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Background: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. Methods: For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at-80°C. Results: In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs. Conclusion: Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation. [ABSTRACT FROM AUTHOR]

Abstract: Non-small-cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases, with a world-wide annual incidence of around 1.3 million. Surgery remains the corner stone of treatment in early-stage NSCLC when feasible, and the addition of adjuvant cisplatin-based chemotherapy has improved these results in resected NSCLC patients. For those patients with non-metastatic NSCLC not suitable for complete surgical resection, chemotherapy plus radiotherapy remains the best treatment option. For patients with metastatic NSCLC, molecular targeted agents have become part of the therapeutic arsenal in recent years. However, to date no targeted agent has been approved for patients with early or locally-advanced stages of NSCLC. Here, we review the rationale, literature and studies addressing the role of targeted agents used in the adjuvant setting or as part of chemoradiotherapy regimens. [Copyright &y& Elsevier]

Background: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC.Methods: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting.Findings: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo.Interpretation: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression.Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co. [ABSTRACT FROM AUTHOR]

• Immune- plus chemo-radiotherapy as promising strategy in curative setting of NSCLC. • Concurrent PD-1/L1-inhibition and radiotherapy not yet assessed in clinical trials. • Safety results of prospective trial of concurrent nivolumab and chemo-radiotherapy. • No unexpected adverse events or increased risk for severe pneumonitis observed. Chemo-radiotherapy (CRT) and concurrent PD-1 inhibition has shown promising results in pre-clinical models. So far, the feasibility of delivering concurrent CRT and PD-1/PD-L1 inhibition has never been assessed in a clinical trial. NICOLAS is a phase-II trial evaluating the safety and efficacy of nivolumab combined with CRT in stage III NSCLC. Patients received 3 cycles of platinum-based chemotherapy and concurrent RT (66 Gy/33fractions). Nivolumab started concurrently with RT. The primary endpoint was 6-month post-RT rate of grade-≥3-pneumonitis. A formal interim safety analysis (IA) was scheduled when the first 21 patients reached 3 months follow-up post-RT. An early positive safety conclusion would be reached at IA if there were no grade ≥3-pneumonitis in those patients. Efficacy evaluation was planned provided the safety conclusion was reached. As of 13 December 2018, 82 patients were recruited with median follow-up of 13.4 months. The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed. For the first 21 patients, no grade-≥3-pneumonitis was observed by the end of the 3-month post-RT follow-up period. The early safety IA provides evidence that the addition of nivolumab to concurrent CRT is safe and tolerable regarding the 6-month rate of pneumonitis grade ≥3 at the one-sided significance level of 5%. Following that, the 1-year progression-free survival will be evaluated in an expanded patient cohort. NICOLAS trial creates the opportunity for assessing the activity of the combination of checkpoint with concurrent CRT in larger prospective trials for locally advanced NSCLC. [ABSTRACT FROM AUTHOR]

Primary analysis (database cutoff, Oct 28, 2020) of the global KEYNOTE-799 study (NCT03631784) in patients (pts) with unresectable, locally advanced stage III NSCLC, showed that pembrolizumab (pembro; anti–PD-1) + cCRT resulted in an ORR of 70.5% in cohort A (n = 112; squamous and nonsquamous) and 70.6% in cohort B (n = 102; nonsquamous only) and grade ≥3 pneumonitis in 9 (8.0%) and 7 (6.9%) pts, respectively. We evaluated outcomes with 1 y of additional follow-up. In this nonrandomized, phase 2 study, eligible pts were aged ≥18 y with previously untreated, unresectable, pathologically confirmed, stage IIIA-C NSCLC with measurable disease per RECIST v1.1. Pts in cohort A (squamous and nonsquamous) received carboplatin AUC 6 + paclitaxel 200 mg/m2 and pembro 200 mg for one 3-wk cycle, followed by carboplatin AUC 2 + paclitaxel 45 mg/m2 QW for 6 wks + 2 cycles of pembro 200 mg Q3W + standard thoracic radiotherapy (TRT). Pts in cohort B (nonsquamous) received 3 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and pembro 200 mg Q3W + standard TRT in cycles 2 and 3. All pts received 14 additional cycles of pembro 200 mg Q3W. Primary endpoints were ORR per RECIST v1.1 by blinded independent central review and the incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0). Of 216 pts enrolled, 112 in cohort A and 102 in cohort B received treatment. Median (range) time from first dose to database cutoff (Oct 18, 2021) was 30.2 (25.3–35.5) mo in cohort A and 25.4 (14.5–35.2) mo in cohort B. ORR (95% CI) was 71.4% (62.1%–79.6%) and 75.5% (66.0%–83.5%), respectively. Median duration of response (DOR) and OS were not reached (NR) in both cohorts; median PFS was 30.6 mo in cohort A, and NR in cohort B (Table). ORR was 66.7% in pts with PD-L1 TPS <1% and 77.3% in pts with PD-L1 TPS ≥1% in cohort A and 78.6% and 72.5%, respectively, in cohort B. ORR was similar by histology (squamous, 72.0%; nonsquamous, 74.1%). Grade ≥3 pneumonitis occurred in 16 pts (7.5%) overall; 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Treatment-related grade ≥3 AEs occurred in 64.3% and 51.0% of pts in cohort A and B, respectively. Data on TRT, including techniques utilized and details for organs at risk with and without pneumonitis, will be presented. With >2 y of follow-up, pembro + cCRT continues to demonstrate robust and durable responses, regardless of PD-L1 TPS and tumor histology, promising survival outcome and manageable safety in pts with previously untreated, locally advanced stage III NSCLC. [ABSTRACT FROM AUTHOR]

Background Malignant pleural mesothelioma (MPM) frequently express elevated AKT/mTOR activity. Previous reports in gliomas, colon, breast and prostate cancer suggest that PTEN/PI3 K pathway may be important for the induction of PD-L1 expression. This study explored the expression of PTEN/PI3 K pathway and PD-L1 in MPM and its relationship with the patient́s prognosis Material and methods Twenty seven consecutive MPM patients were reviewed. Formalin-fixed, paraffin-embedded tissue biopsies were used for immunohistochemical analysis of PTEN/PI3 K pathway and PD-L1 Results Expression of PTEN, mTOR, pAKT, p4EBP1, peif4E, pS6 and FOXO3a was found in 88.5%, 92.3%, 78.3%, 38.5%, 100%, 52.2% and 100% of tumors and PD-L1 in 23%. We found a significant correlation between pAKT, FOXO3a and PD-L1 expression and longer overall survival (p < 0.05). We did not identify significant association between the level of PD-L1 expression and alterations in PI3 K pathway Conclusions This study shows PTEN/PI3 K pathway and PD-L1 in MPM are frequently activated. Our results suggests that there is not association between PD-L1 and the involvement of the PI3 K pathway in MPM. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): KEYNOTE-799 (NCT03631784), a phase 2 study of the anti‒PD-1 antibody pembrolizumab (pembro) plus concurrent chemoradiation therapy (cCRT) in patients (pts) with unresectable, locally advanced stage III NSCLC, completed accrual and follow up is ongoing. Results in a subset of pts from this study showed an ORR of 69.6% in cohort A (squamous [sq]/nonsquamous [nonsq], n = 112) and 70.5% in cohort B (nonsq, n = 61), and grade ≥3 pneumonitis in 8.0% and 7.9% of pts, respectively. We assessed safety and efficacy of pembro + cCRT in all pts from KEYNOTE-799.Materials/methods: This nonrandomized, multisite, open-label trial enrolled pts aged ≥18 y with previously untreated, unresectable, pathologically confirmed, stage IIIA‒C NSCLC with measurable disease per RECIST v1.1. Pts in cohort A (sq and nonsq) received 1 cycle of carboplatin AUC 6 and paclitaxel 200 mg/m2 and pembro 200 mg. After 3 weeks, pts received carboplatin AUC 2 and paclitaxel 45 mg/m2 QW for 6 weeks and 2 cycles of pembro 200 mg Q3W + standard thoracic radiotherapy (TRT; using a standardized 3D conformal radiotherapy technique on a linear accelerator operating at ≥6 MV beam energy for a total target dose of 60 Gy in 30 daily fractions of 2 Gy). Pts in cohort B (nonsq) received 3 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and pembro 200 mg Q3W, and TRT in cycles 2 and 3. All pts received up to 14 additional cycles of pembro 200 mg Q3W. Primary endpoints were ORR per RECIST v1.1 by BICR and incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0); assessed in all pts as-treated.Results: Of 216 pts enrolled (cohort A, n = 112; cohort B, n = 104), 112 in cohort A and 102 in cohort B were treated. As of October 28, 2020, the median (range) time from first dose to database cutoff was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. ORR (95% CI) was 70.5% (61.2%‒78.8%) and 70.6% (60.7%‒79.2%), respectively. Median DOR, OS, and PFS were not reached in either cohort. Twelve-month OS and PFS rates were 81.3% and 67.1% in cohort A; and 87.0% and 71.6% in cohort B. Grade ≥3 pneumonitis occurred in 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Median (range) time to onset of any pneumonitis was 4.3 (1.4-10.4) months in cohort A, and 4.4 (0.1-12.3) months in cohort B. Grade 3-5 treatment-related AEs occurring in ≥10% pts were neutropenia (cohort A, 16.1%; cohort B, 9.8%) and anemia (10.7% and 4.9%). See Table for additional safety data.Conclusion: Pembro + cCRT continues to demonstrate promising antitumor activity, and manageable toxicity in pts with previously untreated, locally advanced, stage III NSCLC with longer follow-up. [ABSTRACT FROM AUTHOR]