Non-sq NSCLC Research Articles

Ancestry-associated co-alteration landscape of KRAS and EGFR-altered non-squamous NSCLC

Racial/ethnic disparities mar NSCLC care and treatment outcomes. While socioeconomic factors and access to healthcare are important drivers of NSCLC disparities, a deeper understanding of genetic ancestry-associated genomic landscapes can better inform the biology and the treatment actionability for these tumors. We present a comprehensive ancestry-based prevalence and co-alteration landscape of genomic alterations and immunotherapy-associated biomarkers in patients with KRAS and EGFR-altered non-squamous (non-Sq) NSCLC. KRAS was the most frequently altered oncogene in European (EUR) and African (AFR), while EGFR alterations predominated in East Asian (EAS), South Asian (SAS), and Admixed American (AMR) groups, consistent with prior studies. As expected, STK11 and KEAP1 alterations co-occurred with KRAS alterations while showing mutual exclusivity with EGFR alterations. EAS and AMR KRAS-altered non-Sq NSCLC showed lower rates of co-occurring STK11 and KEAP1 alterations relative to other ancestry groups. Ancestry-specific co-alterations included the co-occurrence of KRAS and GNAS alterations in AMR, KRAS, and ARID1A alterations in SAS, and the mutual exclusivity of KRAS and NF1 alterations in the EUR and AFR ancestries. Contrastingly, EGFR-altered tumors exhibited a more conserved co-alteration landscape across ancestries. AFR exhibited the highest tumor mutational burden, with potential therapeutic implications for these tumors.

Unraveling the influence of TTF-1 expression on immunotherapy outcomes in PD-L1-high non-squamous NSCLC: a retrospective multicenter study.

Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or more who are highly susceptible to immunotherapy remains unresolved. Therefore, we evaluated whether TTF-1 has a clinical impact on this population. Patients with non-Sq NSCLC and high PD-L1 expression who received PD-1 inhibitor monotherapy or chemoimmunotherapy between May 2017 and December 2020 were retrospectively enrolled. Treatment efficacy was compared after adjusting for baseline differences using propensity score matching. Among the 446 patients with NSCLC with high PD-L1 expression, 266 patients with non-Sq NSCLC were analyzed. No significant differences in therapeutic efficacy were observed between the TTF-1-positive and -negative groups in the overall and propensity score-matched populations. Of chemoimmunotherapy, pemetrexed containing regimen significantly prolonged progression-free survival compared to chemoimmunotherapy without pemetrexed, regardless of TTF-1 expression (TTF1 positive; HR: 0.46 (95% Confidence interval: 0.26-0.81), p<0.01, TTF-1 negative; HR: 0.29 (95% Confidence interval: 0.09-0.93), p=0.02). TTF-1 expression did not affect the efficacy of PD-1 inhibitor monotherapy or chemoimmunotherapy in patients with non-Sq NSCLC with high PD-L1 expression. In this population, pemetrexed-containing chemoimmunotherapy demonstrated superior anti-tumor efficacy, irrespective of TTF-1 expression.

Effects of neutralization of tumor-derived immunosuppressant GDF-15 on anti-PD-1 activity in anti-PD-(L)1 relapsed/refractory non-squamous NSCLC, urothelial, and hepatocellular cancer.

2513 Background: Growth and Differentiation Factor 15 (GDF-15) plays a critical role as potent, local immunosuppressant during pregnancy. Here we report for the first time data identifying GDF-15 as immunosuppressant in non-sq NSCLC, urothelial (UC) and hepatocellular (HCC) cancer and provide clinical evidence that GDF-15 blockade with visugromab can restore anti-PD1 activity in last-line, anti-PD1-(L)1 r/r patients with these tumors. Methods: A large translational research program, analyzing &gt; 11.000 tumors in The Cancer Genome Atlas (TCGA) and paired serum/tumor samples for GDF-15 impact on the tumor microenvironment was conducted. In the GDFather ph2a first-in-human visugromab trial, subjects with advanced-stage, anti-PD1/PD-L1 relapsed/refractory (r/r) last-line solid tumors received the GDF-15 neutralizing antibody visugromab (CTL-002) at 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W om three defined expansion cohorts (NSCLC:n=5 2, UC :n=34, HCC: n=16). All patients were either (1) primary refractory to or (2) relapsed on continued checkpoint inhibitor (CPI) therapy after initial response, with all patients having received minimum of 12 weeks of continuous prior anti-PD-1/-L1 exposure. Primary endpoint was ORR. Results: In in-silico TCGA analyses, an inverse correlation between GDF-15 mRNA expression and key immune-related signatures revealed potent immunosuppression of several solid tumors including non-sq NSCLC and UC by GDF-15. In addition, in newly diagnosed, early-line UC patient samples, correlation of GDF-15 serum levels with reduced density of CD8+ T cells and immune cell proliferation (CD45+ki67+) was demonstrated. In the ph2a trial, visugromab + nivolumab showed excellent overall tolerability in heavily pre-treated patients, with just 6.9% of patients experiencing CTCAE Grade ≥ 3 treatment-related adverse events across these three indications. The observed ORR as per RECIST v1.1 criteria was 13.5% (5/37, 4PR, 1CR) in non-sq NSCLC, and 0% (0/15) in sq-NSCLC, in line with the translational research data. In UC, ORR was 17.6% (6/34, 5 PR, 1CR), and in HCC 18.8% (3/16, 2PR, 1CR); with 25 pts continuing on treatment, respectively. Duration of response (DoR) is surpassing 12 months for non-sq and UC lead cohort patients (N = 27 each) already, and 10/14 responses are ongoing. Conclusions: These analyses presented identify GDF-15 as novel, potent immunosuppressant in the tumor microenvironment of non-sq NSCLC, UC and HCC and identify it as potential key cause for CPI resistance. In heavily pretreated, by strict criteria anti-PD-1/-L1 r/r, late/last-line patients with NSCLC, UC and HCC, neutralization of GDF-15 by visugromab in combination with nivolumab resulted in an ORR of 16.1% (14/87; 11 PR and 3 CR) across these indications and long durability. Clinical trial information: NCT04725474 .

IMM2510, an anti-PD-L1/VEGF bispecific antibody fusion protein, in patients with advanced solid tumors: A phase I dose-escalation study.

e14506 Background: IMM2510 is a novel bispecific antibody fusion protein targeting PD-L1 and VEGF. The preclinical study demonstrated that IMM2510 induced significantly stronger anti-tumor activity than either monotherapy or combination of PD-L1 inhibitor and anti-VEGF antibody through blocking the PD-1/PD-L1 pathway and thus activate T cells and reducing VEGF-mediated tumor angiogenesis as well as an enhanced ADCC effect. We previously disclosed the preliminary clinical data of IMM2510, and here we further report safety and efficacy results of IMM2510 in the phase I dose escalation study. Methods: A phase I, multicenter, open-label, dose-escalation study, was designed to evaluate the safety, efficacy, recommended phase II dose (RP2D), and pharmacokinetics (PK) of IMM2510 in patients (pts) with advanced solid tumors. The study was designed with an accelerated titration followed by a standard 3+3 design. IMM2510 (0.007, 0.03, 0.1, 0.3, 1.0, 3.0, 6.0, 10.0, 20.0 mg/kg) was administered intravenously Q2W as monotherapy. Results: As of Dec 21, 2023, 33 pts had received IMM2510 at 9 dose levels (0.007-20.0 mg/kg), the median age was 57 years (range 36-74), the median prior line of therapy was 3 (range 1-13), and 27.3% pts received prior anti PD-1/PD-L1 inhibitor therapies. Treatment-related adverse events (TRAEs) occurred in 32 pts (97.0%). Most TRAEs were grade 1 or 2. The most common TRAEs (≥ 20%) of all grades were infusion related reaction (IRR) (72.7%), platelet count decreased (39.4%), anemia (33.3%) and diarrhea (21.2%). Grade ≥3 TRAEs occurred in 11 pts (33.3%). Grade ≥3 TRAEs (≥5%) were IRR (9.1%), platelet count decreased (6.1%), lymphocyte count decreased (6.1%) and diarrhea (6.1%). TRAEs leading to treatment discontinuation occurred in 3 pts (9.1%) which were IRR, hypersensitivity and pyrexia, respectively. No DLT occurred. In 25 response evaluable pts, 3 pts had confirmed PR: 1 pt with sq-NSCLC (onco-driver gene negative, previous IO treatment failure) at 3 mg/kg with tumor shrinkage 46% and still on the treatment with treatment duration over 20 months; 1 pt with sq-NSCLC at 10 mg/kg with tumor shrinkage about 32% along with treatment duration 9.4 months; 1 pt with thymus adeno-squamous carcinoma (PD-L1 CPS 80) at 20 mg/kg with tumor shrinkage over 53% and still remains on the treatment along with treatment duration 8.1 months. In addition, 7 pts with BOR SD and 4 of them had over 15% decreased tumor burden (1 cervical cancer at 3 mg/kg, 2 non-sq NSCLC at 10 and 20 mg/kg respectively, 1 ovarian cancer at 20 mg/kg). The half-life of IMM2510 in 20.0mg/kg dose group was around 6.8 days. The RP2D was determined to be 20.0 mg/kg. Conclusions: IMM2510 is well tolerated in general and preliminary anti-tumor activity in solid tumors is encouraging. The phase Ib/II is ongoing to enroll patients. Clinical trial information: NCT05972460 .

Abstract 6120: Genomic profiling of KRAS and EGFR-altered non-squamous non-small cell lung cancer reveal ancestry-specific co-alterations with therapeutic implications

Abstract Background: Racial and ethnic disparities are highly prevalent in cancer care and impact treatment outcomes, with an underrepresentation of minority populations in clinical studies. The impact of genetic ancestry on the genomic landscape of tumors remains understudied. To address this, we sought to comprehensively characterize the ancestry-based genomic co-alteration landscape and immunotherapy-related biomarkers in KRAS and EGFR-altered tumors, two major driver populations in non-squamous non-small cell lung cancer (non-Sq NSCLC). Methods: Our study consisted of 68,197 adult patients with non-Sq NSCLC who underwent comprehensive genomic profiling using FoundationOne® or FoundationOne®CDx during routine clinical care in the United States. Genetic ancestry was inferred using a SNP-based approach. Tumor mutational burden (TMB) was calculated across 0.8-1.2 megabases. PD-L1 expression was determined by immunohistochemistry using the Dako 22C3 PD-L1 antibody. Results: Overall, 81% of the patients were of European (EUR; n= 55,430), 10% of African (AFR; n=7,062), 5% of East Asian (EAS; n=3,297), 3% of Admixed American (AMR; n=2,011) and less than 1% of South Asian ancestry (SAS; n=497). KRAS was the most frequently altered oncogene in EUR (39%) and AFR (33%), whereas EGFR was most frequently altered in EAS (53%), SAS (36%), and AMR (30%) ancestry groups. While STK11 and KEAP1 alterations co-occurred with KRAS across all ancestry groups, they were significantly (FDR p &amp;lt;= 0.05) less frequent in EAS (16%) and AMR (15%) compared to EUR (28%). Additional ancestry-specific co-alteration patterns in KRAS-altered tumors included co-occurrence with GNAS alterations in AMR (Odds ratio, OR: 3.5, p &amp;lt; 10-5), co-occurrence with ARID1A alterations in SAS (OR: 4.7, p = 0.02), and mutual exclusivity with NF1 alterations in EUR (OR: 0.4, p &amp;lt; 10-5) and AFR (OR: 0.4, p &amp;lt; 10-5). In contrast, EGFR-altered tumors had a more conserved co-alteration landscape across all ancestry groups. Despite the known mutual exclusivity of KRAS and EGFR alterations, 13% of patients of EAS ancestry (compared to 2-4% of other ancestry groups) with KRAS alterations had co-occurring EGFR alterations; notably, a majority of these patients had an amplification in KRAS and/or EGFR, potentially representing treatment resistance mechanisms. Among immunotherapy-associated biomarkers, PD-L1 expression was similar across ancestries. Of note, patients of AFR ancestry with KRAS or EGFR alterations had higher TMB and the SAS ancestry group had the lowest TMB. Conclusion: Our study provides a comprehensive landscape of ancestry-specific patterns in KRAS and EGFR-altered non-Sq NSCLC. These findings can help better understand cancer disparities, aid in the development of new therapeutic strategies and inform more inclusive clinical trials and treatment decisions. Citation Format: Saumya D. Sisoudiya, Armande A. Houle, Tharu M. Fernando, Timothy R. Wilson, Jennifer L. Schutzman, Jessica K. Lee, Alexa B. Schrock, Ethan S. Sokol, Smruthy Sivakumar, Zhen Shi, Gaurav Pathria. Genomic profiling of KRAS and EGFR-altered non-squamous non-small cell lung cancer reveal ancestry-specific co-alterations with therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6120.

Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study

BackgroundPemetrexed is an efficacious multi-targeted antifolate with acceptable toxicity for non-squamous non-small cell lung cancer (non-Sq NSCLC) and malignant pleural mesothelioma. Vitamin B12 and folic acid as premedication can reduce the frequency of severe toxicities of pemetrexed chemotherapy. However, adverse effects are frequent in clinical settings. In this study, we aimed to identify the clinical factors and single-nucleotide polymorphisms (SNPs) associated with the toxicity and efficacy of pemetrexed chemotherapy.MethodsThis observational study was conducted from October 2012 to December 2019; we evaluated the toxicities and efficacies of pemetrexed chemotherapy using multivariate logistic or Cox regression analysis. In total, 106 patients received pemetrexed chemotherapy. SNPs were analyzed for four patients with malignant pleural mesothelioma and 67 with non-Sq NSCLC.ResultsThe median progression-free survival (PFS) and overall survival of 63 patients with non-Sq NSCLC, excluding four in the adjuvant setting, were 6.8 and 33.3 months, respectively. Per propensity-score-adjusted multivariate Cox analyses, favorable factors for PFS were folic acid level ≥ 9.3 ng/mL before premedication, platinum combination, bevacizumab combination, vitamin B12 level < 1136 pg/mL before chemotherapy, A/A + A/G of BHMT (742 G > A), and A/A + A/C of DHFR (680 C > A). Favorable prognostic factors included good performance status, low smoking index, body mass index ≥ 20.66 kg/m2, folic acid level ≥ 5.55 ng/mL before premedication, higher retinol-binding protein before chemotherapy, and A/G of MTRR (66 A > G). Among the 71 patients who were analyzed for SNPs, the frequencies of hematologic toxicities and non-hematologic toxicities in Grades 3–4 were 38% and 36.6%, respectively. Per propensity-score-adjusted multivariate logistic analyses, risk factors for Grades 3–4 hematologic toxicities were vitamin B12 level < 486 pg/mL before premedication, leucocyte count < 6120 /µL before chemotherapy, folic acid level < 15.8 ng/mL before chemotherapy, status with a reduced dose of chemotherapy, and C/T + T/T of MTHFR (677 C > T). Risk factors for Grades 2–4 non-hematologic toxicities were homocysteine levels ≥ 11.8 nmol/mL before premedication, transthyretin level < 21.5 mg/dL before chemotherapy, C/C + T/T of MTHFR (677 C > T), and A/A + G/G of SLC19A1 [IVS2 (4935) G > A].ConclusionThe information on metabolites and SNPs of the folate and methionine cycle will help predict the toxicities and efficacies of pemetrexed.Trial registrationThis trial was retrospectively registered with the University hospital Medical Information Network (UMIN000009366) on November 20, 2012.

Using the neutrophil-to-lymphocyte ratio to predict the outcome of individuals with nonsquamous non-small cell lung cancer receiving pembrolizumab plus platinum and pemetrexed.

Factors predicting the response to pembrolizumab plus platinum and pemetrexed combination therapy (Pemb-Plt-PEM) in nonsquamous non-small cell lung cancer (non-sq NSCLC) are unclear. We investigated the Glasgow Prognostic (GP) score, neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) as predictors of response to initial treatment with combination therapy in individuals with advanced non-sq NSCLC. We retrospectively reviewed 236 patients who received initial treatment with combination therapy for non-sq NSCLC at 13 institutions between December 2018 and December 2020. The usefulness of the GP score, NLR, and BMI as prognostic indicators was assessed. Cox proportional hazard models and the Kaplan-Meier method were used to compare progression-free survival (PFS) and overall survival (OS). The response rate was 51.2% (95% CI: 44.9-57.5%). The median PFS and OS after beginning Pemb-Plt-PEM were 8.8 (95% CI: 7.0-11.9) months and 23.6 (95% CI: 18.7-28.6) months, respectively. The NLR independently predicted the efficacy of Pemb-Plt-PEM-the PFS and OS were more prolonged in individuals with NLR <5 than in those with NLR ≥5 (PFS: 12.8 vs. 5.3 months, p = 0.0002; OS: 29.4 vs. 12.0 months, p < 0.0001). BMI predicted the treatment response-individuals with BMI ≥22.0 kg/m2 had longer OS than did those with BMI < 22.0 kg/m2 (OS: 28.4 vs. 18.4 months, p = 0.0086). The NLR significantly predicted PFS and OS, whereas BMI predicted OS, in individuals who initially received Pemb-Plt-PEM for non-sq NSCLC. These factors might be prognosis predictors in non-sq NSCLC.

Retreatment with nivolumab and ipilimumab with or without chemotherapy in patients with metastatic non-small cell lung cancer after progression on immune checkpoint inhibitor therapy.

e21192 Background: The advent of immune checkpoint inhibitor (ICI) has revolutionized the therapeutic arsenal for metastatic non-small cell lung cancer. However, better therapeutic options after a progression on frontline ICIs are urgently needed and remain to be defined. ICI retreatment (rt) may constitute a rational therapeutic alternative in these patients. However prospective studies evaluating such opportunity are still lacking. Methods: We retrospectively collected data from 30 metastatic NSCLC patients (pts) having progressed on ICI (anti-PD-1, anti-PD-L1 or anti-PD-1/anti-CTLA4 combined or not with histologydriven chemotherapy) who were retreated by double-agent ICI (ipilimumab and nivolumab) combined or not with histology-driven ChT in order to evaluate rt overall survival (OS) and rt progression-free-survival (PFS). The rt PFS was calculated from rt ICI initiation to death, last follow-up or disease progression. An assessment of correlation between certain clinical variables like sex, age, smoking history and others; and survival variables was performed. Results: The median age of the 30 pts included in the analysis was 64 years (63% of pts were &lt; 70 years old and 37% ≥ 70 years old) and 53% (n = 16) of the pts were male. Most suffered from a non-sq NSCLC (73%), with bone mets (66%), and were current or former smokers (90%). Median OS and median PFS in the whole group were 9 months (m) [95% confidence interval (CI): 5.7 - 14] and 2.5 m [95% CI: 2 - 4.6] respectively. Retreatment PFS was higher in pts having received dual ICI combined with ChT than dual ICI only [95% CI: 4.3 (3.7 – 6) versus 2.1 (1.5 – 2.9) m; hazard ratio (HR): 0.51 (0.24 – 1.10); p – value (p) = 0.085]. Retreatment OS and PFS were numerically higher in pts having received single- or double- ICI as prior therapy compared to ICI plus ChT [9.6 (6.4 – not reached) m versus 8.4 (3.7 – 13.5) m; HR: 0.53 (0.22 – 1.29), p = 0.15], and [4.2 (2.2 – not reached) m versus 2.4 (2 – 4.5 m); HR: 0.56 (0.25 – 1.24); p = 0.14), respectively], regardless of the rt. When we assessed the correlation between prior therapy and rt, we found the association of ChT to dual-ICI after prior single- or dual-ICI as first line treatment leads to a significantly higher PFS [4.5 (4 – NR) m versus 2.5 (1.6 – NR) m] compared to pts having received first ChT plus ICI then dual-ICI alone as second line treatment [HR 0.35 (95% CI: 0.13 – 0.93); p: 0.03]. The trend in OS benefit probably also favored ChT with dual-ICI as rt after prior single- or dual-ICI (HR 0.55; p = 0.23). Binary variables such as sex, histology, PD-L1 expression, smoking history, therapeutic discontinuation interval (TDI), baseline derived neutrophil-to-lymphocyte ratio dNLR) and baseline absolute lymphocyte counts (ALC) influenced positively the PFS in pts receiving dual ICI combined with ChT [ sex HR: 0.28; non-squamous histology HR: 0.26; PDL1 expression HR:0.22; former smoker HR: 0.23; never-smoker HR: 0.40; TDI less than 30 days HR: 0.09; high (≥ 3) dNLR HR: 0.22; and low (&lt;1000) ALC HR: 0.37]. Conclusions: Patients previously treated by ICI could be retreated by ICI combined with histology-driven chemotherapy in an individual approach, under certain circumstances, which are yet to be formally evaluated and determined.

Relationship Between TTF-1 Expression and PFS of Pemetrexed-containing Chemotherapy in Non-squamous-NSCLC Patients With and Without Driver Genes.

We performed a retrospective study too clarify whether the presence or absence of driver genes affects the relationship between thyroid transcription factor-1 (TTF-1) expression and response to pemetrexed (PEM) in non-squamous non-small cell lung cancer (non-sq-NSCLC) patients. We reviewed the medical charts of patients treated with PEM-containing chemotherapy during the period from February 2016 to February 2022 at Mito Medical Center-University of Tsukuba, Ryugasaki Saiseikai General Hospital, and University of Tsukuba Hospital. During the period of the study, 185 driver gene-negative patients negative, and 65 driver gene-positive patients were evaluated. Among the 165 driver gene-negative patients, progression free survival (PFS) of TTF-1-expressing patients treated with PEM-containing chemotherapy was significantly longer compared to that of TTF-1-negative patients. In the analysis of 65 driver gene-positive patients, the PFS of TTF-1-positive patients treated with PEM-containing chemotherapy did not differ significantly from that of TTF-1-negative patients. There was no significant difference in PFS between driver gene-negative and driver gene-positive patients treated with PEM-containing chemotherapy. Comparison between four groups defined according to the presence of driver gene and TTF-1 expression indicated shorter PFS only in 'driver gene-negative and TTF-1-negative' patients. In driver gene-positive non-sq NSCLC patients, expression of TTF does not affect the survival outcome of PEM-containing-chemotherapy. In other words, in these patients, second-line or later-line PEM-containing chemotherapy after development of resistance for specific-tyrosine kinase inhibitor could be expected to have the same level of efficacy as first-line PEM containing chemotherapy in driver gene-negative, TTF-1-positive non-sq NSCLC patients.

Impact of Results of TTF-1 Immunostaining on Efficacy of Platinum-Doublet Chemotherapy in Japanese Patients with Nonsquamous Non-Small-Cell Lung Cancer

Pemetrexed is a key drug in chemotherapy for nonsquamous non-small-cell lung cancer (nonsq NSCLC). Several studies have reported thyroid transcription factor-1 (TTF-1) as a biomarker of the efficacy in chemotherapy regimens, including pemetrexed in non-Asian people. We aimed to examine the impact of the results of the TTF-1 immunostaining of tumor cells on the therapeutic effect of chemotherapy in Japanese patients with nonsq NSCLC. We examined the results of TTF-1 immunostaining and the clinical background of Japanese patients with nonsq NSCLC who received platinum-doublet chemotherapy at our hospital, from April 2009 to April 2021, and the correlation between regimens with or without pemetrexed in progression-free survival (PFS) and overall survival (OS). The efficacy of each regimen was then compared between TTF-1-positive and TTF-1-negative tumors. TTF-1 immunostaining was performed in 145 patients during the study period: 92 were positive, and 53 were negative. A total of 24 patients presented with EGFR/ALK gene abnormality (16.6%). The PFS and OS of patients who were TTF-1-positive tended to be longer than those of the patients who were TTF-1-negative under either regimen. In other words, patients who were TTF-1-negative were frequently resistant to numerous chemotherapy drugs and experienced a poor prognosis under both regimens. The OS of patients who were TTF-1-positive and treated with the pemetrexed regimen was significantly longer than those on regimens without pemetrexed (963 vs. 412 days, HR = 0.73; 95% CI 0.55-0.96, p = 0.022), whereas there was no difference in PFS. The positivity of TTF-1 immunostaining in tumors could be a predominant prognostic marker for patients who have advanced nonsq NSCLC. Our analysis examined the possibility of a pemetrexed regimen leading to a longer prognosis in Asian patients who were TTF-1-positive for nonsq NSCLC, as shown in previous studies.

Abstract CT552: RATIONALE 304: Tislelizumab (TIS) plus chemotherapy versus chemotherapy alone as first-line (1L) treatment for non-squamous (non-sq) NSCLC in patients (pts) aged 65-75 years

Abstract Background: Primary results from the Phase 3 RATIONALE-304 study (NCT03663205) showed efficacy and a manageable safety/tolerability profile for TIS, an anti-programmed cell protein 1 monoclonal antibody, plus chemotherapy, as 1L treatment for non-sq NSCLC. We report results from pts aged 65-75 years. Methods: In RATIONALE-304, eligible pts (18-75 years) were treatment-naïve and had locally advanced or metastatic non-sq NSCLC. Pts were stratified by disease stage and programmed death-ligand 1 expression, and randomized 2:1 to receive TIS (200 mg intravenously [IV]) plus platinum (carboplatin AUC 5 or cisplatin 75 mg/m2 IV) plus pemetrexed 500 mg/m2 every three weeks for 4-6 cycles followed by maintenance TIS plus pemetrexed (Arm A), or platinum pemetrexed for 4-6 cycles followed by maintenance pemetrexed (Arm B). Progression-free survival (PFS) by independent review committee (IRC), objective response rate (ORR), and safety were assessed in pts aged 65-75 years. Results: In total, 97 pts aged 65-75 years were randomized to Arm A (60 pts) or Arm B (37 pts). The median age of pts was 68.0 years, and 76 pts (78.4%) were male. PFS was longer, and ORR higher, in Arm A vs Arm B (Table). Overall, 59 pts in Arm A, and 37 pts in Arm B experienced ≥ 1 treatment-emergent adverse event (TEAE). In Arm A, Grade ≥ 3 TEAEs occurred in 43 (72.9%) pts aged 65-75 years vs 150 (67.6%) aged ≥ 18 years, and in Arm B, 18 (48.6%) pts aged 65-75 years vs 59 (53.6%) pts aged ≥ 18 years. TEAEs leading to permanent discontinuation of any component of study treatment occurred in 19 (32.2%) pts in Arm A, and 5 (13.5%) pts in Arm B. 21 (35.6%) pts receiving TIS experienced ≥ 1 immune-related TEAE. Conclusions: Observed improvements in PFS and ORR support the treatment benefits of TIS in combination with platinum and pemetrexed chemotherapy in pts aged 65-75 with advanced non-squamous NSCLC. The safety profile of TIS in pts aged 65-75 years was similar to the safety profile for all pts in the overall study population. Table Arm A (N=60) Arm B (N=37) PFS Events (%) 27 (45.0) 20 (54.1) HR (95% CI) 0.727 (0.407, 1.297) - Median, months (95% CI) 9.7 (5.75, 11.53) 7.7 (4.21, 9.76) ORR, % (95% CI) 53.3 (40.0, 66.3) 40.5 (24.8, 57.9) HR, hazard ratio Citation Format: Shun Lu, Jie Wang, Yan Yu, Xinmin Yu, Yanping Hu, Zhiyong Ma, Xingya Li, Wu Zhuang, Yunpeng Liu, Weidong Li, Jiuwei Cui, Dong Wang, Wangjun Liao, Mengzhao Wang, Jianying Zhou, Zhehai Wang, Yuping Sun, Wanyu He, Yuanyuan Bao. RATIONALE 304: Tislelizumab (TIS) plus chemotherapy versus chemotherapy alone as first-line (1L) treatment for non-squamous (non-sq) NSCLC in patients (pts) aged 65-75 years [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 CT552.

Efficacy of Immune Checkpoint Inhibitor With or Without Chemotherapy for Nonsquamous NSCLC With Malignant Pleural Effusion: A Retrospective Multicenter Cohort Study

IntroductionMalignant pleural effusion (MPE) is associated with poor treatment outcome in patients with NSCLC receiving immune checkpoint inhibitors (ICIs). ICIs and chemotherapy (ICI/Chemo) combination therapy is currently the standard therapy for NSCLC, and some ICI/Chemo regimens for nonsquamous (non-Sq) NSCLC contain bevacizumab (BEV), which is effective for controlling MPE and may enhance immune response. This study aimed to determine the optimal first-line treatment for this clinical population. MethodsWe retrospectively enrolled consecutive patients with non-Sq NSCLC with MPE who received ICI/Chemo or pembrolizumab monotherapy. Treatment outcomes were analyzed in patients with programmed death-ligand 1 (PD-L1) tumor proportion score more than or equal to 50% who were administered ICI/Chemo or pembrolizumab monotherapy (PD-L1 high cohort) and in patients with any PD-L1 status, treated with ICI/Chemo with or without BEV (ICI/Chemo cohort). We used propensity score matching (PSM) to reduce bias. ResultsPD-L1 high and ICI/Chemo cohorts included 143 and 139 patients, respectively. In PD-L1 high cohort, 37 patients received ICI/Chemo. With PSM, the median progression-free survival was significantly longer in the ICI/Chemo group than in the pembrolizumab group (11.1 versus 3.9 mo, respectively, p = 0.0409). In the ICI/Chemo cohort, 23 patients received BEV. With PSM, no significant difference occurred in median progression-free survival between BEV and non-BEV groups (6.1 versus 7.4 mo, p = 0.9610). ConclusionICI/Chemo seemed more effective than pembrolizumab monotherapy for patients with non-Sq NSCLC with MPE. Nevertheless, the synergistic effect of BEV with ICI/Chemo may be limited. Further studies are needed to clarify the key factor in the tumor-induced immunosuppression environment in these patients.

Association of comprehensive molecular genotyping and overall survival in patients with advanced non-squamous non-small cell lung cancer.

9022 Background: Current guidelines recommend comprehensive molecular genotyping for newly diagnosed patients (pts) with metastatic non-squamous (non-Sq) NSCLC. We have previously demonstrated that concurrent plasma (P) and tissue (T) based next-generation sequencing (NGS) improves detection of clinically actionable mutations in pts with advanced NSCLC. We analyzed the impact of concurrent T+P NGS on comprehensiveness of molecular genotyping and on overall survival (OS). Methods: A retrospective cohort study of pts with newly diagnosed stage IV non-Sq NSCLC who received therapy at our institution between 01/2019 and 12/2020 was performed. Categories of NCCN guideline testing were defined, i) comprehensive: EGFR, ALK, BRAF, ROS1, MET, RET, and NTRK testing, ii) incomplete: 2-6 genes tested, and iii) no testing performed. The proportion of pts with comprehensive molecular testing performed, prior to 1st-line therapy and by detection modality (T NGS vs. T+P NGS), were compared using Fisher’s exact test. Median OS was estimated using Kaplan-Meier methodology from diagnosis to death or censored at most recent follow-up. Results: 335 patients were included in this analysis, 98.5% (330/335) underwent molecular testing: either comprehensive: n = 291 (86.9%), incomplete testing: n = 39 (11.6%); or no testing n = 5 (1.5%). Testing with T NGS was completed in 32.7% (108/330); 67.2% (222/330) underwent concurrent T+P NGS. These groups were well balanced for baseline characteristics, with the exception of a higher number of never smokers in T+P vs. T NGS (30.2% vs. 14.8%, p &lt; 0.0001). Proportion of pts with comprehensive molecular testing was higher among pts with T+P NGS: 99.5% (221/222) vs. T NGS: 64.8% (70/108), p &lt; 0.0001. All pts with T+P NGS testing had results available prior to 1st line therapy; 100% (204/204) compared to 60.7% (51/84) for T NGS, p &lt; 0.0001. With median follow up of 20.5 months (mos, range 0.3 - 33.1), median OS was 18.6 mos. Median OS for pts tested with T+P NGS vs T alone was numerically longer at 23.2 vs. 14.1 mos, but not statistically significant (p = 0.078). However, regardless of testing modality, patients with comprehensive molecular genotyping had superior OS compared to those with incomplete or no testing (22.1 mos vs. 11.6 mos, p = 0.017). The institution of oral targeted therapy had no bearing on this difference in OS (test for interaction, p = 0.6509). Conclusions: Performance of concurrent T+P NGS testing was associated with a higher likelihood of comprehensive molecular genotyping, as well as improved availability of results, including prior to first line therapy. Patients with comprehensive genotyping have improved OS compared to patients with incomplete or no testing. These results support implementation of a concurrent T+P NGS approach upon initial diagnosis of metastatic non-Sq NSCLC.

Incorporation of plasma-based next-generation sequencing to improve guideline-concordant molecular testing in patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer.

14 Background: Current NCCN guidelines recommend comprehensive molecular profiling for all newly diagnosed patients with metastatic non-squamous NSCLC to enable the delivery of personalized medicine. We have previously demonstrated that incorporation of plasma based next-generation gene sequencing (NGS) improves detection of clinically actionable mutations in patients with advanced NSCLC (Aggarwal et al, JAMA Oncology, 2018). To increase rates of comprehensive molecular testing at our institution, we adapted our clinical practice to include concurrent use of plasma (P) and tissue (T) based NGS upon initial diagnosis. P NGS testing was performed using a commercial 74 gene assay. We analyzed the impact of this practice change on guideline concordant molecular testing at our institution. Methods: A retrospective cohort study of patients with newly diagnosed metastatic non-squamous NSCLC following the implementation of this practice change in 12/2018 was performed. Tiers of NCCN guideline concordant testing were defined, Tier 1: complete EGFR, ALK, BRAF, ROS1, MET, RET, NTRK testing, Tier 2: included above, but with incomplete NTRK testing, Tier 3: &gt; 2 genes tested, Tier 4: single gene testing, Tier 5: no testing. Proportion of patients with comprehensive molecular testing by modality (T NGS vs. T+P NGS) were compared using one-sided Fisher’s exact test. Results: Between 01/2019, and 12/2019, 170 patients with newly diagnosed metastatic non-Sq NSCLC were treated at our institution. Overall, 98.2% (167/170) patients underwent molecular testing, Tier 1: n = 100 (59%), Tier 2: n = 39 (23%), Tier 3/4: n = 28 (16.5%), Tier 5: n = 3 (2%). Amongst these patients, 43.1% (72/167) were tested with T NGS alone, 8% (15/167) with P NGS alone, and 47.9% (80/167) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS: 95.7% (79/80) compared to T alone: 62.5% (45/72), p &lt; 0.0005. Prior to the initiation of first line treatment, 72.4% (123/170) patients underwent molecular testing, Tier 1: n = 73 (59%), Tier 2: n = 27 (22%) and Tier 3/4: n = 23 (18%). Amongst these, 39% (48/123) were tested with T NGS alone, 7% (9/123) with P NGS alone and 53.6% (66/123) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS, 100% (66/66) compared to 52% (25/48) with T NGS alone (p &lt; 0.0005). Conclusions: Incorporation of concurrent T+P NGS testing in treatment naïve metastatic non-Sq NSCLC significantly increased the proportion of patients undergoing guideline concordant molecular testing, including prior to initiation of first-line therapy at our institution. Concurrent T+P NGS should be adopted into institutional pathways and routine clinical practice.

O11-3 Phase 2 trial of atezolizumab with bevacizumab for patients with PD-L1 high non-Sq NSCLC (WJOG10718L/At Be Study)

O11-3 Phase 2 trial of atezolizumab with bevacizumab for patients with PD-L1 high non-Sq NSCLC (WJOG10718L/At Be Study)

Natural history of curatively resected stage IB-IIIA EGFR mutation (+) NSCLC: Clinicopathologic and molecular prognostic factors (ROOT-EGFR-ADJ).

8529 Background: Surgery is the primary therapy for patients with early-stage NSCLC. However, five-year recurrence rates were 45%, 62%, and 76% for pathologic stage (pStage) IB, II, and III respectively. In the ADARUA study, adjuvant osimertinib significantly improved DFS in patients with completely resected EGFR mutation (+) NSCLC. Though marked improvement of DFS is encouraging, OS is not mature yet and several questions remain unanswered; Does this DFS benefit translate to cure? Do all patients need to receive adjuvant Osiemrtinib? In order to address these questions we reviewed the clinical records of pStage IB-IIIA EGFR mutant NSCLC. Methods: From January 2008 and August 2020, total 2,340 patients with pStage IB-IIIA, non-SQ NSCLC underwent curative surgery at Samsung Medical Center. Using innovative in-house algorithm to retrieve medical big data-based cohort called ROOT (Realtime autOmetically updated data warehOuse in healTh care) detailed clinical data were analyzed to investigate any prognostic factors of recurrence. In order to identify any molecular prognostic factors, we did a comprehensive genomic analysis (WTS/WES)in a subset of patients with matched case-control. Results: Total 1,811 patients with pStage IB-IIIA, non-SQ EGFR mutation (+) NSCLC were included (367 patients : no EGFR mutation test). Median follow-up duration was 38.8 (range: 0.5 -156.2). Patient demographics; Deletion 19 was 52.7%, L858R was 47.3%. Female was 64.7% and never smoker was 72%. Stage IB, IIA, IIIA was 50.4%, 26.5%, and 23.2%. Among them, 6.7% of pStage IB, 72.8% of pStage II, and 88.7% of pStage IIIA received adjuvant chemotherapy. Median DFS were 74.0 months (95% CI 63.2-84.8), 48.6 months (95% CI: 40.2-57.0), and 22.4 months (95%: 19.5-25.3) for pStage IB, II, and IIIA, respectively. The median OS were 132.1 months (95% CI: 101.3-162.8), 124.3 months (95% CI: 61.8-186.9), and 82.1 months (95% CI: 71.2-93.1) for pStage IB, II, and IIIA, respectively. In univariate analysis, pStage, poorly differentiation, histologic subtype (micropapillary, solid), lymphatic invasion, vascular invasion, and pleural invasion were related with high recurrence rate statistically. In multivariate analysis, pStage, vascular invasion, and pleural invasion were related with recurrence statistically. To detect molecular factors, 76 patients performed the matched case -control (included pStage, type of EGFR mutation, and sex) analysis (WES/WTS). Conclusions: This study showed that the median DFS of pStage II-IIIA EGFR mutation (+) NSCLC was 31.9 months. With approximately 55% of patients with pStage II-IIIA EGFR mutation (+) NSCLC experienced recurrence at the 3rd year, we need to find the appropriate subset who need 3-year adjuvant osimertinib by comprehensive predictive marker for cure. Updated and detail exploratory biomarker outcome will be presented at the annual meeting.

A randomized phase II trial of olaparib maintenance versus placebo monotherapy in patients with chemosensitive advanced non-small cell lung cancer.

e21649 Background: Impaired DNA damage response (DDR) is a common feature of cancer, however therapeutic exploitation has been limited to cancers harbouring somatic inactivation of BRCA1/2 which causes homologous recombination deficiency (HRD). We hypothesized that patients (pts) with metastatic non-small cell lung cancer responding to platinum doublet based chemotherapy, might enrich for impaired DDR encompassing HRD, rendering these tumours more sensitive to inhibition of poly-ADP ribose polymerase (PARP) inhibition by olaparib. Methods: PIN was a multicentre double-blind placebo controlled randomised phase II screening trial (alpha and beta = 0.2). Chemonaive pts had advanced (stage IIB/IV) squamous (Sq) or non-sq (NS) NSCLC, ECOG performance status 0-1, no EGFR nor ALK mutation. Prior immunotherapy with a PD1/ PDL1 inhibitor was allowed. If tumour shrinkage was observed after 3 cycles of platinum chemotherapy, pts were randomised 1:1 to olaparib (O, 300mg po bd q21) or placebo (P), which was continued until disease progression or withdrawal. Primary end point was progression free survival (PFS), with a one-sided test for significance. Secondary endpoints were overall survival (OS), response (RECIST v1.1) and safety (CTCAE4.0). Results: 70 pts were randomised to O (32) or P (38) between Aug 2014 and Nov 2017. There was no difference in median dose intensity (% (IQR), O vs P) was 86.4 (64.3-95.7) vs 93.3 (80.2-97.6). Pts receiving O had a longer, but not statistically significant median PFS (weeks (IQR) was O 16.6 (7.1-21.7) vs P 12 (5.6-18.7)); and hazard ratio (HR) was 0.83 (80% CI 0.6-1.15, p = 0.23), using intention to treat (ITT) unadjusted analysis. However, the ITT Cox model, adjusted for smoking history and histology, showed a significantly longer PFS for pts receiving O (HR 0.73 (80% CI 0.52-1.02, p = 0.11)). Pts receiving O also had greater, but not statistically significant OS: median (weeks (IQR) was O 59.4 (38.7-67.9) vs P 31.3 (22.4-58.6)). OS HR was 0.68 (95% CI 0.37-1.26; two-sided p = 0.22). 3 patients were completely withdrawn prior to progression. No complete responses were observed and treatment was well tolerated. Conclusions: Design parameters justifying a Phase III trial (p &lt; 0.2) were met in the adjusted, but not unadjusted PFS analysis, with a trend towards longer PFS and OS in the O arm. We speculate that this signal may be driven by a DDR deficient molecular subgroup. Translational studies are warranted to investigate these possibilities. Clinical trial information: NCT01788332.

OA12.02 Randomized Phase II Study of CDDP+S-1 vs CDDP+PEM Combined with Thoracic RT for Locally Advanced Non-Sq NSCLC: SPECTRA Study

OA12.02 Randomized Phase II Study of CDDP+S-1 vs CDDP+PEM Combined with Thoracic RT for Locally Advanced Non-Sq NSCLC: SPECTRA Study

Abstract 4919: Required numbers of biopsy samples and tumor cells for the assessment of PD-L1 expression to predict a response to nivolumab treatment in patients with NSCLC

Abstract Background: PD-L1 expression is a predictive biomarker of response to nivolumab in non-squamous non-small cell lung carcinoma (Non-Sq NSCLC). PD-L1 expression in NSCLC exhibits significant intratumoral heterogeneity. Although multiple biopsy samples are usually obtained during a biopsy procedure, the evaluation of PD-L1 expression is typically performed using only one small sample. The aim of this study was to investigate the required numbers of samples and tumor cells (TCs) to assess PD-L1 expression using biopsy samples to predict the response to nivolumab. Methods: A total of 225 biopsy samples obtained from 80 Non-Sq NSCLC patients treated with nivolumab between January 2016 and August 2017 were collected. In each patient, the samples were obtained from the same lesion at the same time before nivolumab treatment. The number of TCs and the PD-L1 score after staining with anti-PD-L1 antibody (Dako 28-8) were evaluated. We defined the sample containing the largest number of TCs as Max-TCs, the sample containing the smallest number of TCs as Min-TCs and the sum of all the samples from each patient as Multiple-TCs. The concordances of the PD-L1 scores among the Max-TCs, Min-TCs and Multiple-TCs were assessed. And then, the impacts of the numbers of samples and TCs on the prediction of the efficacy of nivolumab using the evaluation of PD-L1 expression were evaluated. Results: The median number of samples was 2 (range: 2-6). The median number of TCs was 148 (13-2976) for the Mini-TCs, 570 (29-4826) for the Max-TCs, and 1022 (55-7062) for the Multiple-TCs.The correlation of the PD-L1 scores between the Max-TCs and Multiple-TCs was significantly high (R2 = 0.98). A mismatch of PD-L1 &amp;lt;1%/≥1% was observed between the Max-TC and the Multiple-TC in one patient (1%). The correlation of the PD-L1 scores between the Max-TCs and the Mini-TCs (R2 = 0.83) was weaker than that between the Max-TCs and the Multiple-TCs. A mismatch of PD-L1 &amp;lt;1%/≥1% was observed between the Max-TCs and the Mini-TCs in six patients (8%). The ROC analysis indicated that the required number of TCs to match PD-L1 &amp;lt;1%/≥1% between the Max-TCs and the Mini-TCs was 80 (AUC: 0.62). PD-L1 ≥1% in Mini-TCs containing the ≥80 TCs was associated with a longer progression-free survival (PFS) (median 8.7 vs 1.8 months, HR 0.39, P &amp;lt; 0.01) and a prolonged overall survival (OS) (median 20.9 vs 9.2 months, HR 0.41, P = 0.01) compared with PD-L1 &amp;lt;1%. On the other hand, there were no difference in the PFS (median 3.0 vs 2.4 months, HR 0.77, P = 0.59) and the OS (median 7.7 vs 5.6 months, HR 0.89, P = 0.81) between PD-L1 ≥1% and PD-L1 &amp;lt;1% in the Mini-TCs containing &amp;lt;80 TCs. Conclusion: Evaluating the PD-L1 score using multiple biopsy samples did not provide any added benefit. One biopsy sample containing ≥80 TCs is required to evaluate PD-L1 expression to predict the response to nivolumab. Citation Format: Jun Sato, Tomoyuki Naito, Hibiki Udagawa, Hidehito Horinouchi, Shuji Murakami, Yasushi Goto, Shintaro Kanda, Yutaka Fujiwara, Noboru Yamamoto, Yuichiro Ohe, Yoshitaka Zenke, Keisuke Kirita, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Noriko Motoi, Genichiro Ishii, Koichi Goto. Required numbers of biopsy samples and tumor cells for the assessment of PD-L1 expression to predict a response to nivolumab treatment in patients with NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4919.

P1.01-33 Randomized Phase 2 Study Comparing CBDCA+PTX+BEV and CDDP+PEM+BEV in Treatment-Naïve Advanced Non-Sq NSCLC (CLEAR study)

P1.01-33 Randomized Phase 2 Study Comparing CBDCA+PTX+BEV and CDDP+PEM+BEV in Treatment-Naïve Advanced Non-Sq NSCLC (CLEAR study)