Non-Small-Cell Lung Cancer Patients Harboring ROS1 Rearrangement: Real World Testing Practices, Characteristics and Treatment Patterns (ROS1REAL Study).

ROS1 rearrangements are considered rare in non-small-cell lung cancer (NSCLC). This retrospective real-world study aimed to evaluate first-line treatment with crizotinib, a tyrosine kinase inhibitor (TKI) standard of care vs. new generation ROS1 anti-cancer agents. Forty-nine ROS1-expressing NSCLC patients, diagnosed with advanced metastatic disease, were included. Molecular profiling using either FISH/CISH or NGS was performed on tissue samples. Twenty-eight patients were treated with crizotinib, while fourteen patients were administered newer drugs (entrectinib, repotrectinib) and seven patients received platinum-doublet chemotherapy in a first-line setting. Overall response rate and disease control rate for the crizotinib and entrectinb/repotrectinib cohort were 68% and 82% vs. 86% and 93%, respectively. Median progression free survival was 1.6 years (95% CI 1.15-2.215) for the crizotinib treatment vs. 2.35 years for the entrectinib/repotrectinib cohort (95% CI 1.19-3.52). Central nervous system progression was noted in 20% and 25% of the crizotinib and entrectinib/repotrectinib cohorts, respectively. This multi-center study presents real-world treatment patterns of ROS1 NSCLC population, indicating that crizotinib exhibited comparable results to entrectinib/repotrectinib in a first-line setting, although both response rate and survival was numerically longer with treatment with newer agents.

Effects of EGFR driver mutations on pathologic regression in resectable locally advanced non-small cell lung cancer treated with neoadjuvant chemoradiation and completion surgery.

OBJECTIVE: We hypothesized that driver mutations in epidermal growth factor receptor (EGFR) are associated with decreased pathologic response to neoadjuvant chemoradiation (NA-ChRT) in locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Patients with Stage IIB-IIIA NSCLC treated with NA-ChRT, completion surgery, and underwent molecular profile testing were identified in a lung cancer database. Pathologic response was quantified using: (i) major pathologic response (MPR), (ii) complete pathologic response (pCR), and (iii) mean residual viable tumor cells (MRTC). Two groups were formed based on the presence or absence of driver mutations. Clinical and pathological correlations between the groups were studied. RESULTS: Forty-seven patients underwent tumor molecular profile testing, NA-ChRT, and completion surgery. Compared to the no-driver mutation group, the driver mutation group had lower MPR (23% vs 71%, p = 0.003), pCR (0% vs 26%, p = 0.02), and higher MRTC (43.4% vs 15.8%, p = 0.009). Univariate analysis showed an increased MPR rate for smokers, squamous cell histology, ChRT-surgery interval >65 days, and no-driver mutations. Multivariate analysis showed that only no-driver mutations (OR 0.39, p = 0.02) remained significant for MPR. PD-L1 status did not affect MPR. At 2 years, the driver mutation group had lower rates of local control (Hazard ration [HR] 0.67, p = 0.17) and disease-free survival (HR 0.5, p = 0.001). Overall survival was similar for both groups (HR = 1.04, p = 0.86). CONCLUSION: Following 60 Gray NA-ChRT, tumors with a driver mutation had lower MPR and pCR rates than tumors without a driver mutation. PD-L1 was not associated with tumor regression. ADVANCES IN KNOWLEDGE: Patients with resectable LA-NSCLC and an EGFR driver mutation treated with neoadjuvant-ChRT and completion surgery have reduced pathologic regression, lower local control rates, and shorter disease-free survival than patients without a driver mutation. Evaluation of molecular testing should be introduced in LA-NSCLC intended for prognostication and treatment decisions.

Driver mutation characteristics of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in advanced non-small cell lung cancer.

OBJECTIVES: The identification and targeting of actionable genomic alterations (AGA) have revolutionized the treatment of cancer in general and mostly for non-small cell lung cancer (NSCLC). We investigated whether in NSCLC patients PIK3CA mutations are actionable. MATERIALS AND METHODS: Chart review was performed of advanced NSCLC patients. PIK3CA mutated patients were analyzed as two groups: Group A: without any non-PIK3CA established AGA; Group B: with coexisting AGA. Group A was compared to a cohort of non-PIK3CA patients (group C), using t-test and chi-square. To evaluate the impact of PIK3CA mutation on outcome, we compared Group A survival to age/sex/histology matched cohort of non-PIK3CA mutated patients (group D) by Kaplan-Meier method. A patient with a PIK3CA mutation was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib). RESULTS: Of a cohort of 1377 patients, 57 are PIK3CA mutated (4.1%). Group A: n-22, group B: n-35. Group A median age is 76 years, 16 (72.7%) men, 10 (45.5%) squamous, 4 (18.2%) never smokers. Two never-smoker female adenocarcinoma patients had solitary PIK3CA mutation. One of them was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib), with rapid clinical and partial radiological improvement. Group B, compared with Group A, included younger patients (p = 0.030), more females (p = 0.028) and more adenocarcinoma cases (p < 0.001). Compared to group C, group A patients were older (p = 0.030) and had more squamous histology (p = 0.011). CONCLUSION: In a small minority of NSCLC patients with PIK3CA mutation there are no additional AGA. PIK3CA mutations may be actionable in these cases.

Gut microbial signature in lung cancer patients highlights specific taxa as predictors for durable clinical benefit.

We aimed to determine microbial signature linked with lung cancer (LC) diagnosis and to define taxa linked with durable clinical benefit (DCB) of advanced LC patients. Stool samples for microbial 16S amplicon sequencing and clinical data were collected from 75 LC patients (50 of which were treated with checkpoint inhibitors) and 31 matched healthy volunteers. We compared LC to healthy controls and patients with DCB to those without. LC patients had lower α-diversity and higher between-subject diversity. Random Forests model to differentiate LC cases from controls ROC-AUC was 0.74. Clostridiales, Lachnospiraceae, and Faecalibacterium prausnitzii taxa abundance was decreased in LC compared to controls. High Akkermansia muciniphila correlated with DCB (HR 4.26, 95% CI 1.98-9.16), not only for the immunotherapy-treated patients. In addition, high Alistipes onderdonkii (HR 3.08, 95% CI 1.34-7.06) and high Ruminococcus (HR 7.76, 95% CI 3.23-18.65) correlated with DCB.Our results support the importance of gut microbiome in LC. We have validated the apparent predictive value of Akkermansia muciniphila, and highlighted Alistipes onderdonkii and Ruminococcus taxa correlation with DCB. Upon additional validations those can be used as biomarkers or as targets for future therapeutic interventions.

Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP): a retrospective analysis from an early access program.

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal-epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48-91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47-69), whereas it was 68% (95% CI, 50-82) in treatment-naïve and 50% (95% CI, 35-65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7-14.3), whereas it was 10.6 months (95% CI, 5.5-15.7) in first-line and 9.1 months (95% CI, 3.1-15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2-23.1). In patients with measurable brain metastases (n = 11), the intracranial ORR was 46% (95% CI, 17-77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.

Chemoradiation followed by adjuvant durvalumab in stage III non-small cell lung cancer: Real-world comparison of treatment outcomes to historical controls treated with chemoradiation alone.

OBJECTIVE: Compare outcomes in patients with stage III non-small cell lung cancer (NSCLC) treated with chemoradiation and adjuvant durvalumab to historical controls treated with chemoradiation alone. METHODS: The records of patients with stage III NSCLC treated with definitive chemoradiation ± adjuvant durvalumab were reviewed retrospectively. Primary endpoints were progression free survival (PFS), overall survival (OS), and adverse events (AE). RESULTS: Between September 2009 and September 2020, 215 patients were treated with concurrent chemoradiation (n = 144) or concurrent chemoradiation followed by adjuvant durvalumab (n = 71). Compared to historical controls, durvalumab use was associated with improved PFS: median (27 months vs. 10 months, p < 0.0001), 1-year (83.1% vs. 43.8, p < 0.0001); and improved OS; median (not reached vs. 24 months, p < 0.0001), 1-year (85.9% vs. 81.9%, p < 0.0001). Multivariate analysis showed adjuvant durvalumab was associated with increased OS (p = 0.005) and PFS (p = 0.001). Within the durvalumab group, only clinical stage IIIA versus IIIB/C was associated with improved OS (p = 0.049), but not PFS. There was no association between PFS or OS and Eastern Cooperative Oncology Group (ECOG) score, prior history of immune disease, programmed death-ligand 1 (PD-L1) receptor status, delay in starting durvalumab beyond 42 days, or development of an AE. During durvalumab treatment, 63 AE were reported in 52 patients with treatment discontinuation in 11. Pneumonitis was the most common AE reported (n = 35, 49%). Most AE were grade 1-2 (n = 57). Grade 3-4 AE were uncommon (n = 6) and none were grade 5. CONCLUSION: Treatment with adjuvant durvalumab following chemoradiation was associated with improved PFS and OS compared to chemoradiation alone.

dNLR-Based Score Predicting Overall Survival Benefit for The Addition of Platinum-Based Chemotherapy to Pembrolizumab in Advanced NSCLC With PD-L1 Tumor Proportion Score ≥50.

INTRODUCTION: Both pembrolizumab (P) as a monotherapy or in combination with platinum-based chemotherapy (PCT) represent standard first-line treatment options for advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score (TPS)≥50%. No predictive biomarkers exist to guide treatment decisions. METHODS: 423 consecutive patients with EGFR/ALK/ROS1-wild-type PD-L1 TPS≥50% aNSCLC receiving P (n = 302) or PCT (n = 121) as a first-line treatment were identified in the electronic databases of 5 Israeli cancer centers. Overall survival (OS, months [mo]) was assessed in correlation with blood biomarkers (BB: NLR, dNLR, PLR, SII, LIPI, ALI); a predictive score was developed. RESULTS: In the propensity score matching analysis (n = 236; 118 patients in each group matched for age, sex and ECOG PS), mOS was 17.2mo (95% CI, 13.2-36.5) and 21.3mo (95% CI, 14.8-NR) in groups P and PCT, respectively (P = .44). In group P, NLR, dNLR, PLR, LIPI, and ALI significantly correlated with OS in uni- and multivariate COX regression analyses (P < .05), whereas in group PCT, none of the BB demonstrated a significant correlation. A predictive score was developed (each parameter receiving one point): age≥65, female sex, never-smoking status, adenocarcinoma histology, dNLR≥3. In patients with predictive score 3-5, OS was significantly longer with PCT as compared to P: mOS NR (95% CI, 15.3-NR) and 8.7mo (95% CI, 5.8-13.7) (P = .0005), while OS didn't differ significantly in patients with predictive score 0-2 (P = .61). CONCLUSION: With the limitations of the retrospective analysis, the proposed dNLR-based score appears to predict OS with P and PCT.

Nivolumab in Non-Small Cell Lung Cancer: Real World Long-Term Survival Results and Blood-Based Efficacy Biomarkers.

OBJECTIVES: We aimed to examine clinical data and baseline blood test results as potential predictive biomarkers for benefit from nivolumab, in advanced non-small cell lung cancer patients (NSCLC). MATERIALS AND METHODS: A chart review was performed of 108 advanced NSCLC patients who commenced treatment with nivolumab between 2015-6 at three Israeli cancer centers, and for whom laboratory tests results were available. Data collected included sex, age, ECOG-PS, histology and number of previous lines of treatment. Baseline blood test results collected: absolute lymphocyte and neutrophil count (ANC), white blood cells (WBC), hemoglobin, platelets, albumin and lactate dehydrogenase (LDH). Neutrophil to Lymphocyte Ratio and 'derived NLR' (dNLR = (ANC/[WBC-ANC])) were calculated. Disease control at six months (DC6) was defined as any tumor shrinkage or stable disease during the first six months of nivolumab treatment. The association between clinical/laboratory variables and survival was tested with a Cox proportional hazard model. Data cut-off occurred in November 2019. RESULTS: 35 patients (32.4%) achieved DC6. Median overall survival (OS) of entire study population was 5.4 months. Four year survival rate was 16%. Achievement of DC6 strongly correlated with longer OS (HR 0.12, 95% C.I. 0.07-0.21, p<0.001). In univariate and multivariate analysis, dNLR, albumin and LDH correlated significantly with OS. No variables correlated significantly with DC6 in multivariate analysis. Based on albumin and LDH, we produced a score called CLAS (combined LDH and albumin score), including four prognostic groups of patients. Patients having low albumin and high LDH had the worst prognosis. CONCLUSION: In real-life setting, long-term efficacy of nivolumab in advanced line treatment of NSCLC is consistent with clinical trials. Response or stability of disease during first six months of treatment is associated with prolonged survival. We propose a novel score (CLAS) that may be useful for predicting outcome in nivolumab-treated NSCLC patients, but further validation is required.

Real-World Analysis of the Impact of Radiotherapy on Immunotherapy Efficacy in Non-Small Cell Lung Cancer.

BACKGROUND: Immunotherapy (IO) provides a significant benefit for a subgroup of non-small cell lung cancer (NSCLC) patients. Radiotherapy (XRT) might enhance the efficacy of IO. We evaluated the impact of the specifics of XRT treatments on the OS of IO-treated NSCLC patients. METHODS: Metastatic NSCLC patients treated with IO were retrospectively identified. Parameters included demographics, tumor characteristics, IO and XRT details. Correlation between the parameters and OS was tested with Cox regression. RESULTS: 453 patients were included. No XRT was given to 167 (36.9%) patients, whereas XRT prior and after IO had 182 (40.2%) and 104 (22.9%) patients, respectively. XRT total doses between 30 and 40 Gy had better overall survival (OS) compared to non-irradiated patients (hazard ratio (HR) 0.5, 95% CI 0.25-1.0, p = 0.049). Worse outcome was seen with total doses ≤ 10 Gy (HR 1.67, 95% 1.13-2.5, p = 0.01), XRT fractions of 4.1-8 Gy (HR 1.48, 95% CI 1.05-2.1, p = 0.027) and XRT to the bone (HR 1.36, 95% CI 1.01-1.8, p = 0.04). Several clinical parameters correlated with OS in the univariate analysis of the IO-treated patients. While, in the multivariate analysis, only ECOG-PS, treatment line, type of IO, albumin and NLR remained statistically significant. CONCLUSION: Specific doses, fractions and sites of XRT correlated with the OS of IO-treated NSCLC patients in the univariate analysis, although not in the multivariate analysis.

Pembrolizumab as a monotherapy or in combination with platinum-based chemotherapy in advanced non-small cell lung cancer with PD-L1 tumor proportion score (TPS) ≥50%: real-world data.

Both pembrolizumab (P) and combination of pembrolizumab with platinum-based chemotherapy (PCT) represent standard 1st-line options for advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score (TPS) ≥50%. The two strategies have never been compared in a randomized trial. 256 consecutive patients with EGFR/ALK/ROS1-wild-type PD-L1 TPS ≥50% aNSCLC receiving P (group P, n = 203) or PCT (group PCT, n = 53) as a 1st-line treatment were identified in the electronic databases of 4 Israeli cancer centers. Time-to-treatment discontinuation (TTD) and overall survival (OS) were assessed. Baseline characteristics were well balanced, except for age and ECOG PS differences in favor of group PCT. Median (m)TTD was 4.9 months (mo) (95% CI, 3.1-7.6) vs 8.0mo (95% CI, 4.7-15.6) (p-0.09), mOS was 12.5mo (95% CI, 9.8-16.4) vs 20.4mo (95% CI, 10.8-NR) (p-0.08), with P and PCT, respectively. In the propensity score matching analysis (n = 106; 53 patients in each group matched for age, sex and ECOG PS), mTTD was 7.9mo (95% CI, 2.8-12.7) vs 8.0mo (95% CI, 4.7-15.6) (p-0.41), and mOS was 13.3mo (95% CI, 6.8-20.3) vs 20.4mo (95% CI, 10.8-NR) (p-0.18), with P and PCT, respectively. Among various subgroups of patients examined, only in females (n = 86) mOS differed significantly between treatments (10.2mo (95% CI, 6.8-17.2) with P vs NR (95% CI, 11.4-NR) with PCT; p-0.02). In the real-world setting, no statistically significant differences in long-term outcomes with P vs PCT were observed; a prospective randomized trial addressing the comparative efficacy of P and PCT in different patient subgroups is highly anticipated.List of abbreviations: AE - adverse events; ALK - anaplastic lymphoma kinase gene; ALT - alanine aminotransferase; (a)NSCLC - (advanced) non-small cell lung cancer; AST - aspartate aminotransferase; BRAF - v-Raf murine sarcoma viral oncogene homolog B; BRCA2 - BReast CAncer gene 2; c-Met - tyrosine-protein kinase Met; CTCAE, v. 4.03 - Common Terminology Criteria for Adverse Events, version 4.03; CTLA-4 - cytotoxic T-lymphocyte-associated protein 4; ECOG PS - Eastern Cooperative Oncology Group performance status; EGFR - epidermal growth factor receptor gene; FISH - fluorescent in situ hybridization; HER2 - human epidermal growth factor receptor 2; IC - tumor-infiltrating immune cells; ICI - immune check-point inhibitors; IHC - immunohistochemistry; IQR - interquartile range; irAE - immune related adverse events; ISCORT - Israeli Society for Clinical Oncology and Radiotherapy; KRAS - Kirsten rat sarcoma viral oncogene homolog; (m)TTD -(median) time-to-treatment discontinuation; mo - months; (m)OS - (median) overall survival; (m)PFS - (median) progression-free survival; muts/Mb - mutations per megabase; NA - not specified/not available; NOS - not otherwise specified; NR - not reported/not reached; ORR - objective response rate; P - pembrolizumab; PCR - polymerase chain reaction; PCT - combination of pembrolizumab with platinum-based chemotherapy; PD - progression of disease; PD-1 - programmed cell death-1; PD-L1 - programmed cell death ligand-1; pts - patients; RET - proto-oncogene RET; ROS1 - proto-oncogene tyrosine-protein kinase ROS1; SD - standard deviation; STK11 - serine/threonine kinase 11; TC - tumor cells; TMB - Tumor mutation burden; TPS - tumor proportion score.