A phase II study of metformin plus pemetrexed and carboplatin in patients with non-squamous non-small cell lung cancer (METALUNG).

Immune checkpoint inhibitors (ICIs) ± chemotherapy is the standard treatment for driver mutation-negative non-small cell lung cancer (NSCLC). However, accessibility to ICIs in LMICs is limited due to high cost, and platinum-based chemotherapy remains the mainstay of treatment. Metformin has anticancer properties, and studies suggest synergism between metformin and pemetrexed. Based on preclinical evidence, this combination may be more beneficial for STK11-mutated NSCLC, a subgroup, inherently resistant to ICIs. In this Simon two-stage, single-arm phase 2 trial, we investigated metformin with pemetrexed-carboplatin (PC) in patients with treatment-naive stage IV non-squamous NSCLC. The primary outcome was 6-month progression-free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK11 mutation, and effect of STK11 mutation on 6-month PFS rate. The study was terminated for futility after interim analysis. The median follow-up was 34.1 months. The 6-month PFS rate was 28% (95% CI 12.4-0.46). The median PFS and OS were 4.5 (95% CI 2.2-6.1) and 7.4 months (95% CI 5.3-15.3), respectively. The ORR was 72%. Gastrointestinal toxicities were the most common. No grade 4/5 toxicities were reported. Targeted sequencing was possible in nine cases. Two patients had STK11 mutation and a poor outcome (PFS < 12 weeks). We could not demonstrate the benefit of metformin with CP in terms of improvement in 6-month PFS rate; however, the combination was safe (CTRI/2019/02/017815).

Dose-dense Paclitaxel and Carboplatin as Neoadjuvant Chemotherapy for Stage IIB/IIIA Non-small Cell Lung Cancer - A Phase II trial.

AIMS: The approach to potentially resectable non-small cell lung cancer (NSCLC) remains controversial. There is a benefit of neoadjuvant chemotherapy (NACT), but the ideal regimen is unknown. We evaluated the efficacy and safety of dose-dense NACT in potentially resectable NSCLC in this phase II trial. MATERIALS AND METHODS: Paclitaxel at 80 mg/m2 on days 1, 8 and 15 with AUC-6 carboplatin on day 1, 3 weekly for four cycles was evaluated as NACT. Patients with Eastern Cooperative Oncology Group performance status 0-2, stage IIB and IIIA (with only non-bulky N2 nodes) were included. The primary end point was the objective response rate. Secondary end points included toxicity, progression-free survival, recurrence-free survival, complete resection rate and overall survival. The relative dose intensity (RDI) was calculated to define tolerability (CTRI/2016/05/006916). RESULTS: In total, 37 patients were enrolled (median age 55 years). Most (78.8%) were smokers. Most patients had adenocarcinoma (57.6%) and stage IIIA disease (81.0%) according to the seventh American Joint Committee on Cancer staging system. Seventy-eight per cent of patients completed four cycles. The objective response rate was 75.6% with a complete response in 10.8%. The mean RDI of paclitaxel was 88.61%, with 68.0% of patients able to maintain an RDI ≥85.0%. In total, 187 toxicity events were recorded (120 grade 1, 64 grade 2 and three grade 3 events). Common toxicities were peripheral neuropathy (20.3%), myalgia (19.8%), nausea (15.7%) and neutropenia (10.2%). There were no treatment-related deaths. Seventeen patients underwent surgery (lobectomy 82.4%). After a median follow-up of 47 months (95% confidence interval 27-50.7 months), the median progression-free survival was 9.6 months (7.4-17.4) and overall survival was 29.2 months (16.0-37.2). CONCLUSION: Dose-dense paclitaxel-carboplatin is feasible, safe and efficacious and should be evaluated further in potentially resectable NSCLC.

Anaplastic lymphoma kinase immunohistochemistry in lung adenocarcinomas: Evaluation of performance of standard manual method using D5F3 antibody.

OBJECTIVE: Immunohistochemistry (IHC) with anaplastic lymphoma kinase (ALK) antibodies is considered as an economical screening method in lung adenocarcinomas. Automated Ventana D5F3-IHC is approved by US Food and Drug Administration for targeted therapy; however, the automated IHC apparatus are not widely used in most laboratories. We evaluated the performance of ALK IHC using the manual semiquantitative method to assess the concordance with Ventana ALK IHC assay. MATERIALS AND METHODS: We tested 156 cases of primary lung adenocarcinomas for ALK protein expression by D5F3-IHC. The intensity of cytoplasmic staining was classified as 0 or 1+/2+/3+ (weak/medium/strong). Binary score of positive and negative was used for Ventana assay. A comparison analysis and clinicopathological features were recorded. RESULTS: ALK IHC was positive in 25 (16.02%) cases, of which 18 were men and mostly nonsmokers. The mean age for all patients was 55 years, and for ALK IHC-positive cases was 48 years. Nine of 25 (36%) ALK IHC-positive cases showed signet ring cell and mucinous morphology. On comparison, all, but one, cases positive by manual method showed positive results by automated assay. IHC negative cases by manual method were negative by Ventana assay. CONCLUSION: Manual IHC is equally effective in the detection of ALK-rearranged cases as automated methods. It can be easily integrated as a screening method into routine practice thus reducing the cost of automated systems. However, equivocal cases should be tested by approved methods.