brain metastasis, 19.7% and 22.1% had ECOG PS≥2 (∼26% had missing PS data in both groups). Most pts received nivolumab as 2L (NSQ 83.4% and SQ 85.3%); pts receiving nivolumab as 3L and 4L were included. Survival outcomes are reported in the Table. ConclusionsPts receiving 2L+ nivolumab monotherapy for advanced NSQ and SQ NSCLC in US real-world clinical practice had numerically lower OS than pts in registrational trials, likely due to inclusion of pts with more impaired function. PFS was similar to that in registrational trials, but may be measured differently in routine clinical practice. Analyses with additional follow-up are planned to confirm long-term benefit of nivolumab in 2L+ NSCLC.Table1498PTableSurvival outcomes of pts receiving 2L+ nivolumab monotherapyOSPFSnMedian (95% CI), months12-month rate, %18-month rate, %Median (95% CI), months12-month rate, %18-month rate, %NSQ19728.5 (7.9–9.3)40313.2 (3.0–3.5)1712SQ10517.4 (6.8–8.5)36243.0 (2.8–3.3)1510 Editorial acknowledgementLeah Bernstein of Evidence Scientific Solutions Inc, funded by Bristol-Myers Squibb. Legal entity responsible for the studyBristol-Myers Squibb. FundingBristol-Myers Squibb. DisclosureD.D. Stenehjem: Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bioverativ; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Salarius Pharmaceuticals; Advisory / Consultancy: Iterion Therapeutics; Advisory / Consultancy: GlycosBio. S.J. Lubinga: Full / Part-time employment: BMS. K. Gupte-Singh: Full / Part-time employment: BMS. Y. Zhang: Full / Part-time employment: BMS. K. Le Trong: Full / Part-time employment: BMS. J.R. Penrod: Full / Part-time employment: BMS.

Early clinical experience with the pan-FGFR inhibitor rogaratinib in patients with non-small cell lung cancer selected based on FGFR mRNA expression levels.

e20661 Background: FGFR1 gene amplifications are observed in squamous (sq) non-small cell lung cancer (NSCLC) and may suggest tractable oncogenic dependency. However, their value in predicting clinical activity of FGFR inhibitors is unclear. We explored tumor FGFR1-3 mRNA expression levels to select patients (pts) for treatment with rogaratinib, an oral, potent, small-molecule inhibitor of FGFR1-4. The first-in-human study of rogaratinib included pts with all NSCLC histologies. Methods: Pts with refractory advanced NSCLC were screened for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples, and FGFR1-3 overexpression was defined by pre-specified cut-offs. Pts received rogaratinib 800 mg BID on a continuous 21-day cycle. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1 after cycles 2, 5, and 8. Results: 260 NSCLC biopsies were screened for FGFR1-3 tumor mRNA expression; 244 (93.8%) were evaluable. FGFR1-3 mRNA overexpression was found in 47% of sq NSCLC, and only 14% of non-sq NSCLC, with FGFR3 being the most commonly overexpressed subtype. 40 FGFR mRNA-positive pts were enrolled and treated. Rogaratinib was well tolerated; hyperphosphatemia (75%), diarrhea (53%), and decreased appetite (35%) were the most frequent treatment-emergent adverse events. Events were mostly mild or moderate. 36 treated pts were evaluable for response. The overall response rate was 5.6% (2 partial responses, 1 lasting for &gt; 16 months). Disease control rate was 64%. Disease stabilization was seen in pts with mRNA overexpression across all FGFR subtypes and also in pts who failed prior lines of therapy, including anti-PD-L1. Molecular studies are ongoing to identify additional predictors of response to improve pt selection. Conclusions: Rogaratinib has a favorable safety and tolerability profile and clinical activity in pts with refractory FGFR1-3 tumor mRNA-positive NSCLC. It has potential for further exploration in combination with other agents. A clinical trial is currently enrolling FGFR mRNA-overexpressing pts with advanced and pre-treated sq NSCLC. Clinical trial information: NCT03762122.

Immune Microenvironment Differences Between Squamous and Non-squamous Non–small-cell Lung Cancer and Their Influence on the Prognosis

IntroductionCheckpoint blockades have entered routine clinical use for non–small-cell lung cancer (NSCLC). However, there were some differences in efficacy and response predictors for anti-programmed cell death protein 1 (PD-1) antibodies between squamous (SQ) and nonsquamous (non-SQ) NSCLC. The study aims to elucidate the possible difference in immune microenvironment between SQ-NSCLC and non-SQ-NSCLC and their influence on the prognosis. Patients and MethodsA total of 197 patients with stages I to III NSCLC were included. cluster of differentiation 8 (CD8), cluster of differentiation 4 (CD4), transcription factor forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1) expression were examined in cancer nest and stroma on 85 SQ-NSCLC and 112 non-SQ-NSCLC samples using immunohistochemistry. ResultsMore CD8+ tumor infiltrating lymphocytes (TILs) were detected in the cancer nests (cCD8) from patients with SQ-NSCLC than those with non-SQ-NSCLC (56% vs. 34%; P = .002). There were no significant differences between the SQ and non-SQ groups in terms of other TIL markers or PD-L1 expression. Multivariate analysis showed that the degree of cCD8+ TIL infiltration was an independent positive predictor for overall survival (OS) in the SQ-NSCLC group (P = .003) and in the non-SQ-NSCLC group (P = .024). In the univariate analysis, CD8+ TILs in the stroma, CD4+ TILs in the cancer nest and stroma, and FOXP3+ TILs in the cancer stroma associated with different prognoses for patients with either non-SQ-NSCLC or SQ-NSCLC. Using a 10% cutoff, PD-L1 expression was a poor prognostic factor in total NSCLC (P = .011), stage I (P = .037), SQ-NSCLC (P = .097), and non-SQ-NSCLC (P = .051). ConclusionThe different cCD8+ TIL profile and different prognostic value with certain TILs indicates that SQ-NSCLC and non-SQ-NSCLC are likely different cancer types with respect to their immune microenvironments.

Somatic STK11/LKB1 mutations to confer resistance to immune checkpoint inhibitors as monotherapy or in combination in advanced NSCLC.

3028Background: Although PD-1/PD-L1 checkpoint blockade has become standard of care for non-small cell lung cancer (NSCLC), some treated patients (pts) do not respond. A deeper understanding of mechanisms of resistance to PD-(L)1 blockade is needed to improve therapeutic decisions. The aim of this study was to identify molecular alterations associated with innate resistance to durvalumab (D) and durvalumab + tremelimumab (D + T) combination therapy in advanced non-squamous (Non-SQ) NSCLC. Methods: CP1108/NCT01693562 and ATLANTIC/NCT02087423 were nonrandomized phase 1/2 and 2 trials of D (10 mg/kg, Q2W). D41906/NCT02000947 was a nonrandomized phase Ib trial of D + T (20 mg/kg + 1 mg/kg, Q4W). Circulating tumor DNA (ctDNA) analysis (Guardant360 70 gene cancer panel) was conducted in pre-treatment plasma samples for 119 and 63 Non-SQ NSCLC pts in CP1108 and ATLANTIC, respectively. Targeted sequencing of pre-treatment tumors (FoundationOne CDx™) was conducted in 120 Non-SQ NSCLC pts in D41906. Assoc...

Comparative effectiveness of carboplatin-pemetrexed (Carbo-Pem) with vs. without bevacizumab (Bev) in patients with advanced non-squamous (Sq) non-small cell lung cancer (NSCLC).

9073Background: The majority of patients with advanced non-sq NSCLC do not have high programmed death ligand 1 (PD-L1) expression or a targetable genetic alteration. Carbo-pem-bev is commonly used ...

Prognostic Impact of TTF-1 Expression in Non-Squamous Non-Small-Cell Lung Cancer: A Meta-Analysis.

Thyroid transcription factor-1 (TTF-1) is overexpressed in up to 95% of primary lung adenocarcinoma while negative for almost all squamous cell carcinomas. TTF-1 expression has been investigated as a prognostic factor in non-small-cell lung cancer (NSCLC) with conflicting results. We conducted this meta-analysis to gain a better insight into the prognostic role of TTF-1 in patients only with non-squamous (non-SQ) NSCLC. A systematic computerized search of the electronic databases including PubMed, PMC, EMBASE, Web of Science, and Cochrane Library was performed. From 21 studies, 6,451 patients were included in the combined analysis of hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival. Compared with patients with non-SQ NSCLC showing negative TTF-1 expression, those with tumors harboring TTF-1 overexpression had significantly better survival (HR = 0.49, 95% CI: 0.42-0.57, p < 0.00001). Subgroup analyses revealed that TTF-1 expression significantly correlated with a better prognosis in stage I (HR = 0.65, 95% CI: 0.50-0.84, p = 0.0008) as well as stage III-IV non-SQ NSCLC (HR = 0.38, 95% CI: 0.29-0.49, p < 0.00001). In conclusion, this meta-analysis demonstrates that TTF-1 overexpression is a favorable prognostic factor in patients with non-SQ NSCLC. The subgroup analyses indicate that TTF-1 is a good prognostic marker for survival not only in early-stage but also in advanced non-SQ NSCLC.

1333P - Detectability of RET fusions by amplicon-based next generation sequencing in nationwide lung cancer genomic screening project: LC-SCRUM-Japan

Background: RET fusions have been identified as a therapeutic target in non-small cell lung cancer (NSCLC). The establishment of molecular diagnostics for RET fusions is required for the development of molecular-targeted therapies for fusion-positive patients. We have operated molecular testing for various actionable gene alterations, including RET fusions, in our nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan). Methods: Since 2013, RET fusions were analyzed by multiplex RT-PCR, and fusion-positive samples were confirmed by break-apart FISH. Since 2015, an amplicon-based next generation sequencing (NGS) system, Oncomine™ Comprehensive Assay was also applied in our genomic screening. Results: As of February 2017, 244 institutions across Japan were participating, and a total of 4015 lung cancer patients including 3392 non-squamous (Non-Sq) NSCLCs were enrolled into the LC-SCRUM-Japan. Of the Non-Sq NSCLCs, available samples for multiplex RT-PCR and NGS were 94% (3186/3392) and 90% (1671/1852), respectively. RET fusions were detected in 89 samples (2.8%), including 54 detected by NGS. The types of variants found were KIF5B-RET (n = 50, 56%), CCDC6-RET (n = 20, 22%) and undetermined (n = 19, 21%). Of the 54 RET fusion-positive samples by NGS, the positivity was confirmed using break-apart FISH in 35 (92%) of 38 available samples. Among the 1335 samples available for both RT-PCR and NGS, the concordance rate between the two assays for the detection of RET fusions were 0.99. The detection sensitivity and specificity of the fusions in NGS assay were 0.98 and 0.99. Conclusions: Our nation-wide screening results revealed that this amplicon-based NGS assay showed high sensitivity and specificity for the detection of RET fusions and is clinically applicable for diagnosis of RET fusions in lung cancer. Legal entity responsible for the study: National Cancer Center Funding: Astra Zeneka, Eisai, Chugai Pharmaceutical, Pfizer, DAIICHI SANKYO, Astellas Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Kyowa Hakko Kirin, Eli Lilly Japan, Takeda Pharmaceutical, Novartis Pharma, Amgen Astellas BioPharma, MSD, Merck Serono. Disclosure: S. Matsumoto: Astra Zeneka, Eisai, Chugai Pharmaceutical, Pfizer, Daiichi Sankyo, Astellas Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Kyowa Hakko Kirin, Eli Lilly Japan, Takeda Pharmaceutical, Novartis Pharma, Amgen Astellas BioPharma, MSD, Merck Serono. Y. Ohe: Honorarium/Consultant/Expert Testimony/Research Funding (Institution); AstraZeneca, Chugai, Lilly, ONO, BMS, Daiichi-Sankyo, Nipponkayaku, Boehringer, Bayer, Pfizer, MSD, Taiho, Clovis, Sanofi, Novartis, Kyorin, Dainippon-Sumitomo, Merck. M. Nishio: Novartis, Ono Pharmaceutical, Bristol-Myers Squibb, TAIHO Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma, AstraZeneca and Honoraria, Pfizer, Bristol-Myers Squibb, Chugai Pharmaceutical, Taiho Pharmaceutical, AstraZeneca. T. Seto: AstraZeneca, Astellas Pharma, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Merck Serono, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, Bristol-Myers Squibb, Kissei, Kyowa Hakko Kirin, Nippon Kayaku, Ono, Roche Singapore Pte, Taiho, Yakult. K. Yoh: AstraZeneca, Chugai Pharma, Boehringer Ingelheim, Lilly Japan, Bristol-Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical, Pfizer. K. Goto: Astellas Pharma, Astra Zeneka, Amgen Astellas BioPharma, Eisai, Ono, Kyowa Hakko Kirin, Daiichi Sankyo, Taiho, Takeda, Chugai, Novartis, Pfizer, MSD, Eli Lilly, Merck Serono, Bristol-Myers Squibb, Life Technologies. All other authors have declared no conflicts of interest.

Abstract 2635: Baseline myeloid-derived suppressor cell and eosinophil cell counts predict clinical efficacy in patients with non-small cell lung cancer (NSCLC) treated with nivolumab in second line

Abstract The anti-PD-1 monoclonal antibody nivolumab is clinically active in a variety of tumor types including squamous (sq) and non-squamous (non-sq) NSCLC in second-line, where randomized phase III trials have shown a survival benefit. However, no predictive/prognostic or dynamic biomarkers have been found so far to correlate with clinical benefit in patients treated with anti-PD-1 antibodies. The aim of the present study is to investigate the potential role of baseline peripheral blood cell counts in relation to survival and response rate in NSCLC patients treated with nivolumab in a second-line setting. From July to May 2016 we evaluated 45 patients with Sq (n = 10) and non-Sq (n = 35) NSCLC, previously treated with first-line platinum-based chemotherapy, who received nivolumab 3 mg/kg IV on day 1 of each 2 week treatment cycle. Clinical characteristics (T-Stage, lymph nodes involvement, M-Stage) were assessed. Total numbers of white blood cells, myeloid-derived suppressor cells (MDSCs, including both monocytic [Mo-MDSC]) and polymorphonuclear [PMN-MDSC] types), regulatory T cells (T-regs), and serum lactate dehydrogenase (LDH) were assessed. Endpoints were correlations with objective response rate (RR), progression-free survival (PFS, categorized as ≤ 3 or &amp;gt; 3 months) and overall survival (OS). Tumor response was assessed using RECIST criteria, version 1.1, at week 9 and every 6 weeks thereafter until disease progression. Statistical investigations were based on univariate analyses by the Wilcoxon rank test. The median PFS of the overall study population was 3 months. Data about PMN-MDSCs (identified by flow cytometry as Lin-CD15+CD14-CD11b+HLA-DRlow/-), Mo-MDSCs (Lin-CD14-CD11b+HLA-DRlow/-) and absolute eosinophil count (AEC) were available in 37/45 patients (82% of treated patients). Baseline absolute numbers of PMN-MDSCs, Mo-MDSCs and AEC were greater in patients with a good prognosis (PFS &amp;gt; 3 months) and a better RR. In particular, among patients with shorter PFS and lower RR, the median numbers of PMN-MDSCs, Mo-MDSCs and AEC were significantly lower than those detected in patients with longer PFS (4 vs 13 cell/µl, p=0.01; 4 vs 21 cell/µl, p=0.06; 55 vs 155 cell/µl; p=0.02, respectively). Our data suggest that a baseline blood signature characterized by low levels of PMN-MDSCs, Mo-MDSCs and AEC is associated with a poor clinical outcome (median PFS ≤ of 3 months and low RR) in 67.6% of patients treated with nivolumab. In contrast, patients with high levels of these three biomarkers showed a median PFS significantly longer than 3 months and a higher RR. The OS analysis is ongoing, and further studies have been planned to understand whether this signature has a biomarker potential also in chemotherapy-naïve, first line NSCLC patients. Citation Format: Patrizia Mancuso, Antonio Passaro, Valentina Labanca, Sara Gandini, Gianluca Spitaleri, Elena Guerini, Massimo Barberis, Cristina Noberasco, Ester del Signore, Alessia Pochesci, Chiara Catania, Filippo De Marinis, Francesco Bertolini. Baseline myeloid-derived suppressor cell and eosinophil cell counts predict clinical efficacy in patients with non-small cell lung cancer (NSCLC) treated with nivolumab in second line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2635. doi:10.1158/1538-7445.AM2017-2635

Abstract CT077: Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors

Abstract Introduction: Prior to the introduction of immunotherapies, treatment options were limited for patients (pts) with NSCLC who progressed after first-line platinum doublet chemotherapy. The majority of pts with advanced disease died within 1 y of diagnosis, and 5-y survival for metastatic NSCLC was ~1%. Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, showed encouraging activity in pts with heavily pretreated advanced NSCLC in a phase 1 dose-escalation cohort expansion trial (CA209-003; NCT00730639). Based on improved overall survival (OS) versus docetaxel in 2 phase 3 studies in previously treated advanced NSCLC (CheckMate 017 and 057), nivolumab was approved in this population. Reports of long-term efficacy and safety with immune checkpoint inhibitors are limited. Here we report updated results from CA209-003 based on ~5 y of follow-up, representing the longest survival follow-up for an immune checkpoint inhibitor in advanced NSCLC to date. Methods: Pts with heavily pretreated (1-5 prior systemic regimens) advanced NSCLC received nivolumab (1, 3, or 10 mg/kg) every 2 wk in 8-wk cycles for up to 96 wk. The primary objective was safety and tolerability; secondary objectives included objective response rate and duration of response. OS from the time of first dose was an exploratory objective. The minimum follow-up for the current analysis was 58.25 mo. Results: At database lock, the Kaplan-Meier-estimated 5-y OS rate in all pts (N = 129) was 16% (95% confidence interval [CI]: 10, 23). OS rates at 5 y were similar in pts with squamous (SQ; n = 54; 16% [95% CI: 8, 28]) and non-SQ (n = 74; 15% [95% CI: 8, 25]) NSCLC (excludes 1 pt with unknown histology). Of the 16 pts who survived ≥5 y (median age: 61.5 y [range: 44, 80]), 9 pts were male and 12 were current smokers at baseline (2 former smokers; 2 unknown). In 10 evaluable pts, PD-1 ligand 1 (PD-L1) expression was ≥1% in 7 pts (≥50% in 5) and &amp;lt;1% in 3 pts. Nine of the 16 pts completed the maximum number of nivolumab cycles per protocol; the remainder discontinued due to adverse events (n = 4), disease progression (n = 2), and initiation of a new treatment regimen (n = 1). Twelve of the 16 pts achieved a partial response, and 2 pts each had stable disease (SD) and progressive disease (PD) as best overall response (BOR) to nivolumab. At 5 y, per investigator, 12 pts had received no further therapy after stopping nivolumab treatment and were without evidence of PD. Further details of the disease and treatment course in select pts will be presented. Conclusions: Nivolumab resulted in durable OS in a notable proportion of pts with pretreated advanced NSCLC, as demonstrated by a 5-y OS rate of 16%. Long-term survivors had diverse baseline and on-treatment characteristics including histology, PD-L1 expression level (including pts with &amp;lt;1% PD-L1), and BOR to nivolumab (including pts with SD/PD). Citation Format: Julie Brahmer, Leora Horn, David Jackman, David Spigel, Scott Antonia, Matthew Hellmann, John Powderly, Rebecca Heist, Lecia Sequist, David C. Smith, Philip Leming, William J. Geese, Dennis Yoon, Ang Li, Scott Gettinger. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT077. doi:10.1158/1538-7445.AM2017-CT077

Survival benefit of immune checkpoint inhibitors according to the histology in non-small-cell lung cancer: A meta-analysis and review.

Immune checkpoint inhibitors (ICIs) have been approved for patients with advanced non-small-cell lung cancer (NSCLC), regardless of histology. However, histologic subtypes of NSCLC may influence treatment outcomes of ICIs. We conducted this meta-analysis to investigate if there is difference in survival benefits of ICIs between squamous (SQ) and non-squamous (non-SQ) NSCLC. We searched PubMed, MEDLINE, EMBASE and ESMO databases. We included randomized controlled trials with the data of survival outcomes in advanced NSCLC patients treated with ICIs. From 7 eligible studies, 998 patients with SQ NSCLC and 2,769 with non-SQ NSCLC were included in the meta-analysis. ICIs improved progression-free survival (PFS) significantly in patients with SQ NSCLC (HR = 0.68 [95% confidence interval (CI), 0.51-0.91], P = 0.01), compared to chemotherapy. For patients with non-SQ NSCLC, however, ICIs were not associated with significant improvement of PFS (HR = 0.88 [95% CI, 0.67-1.16], P = 0.37). In terms of overall survival (OS), ICIs prolonged OS significantly in both SQ (HR = 0.71 [95% CI, 0.60-0.83], P < 0.0001) and non-SQ NSCLC (HR = 0.77 [95% CI, 0.63-0.94], P = 0.01). In conclusion, this meta-analysis indicates that ICIs significantly prolong OS in both SQ and non-SQ NSCLC.

MA15.09 Response to the Treatment Immediately before Nivolumab Monotherapy May Predict Clinical Response to Nivolumab

Nivolumab was approved in Japan on December 17, 2015 for previously treated non-small cell lung cancer (NSCLC). The expression of programmed death-ligand 1 (PD-L1) in tumor tissue is considered a predictive factor for clinical response to nivolumab. However, in Japan, there are no commercially available diagnostic kits for evaluating PD-L1 expression. In addition, little is known regarding other predictive factors of response to nivolumab monotherapy in patients with NSCLC. Therefore, we examined the relationships between the response to nivolumab monotherapy and clinical parameters in patients with NSCLC. Between December 2015 and April 2016, we performed a retrospective analysis of 50 patients with NSCLC treated with nivolumab monotherapy (3 mg/kg, every 2 weeks) at our Institution in the clinical setting. Baseline characteristics of patients who received nivolumab monotherapy were: median age, 65 years [range:39–76]; 60% male; 26% ECOG-PS 0, 64% ECOG-PS 1; 38% smoker; 58% stage IV disease, 22% postoperative recurrence; 80% non-squamous (SQ) NSCLC; 36% non-SQ NSCLC patients had active EGFR mutations; 20% second-line, 18% third-line. The objective response rate (ORR) for all patients treated with nivolumab monotherapy was 18% (95%CI 10–31). Univariate analysis revealed that predictive factors of response to nivolumab monotherapy were associated with “SQ”, “response to the treatment immediately before nivolumab monotherapy”, “therapeutic line of nivolumab (second-line and third-line treatment)” and “smoker” categories (Table 1). In the multivariate logistic regression analysis, the independent predictive factors were “SQ” (P = 0.0069) and “response to the treatment immediately before nivolumab monotherapy” (P < 0.0001) (Table 1). “Response to the treatment immediately before nivolumab monotherapy”, other than “SQ” histology may be predictors of clinical response to nivolumab in patients with NSCLC.