Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer.

BACKGROUND: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone. METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety. RESULTS: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events. CONCLUSIONS: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.).

First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC.

BACKGROUND: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study. METHODS: In a randomized phase 3 trial, we evaluated the efficacy and safety of first-line selpercatinib as compared with control treatment that consisted of platinum-based chemotherapy with or without pembrolizumab at the investigator's discretion. The primary end point was progression-free survival assessed by blinded independent central review in both the intention-to-treat-pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were assigned to the control group) and the overall intention-to-treat population. Crossover from the control group to the selpercatinib group was allowed if disease progression as assessed by blinded independent central review occurred during receipt of control treatment. RESULTS: In total, 212 patients underwent randomization in the intention-to-treat-pembrolizumab population. At the time of the preplanned interim efficacy analysis, median progression-free survival was 24.8 months (95% confidence interval [CI], 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001). The percentage of patients with an objective response was 84% (95% CI, 76 to 90) with selpercatinib and 65% (95% CI, 54 to 75) with control treatment. The cause-specific hazard ratio for the time to progression affecting the central nervous system was 0.28 (95% CI, 0.12 to 0.68). Efficacy results in the overall intention-to-treat population (261 patients) were similar to those in the intention-to-treat-pembrolizumab population. The adverse events that occurred with selpercatinib and control treatment were consistent with those previously reported. CONCLUSIONS: Treatment with selpercatinib led to significantly longer progression-free survival than platinum-based chemotherapy with or without pembrolizumab among patients with advanced RET fusion-positive NSCLC. (Funded by Eli Lilly and others; ClinicalTrials.gov number, NCT04194944.).

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial.

BACKGROUND: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. METHODS: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. FINDINGS: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). INTERPRETATION: Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. FUNDING: Amgen.

CT-Guided Core-Needle Biopsy of Pulmonary Lesions Associated With Cystic Airspaces: A Case-Control Study.

Background: Concern may exist that pulmonary lesions associated with cystic airspaces are at risk of increased biopsy complications or lower biopsy accuracy given challenges in targeting tissue abutting or intermingled with the cystic airspaces. Objective: To evaluate the safety and diagnostic performance of CT-guided core-needle biopsy (CNB) of pulmonary lesions with cystic airspaces. Methods: This retrospective study included 90 patients (median age, 69.5 years; 28 female, 62 male) who underwent CT-guided CNB of pulmonary lesions associated with cystic airspaces (based on review of procedural images) from February 2010 to December 2022 and a matched control group (2:1 ratio) of 180 patients (median age, 68.0 years; 56 female, 124 male) who underwent CNB of noncystic noncavitary lesions during the same period. The groups were compared in terms of complications, nondiagnostic biopsies (i.e., nonspecific benignities, atypical cells, or insufficient specimens), and CNB diagnostic performance for detecting malignancy using as reference the final diagnosis from a joint review of all available records. For lesions associated with cystic airspaces that underwent surgical resection after CNB, histologic slides were re-reviewed to assess cystic airspace etiology. Results: The final diagnosis was malignant in 90% (81/90) of lesions associated with cystic airspaces and 92% (165/180) of noncystic noncavitary lesions. Patients with lesions associated with cystic airspaces and patients with noncystic noncavitary lesions showed no significant difference in frequencies of complication (all: 40% [36/90] vs 38% [68/180], p=.79; major: 4% [4/90] vs 6% [10/180], p=.78; minor: 36% [32/90] vs 32% [58/180], p=.59), frequency of nondiagnostic biopsies (12% [11/90] vs 9% [16/180], p=.40), or diagnostic performance (accuracy: 94.% [85/90] vs 97% [175/180], p=.50; sensitivity: 94% [76/81] vs 97% [160/165], p=.50; specificity: 100% [9/9] vs 100% [15/15]; p>.99), respectively. All false-negative results for malignancy in both groups occurred in patients with nondiagnostic CNB results. Among lesions associated with cystic airspaces that were resected after CNB (all malignant), the cystic airspaces most commonly represented tumor degeneration (22/31, 71%). Conclusion: CT-guided CNB is safe and accurate for assessing pulmonary lesions associated with cystic airspaces. Clinical Impact: CNB may help avoid a missed or delayed cancer diagnosis in pulmonary lesions with cystic airspaces.

HERTHENA-Lung02: phase III study of patritumab deruxtecan in advanced EGFR-mutated NSCLC after a third-generation EGFR TKI.

After disease progression on EGFR tyrosine kinase inhibitor (TKI) therapy, patients with EGFR-mutated NSCLC who are then treated with platinum-based chemotherapy (PBC) obtain only limited clinical benefit with transient responses. Therapies with greater efficacy and tolerable safety profiles are needed in this setting. The receptor tyrosine kinase HER3 is widely expressed in NSCLC, and increased expression is associated with poor treatment outcomes. In the U31402-A-U102 phase I trial, HER3-DXd showed promising antitumor activity with manageable safety in heavily pre-treated patients with EGFR-mutated NSCLC across a range of tumor HER3 expression levels and EGFR TKI resistance mechanisms. HERTHENA-Lung02 is the first phase III trial to evaluate the safety and efficacy of HER3-DXd versus PBC in patients with progression on a third-generation EGFR TKI. Clinical Trial Registration: NCT05338970 (clinicaltrials.gov); 2021-005879-40 (EudraCT Number).

In some patients with non-small-cell lung cancer, changes (or mutations) in the DNA sequence can alter a protein called EGFR and allow tumors to grow and survive. Drugs called EGFR tyrosine kinase inhibitors (EGFR TKIs for short) are used to treat these tumors by interfering with the abnormal EGFR protein. Treatment with these drugs can work well at first, but some tumors never respond, and for tumors that do respond, the cancer eventually becomes resistant to the EGFR TKI and the drug stops working. Platinum-based chemotherapy is often prescribed after an EGFR TKI stops working; however, platinum-based chemotherapy can provide only temporary control of the tumor growth. Most patients with non-small-cell lung cancer have a protein called HER3 on the surface of their tumor cells. A new drug candidate called patritumab deruxtecan (HER3-DXd) finds tumor cells and attaches to the HER3 protein on their surface. HER3-DXd then moves inside the cancer cells, where a novel antitumor payload is released and kills the tumor cells. This article describes the phase III clinical trial HERTHENA-Lung02 (NCT05338970) that compares the benefit of HER3-DXd to platinum-based chemotherapy for patients who have non-small-cell lung cancer with the abnormal EGFR protein and whose disease stopped responding or never responded to EGFR TKI therapy.

Real-world retrospective study of KRAS mutations in advanced non-small cell lung cancer in the era of immunotherapy.

BACKGROUND: KRAS mutation-positive (KRAS-positive), advanced nonsmall-cell lung cancer (NSCLC) is characterized by a poor prognosis. KRAS mutations are extremely heterogeneous from a biologic point of view, and real-world data by mutation subtype in the era of immunotherapy are still incomplete. METHODS: The objective of this study was to retrospectively analyze all consecutive patients with advanced/metastatic, KRAS-positive NSCLC who were diagnosed at a single academic institution since the advent of immunotherapy. The authors report on the natural history of the disease as well as the efficacy of first-line treatments in the entire cohort and by KRAS mutation subtypes as well as the presence/absence of co-mutations. RESULTS: From March 2016 to December 2021, the authors identified 199 consecutive patients who had KRAS-positive, advanced or metastatic NSCLC. The median overall survival (OS) was 10.7 months (95% confidence interval [CI], 8.5-12.9 months), and there were no differences by mutation subtype. Among 134 patients who received first-line treatment, the median OS was 12.2 months (95% CI, 8.3-16.1 months), and the median progression-free survival was 5.6 months (95% CI, 4.5-6.6 months). At multivariate analysis, only an Eastern Cooperative Oncology Group performance status of 2 was associated with significantly shorter progression-free survival and OS. CONCLUSIONS: KRAS-positive, advanced NSCLC is characterized by a poor prognosis despite the introduction of immunotherapy. Survival was not associated with KRAS mutation subtype. PLAIN LANGUAGE SUMMARY: This study evaluated the efficacy of systemic therapies for advanced/metastatic nonsmall cell lung cancer harboring KRAS mutations, along with the potential predictive and prognostic role of mutation subtypes. The authors found that advanced/metastatic, KRAS-positive nonsmall cell lung cancer is characterized by a poor prognosis and that first-line treatment efficacy is not related to different KRAS mutations, although a numerically shorter median progression-free survival was observed in patients who had p.G12D and p.G12A mutations. These results underline the need for novel treatment options in this population, such as next-generation KRAS inhibitors, which are in clinical and preclinical development.

RET Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape.

The objective of this narrative review is to summarize the efficacy and safety of available therapies for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases. Background information is provided on RET rearrangements in NSCLC and the molecular testing options available as well as an overview of clinical guidelines for molecular testing, which recommend broad molecular testing, including for RET rearrangements. The efficacy and safety of potential treatments for RET fusion-positive NSCLC, including multikinase inhibitors, RET-selective inhibitors, pemetrexed-based therapy, and immunotherapies are reviewed from Phase I/II and `real-world' studies, alongside an overview of primary and secondary resistance mechanisms. The RET-selective inhibitors, selpercatinib and pralsetinib, are preferred first-line therapy options for patients with RET fusion-positive metastatic NSCLC and are recommended as subsequent therapy if RET inhibitors have not been used in the first-line setting.

Targeted Therapies in Small Cell Lung Cancer: From Old Failures to Novel Therapeutic Strategies.

The clinical management of small cell lung cancer (SCLC) treatment remains a major challenge for thoracic oncologists, with very few therapeutic advances significantly impacting patients' survival. The recent introduction of immunotherapy in the clinical setting produced a marginal benefit for a limited subset of metastatic patients, while the therapeutic scenario for relapsing extended-disease small cell lung cancers (ED-SCLCs) remains almost deserted. Recent efforts clarified the molecular features of this disease, leading to the identification of key signalling pathways which may serve as potential targets for clinical use. Despite the large number of molecules tested and the numerous therapeutic failures, some targeted therapies have recently shown interesting preliminary results. In this review, we describe the main molecular pathways involved in SCLC development/progression and provide an updated summary of the targeted therapies currently under investigation in SCLC patients.

Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial.

BACKGROUND: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. METHODS: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed. FINDINGS: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia). INTERPRETATION: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma. FUNDING: Bayer Healthcare Pharmaceuticals.

Multicentre, randomised, open-label, parallel-group, clinical phase II study to evaluate immunonutrition in improving efficacy of immunotherapy in patients with metastatic non-small cell lung cancer, undergoing systematic nutritional counseling.

BACKGROUND: Nutritional support, including nutritional counseling and oral nutritional supplements (ONS), has been recommended as a first-line strategy in patients with non-small cell lung cancer (NSCLC). Evidence on the efficacy of immunonutrition during immunotherapy in these patients is positive, but still limited some secondary endpoints, such as treatment toxicity and tolerance. We hypothesize that early systematic provision of ONS with a high-protein-high calorie mixture containing immunonutrients (Impact®) in addition to nutritional counseling, compared to nutritional counseling alone, is beneficial to patients with NSCLC receiving immunotherapy with or without chemotherapy. We designed the present study to evaluate the efficacy of early systematic provision of ONS enriched with immunonutrients compared to nutritional counseling alone, in patients with NSCLC undergoing immunotherapy. Study endpoints were: treatment response (primary endpoint: progression-free survival), treatment tolerance and toxicity, body weight, body composition, protein-calorie intake, quality of life, fatigue, muscle strength and immunological profile. METHODS: This is a pragmatic, multicentre, randomized (1:1), parallel-group, open label, controlled, pilot clinical trial (N = 180). DISCUSSION: The improvement of efficacy of nutritional support in oncology still deserves many efforts. Immunonutrition represents a promising approach also in patients with NSCLC, but evidence on its efficacy on clinical outcomes during immunotherapy is still inconclusive. The present pilot study, which guarantees early high-quality nutritional care (assessment and treatment) to all patients in agreement with current guidelines and recommendations, could represent one of the first proofs of efficacy of early oral immunonutrition in patients with cancer undergoing immunotherapy. Further large randomized trials addressing the improvement of supportive care could be hypothesized, accordingly. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov Identifier: NCT05384873.

Targeting KRASp.G12C Mutation in Advanced Non-Small Cell Lung Cancer: a New Era Has Begun.

OPINION STATEMENT: KRASp.G12C mutation occurs in 12% of newly diagnosed advanced NSCLC and has recently emerged as a positive predictive biomarker for the selection of advanced NSCLC patients who may respond to novel KRASp.G12C inhibitors. The recent discovery of a new binding pocket under the effector region of KRAS G12C oncoprotein has made direct pharmacological inhibition of the KRASp.G12 mutation possible, leading to the clinical development of a new series of direct selective inhibitors, with a potential major impact on patients' survival and quality of life. Promising efficacy and tolerability data emerging from the early phase CodeBreak trial have already supported the regulatory approval of sotorasib as first in class targeted treatment for the second-line treatment of KRASp.G12C-positive NSCLC population, following immunotherapy-based first-line therapies, while the randomized phase III CodeBreak 200 clinical study has recently confirmed a significant superiority of sotorasib over docetaxel in terms of progression-free survival and quality of life. However, KRAS mutant NSCLC is a high heterogeneous disease characterized by a high rate of co-mutations, most frequently involving P53, STK11, and KEAP1 genes, which significantly modulate the composition of the tumor microenvironment and consequently affect clinical responses to both immunotherapy and targeted inhibitors now available in clinical practice. Both pre-clinical and clinical translational series have recently revealed a wide spectrum of resistance mechanisms occurring under selective KRASG12C inhibitors, including both on-target and off-target molecular alterations as well as morphological switching, negatively affecting the antitumor activity of these drugs when used as single agent therapies. The understanding of such biological background along with the emergence of pre-clinical data provided a strong rational to investigate different combination strategies, including the inhibition of SHP2, SOS1, and KRAS G12C downstream effectors, as well as the addition of immunotherapy and/or chemotherapy to targeted therapy. The preliminary results of these trials have recently suggested a promising activity of SHP2 inhibitors in the front-line setting, while toxicity issues limited the concurrent administration of immune-checkpoint inhibitors and sotorasib. The identification of predictive genomic/immunological biomarkers will be crucial to understand how to optimally sequencing/combining different drugs and ultimately personalize treatment strategies under clinical investigation, to definitively increase the survival outcomes of KRASp.G12C mutant advanced NSCLC patients.

Single agent VS-6766 or VS-6766 plus defactinib in KRAS-mutant non-small-cell lung cancer: the RAMP-202 phase II trial.

KRAS mutations occur in approximately 30% of lung adenocarcinomas, mainly in codon 12 (83% of cases), p.G12C being the prevalent one (40%), followed by p.G12V and p.G12D (22 and 16%, respectively). Treatment options for advanced KRAS mutant non-small-cell lung cancer (KRAS-MT NSCLC) are limited to chemotherapy and immune checkpoint inhibitors (CPIs). However, clinical trials exploring specific targeted agents are expected to change the treatment landscape of this disease. Here, we describe the design and scientific rationale of the randomized, phase II, open label, RAMP-202 study, which will evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib in advanced KRAS-MT NSCLC patients after failure of prior platinum-based chemotherapy and CPI.

The alteration of KRAS gene occurs in approximately 30% of lung cancers. According to international guidelines, treatment options for patients with advanced KRAS mutant lung cancer are now limited to chemotherapy and immunotherapy. However, clinical trials are exploring how specific targeted agents are expected to change the treatment landscape of this disease. Here, we describe the design and scientific rationale of the RAMP-202 study, which will evaluate the efficacy and safety of two new biological agents for patients with KRAS mutant lung cancer. The enrolled patients were those who had failure of prior platinum-based chemotherapy and immunotherapy. Clinical Trial Registration: NCT04620330 (ClinicalTrials.gov).

Immunohistochemistry with 3 different clones in anaplastic lymphoma kinase fluorescence in situ hybridization positive non-small-cell lung cancer with thymidylate synthase expression analysis: a multicentre, retrospective, Italian study.

Introduction: ALK rearrangement is the only druggable oncogenic driver detectable by immunohistochemistry (IHC) not requiring further confirmation of positivity in accessing first-line specific inhibitors. ALK-positive patients experience clinical benefit from pemetrexed-based chemotherapy possibly due to lower thymidylate synthase (TS) levels. This study assesses agreement with three different ALK IHC clones in 37 FISH-positive NSCLC. TS expression by real time (RT)-PCR was compared with ALK FISH-negative cases. Materials and methods: 37 ALK FISH-positive NSCLC cases diagnosed between 2010 and 2015 in 7 Italian centres were investigated with ICH using three different anti-ALK antibodies (ALK1, 5A4 and D5F3). Staining for ALK1 and 5A4 was graded as 0+,1+,2+, and 3+, while the scoring for D5F3 was recorded as negative or positive. Proportion agreement analysis was done using Cohen's unweighted kappa (k). TS and ß-actin expression levels were analysed by quantitative RT-PCR. Comparison between TS expression in ALK FISH-positive specimens and a control cohort of ALK FISH-negative ones was performed with the Mann-Whitney and Kruskal-Wallis tests. Results: Considering 2+ and 3+ as positive, the proportion of IHC agreement was 0.1691 (95% CI 0-0.4595) for ALK1/5A4, 0.1691 (95% CI 0-0.4595) for ALK1/D5F3, and 1 for D5F3/5A4. Considering 3+ as positive, it was 0.1543 (95% CI 0-0.4665) for ALK1/ 5A4, 0.0212 (95% CI 0-0.1736) for ALK1/D5F3, and 0.2269 (95% CI 0-0.5462) for 5A4/D5F3. Median TS expression was 6.07 (1.28-14.94) and ALK-positive cases had a significant lower TS expression than ALK-negative tumours (p = 0.002). Conclusions: IHC proved to be a reliable tool for the diagnosis of ALK-rearranged NSCLC. D5F3 and 5A4 clones have the highest percentage of agreement. TS levels are significantly lower in FISH-positive patients.

Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.

BACKGROUND: Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. METHODS: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival. RESULTS: After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%). CONCLUSIONS: In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).

Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.

BACKGROUND: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).

Upfront Management of ALK-Rearranged Metastatic Non-small Cell Lung Cancer: One Inhibitor Fits All?

PURPOSE OF REVIEW: Anaplastic lymphoma kinase (ALK) rearrangements represent a seldom event in non-small cell lung cancer (NSCLC). Given the oncogene alteration, ALK targeting represents the main therapeutic strategy. Here, we review evidence regarding ALK inhibitors (ALKi): clinical activity, safety profiles, financial costs, and biomarkers of efficacy. RECENT FINDINGS: During the past 10 years, multiple ALKi have been developed, and four different compounds are currently available as upfront options for ALK+ NSCLC patients: crizotinib, ceritinib, alectinib, and brigatinib. Second-generation (2G) ALKi demonstrated superior clinical activity in terms of median progression-free survival (mPFS), objective response rate (ORR), intracranial disease control, and duration of response (DOR) when compared with crizotinib. 2G ALKi represent the current gold-standard first-line treatment for ALK-rearranged metastatic NSCLC. Among all available options, in our opinion, alectinib has likely the best profile of clinical activity and safety, thus emerging as the best upfront therapy. More insights will come from ongoing trials and analysis of biomarkers.

Phase III study of selpercatinib versus chemotherapy ± pembrolizumab in untreated RET positive non-small-cell lung cancer.

Selpercatinib, a novel, highly selective and potent, inhibitor of RET, demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive RET fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic RET fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review. Key secondary end points include overall survival, response rate, duration of response and progression-free survival. Clinical trial registration: NCT04194944 (ClinicalTrials.gov).

Wnt/IL-1ß/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.

Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM-initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness-related pathways determine chemoresistance. Moreover, there are no predictive markers of IC-associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness-related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo-sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5-knocked-out (KO) IC clones were resensitized to the drugs in vitro and in patient-derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3ß/ß-catenin/c-myc axis that also increased IL-8 and IL-1ß production. IL-8 and IL-1ß-KO IC clones reduced the c-myc-driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5-KO clones had lower IL-8 and IL-1ß secretion, and c-myc transcriptional activity, suggesting that either Wnt/GSK3ß/ß-catenin and IL-8/IL-1ß signaling drive c-myc-mediated transcription of ABCB5. ABCB5 correlated with lower time-to-progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first-line chemotherapy in MPM patients.

An examination of two dichotomies: Women with lung cancer and living with lung cancer as a chronic disease.

Lung cancer remains the leading cause of cancer death globally, yet with many recent advances in the diagnosis and treatment of lung cancer, the face of the disease is shifting. Historically, lung cancer is often thought of as a predominantly male disease with more than twice as many men as women being diagnosed worldwide-mostly due to the influence of smoking as the leading risk factor. However, lung cancer is also the second leading cause of cancer death in women and there is a growing population of young women who have never smoked and are being diagnosed. The past decade has seen groundbreaking innovations in both the early detection and treatment of lung cancer. In this new era, survival rates are beginning to increase and many of those diagnosed are finding themselves in a new situation-living long term with a deadly cancer. Here, we review pertinent aspects of women and lung cancer as well as the concept of living with lung cancer as a chronic disease to give a new perspective on the changing face of lung cancer treatment and care.

Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. METHODS: This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up. FINDINGS: Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group. INTERPRETATION: Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC. FUNDING: Eli Lilly.