Antibiotic use reduces efficacy of tyrosine kinase inhibitors in patients with advanced melanoma and non-small-cell lung cancer.

BACKGROUND: Antibiotic (ABX) use can reduce the efficacy of immune checkpoint inhibitors and chemotherapeutics. The effect for patients treated with targeted therapies, namely, small-molecule tyrosine kinase inhibitors (TKIs), is less known. PATIENTS AND METHODS: Retrospective data were analysed for TKI-treated patients with advanced melanoma and non-small-cell lung cancer (NSCLC) between January 2015 and April 2017 at The Christie NHS Foundation Trust. Data on demographics, disease burden, lactate dehydrogenase (LDH) level, presence of brain metastases, ECOG performance status (PS) and ABX use were collected. Progression-free survival (PFS) and overall survival (OS) were compared between the ABX+ group (ABX within 2 weeks of TKI initiation-6 weeks after) and the ABX- group (no ABX during the same period). RESULTS: A total of 168 patients were included; 89 (53%) with NSCLC and 79 (47%) with melanoma. 55- (33%) patients received ABX. On univariable analysis, ABX+ patients demonstrated shorter PFS (208 versus 357 days; P = 0.008) and OS (294 versus 438 days; P = 0.024). Increased age, poorer PS and higher LDH were associated with shorter PFS and OS. On multivariable analysis, ABX use was independently associated with shorter PFS [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.05-2.34, P = 0.028] and OS (HR 2.19, 95% CI 1.44-3.32, P = 0.0002). The negative impact of ABX on OS was particularly pronounced for patients with PS of ≥2 (HR 3.82, 95% CI 1.18-12.36, P = 0.025). CONCLUSION: For patients treated with TKIs, ABX use is independently associated with reduced PFS and OS and judicious use is warranted, particularly in patients with poorer PS.

ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer.

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.

Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer.

BACKGROUND: The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating treatment response. Selumetinib inhibits MEK and enhances effects of radiotherapy in preclinical studies. PATIENTS AND METHODS: Single-arm, single-centre, open-label phase I trial. Patients with stage III NSCLC unsuitable for concurrent chemo-radiotherapy, or stage IV with dominant thoracic symptoms, were recruited to a dose-finding stage (Fibonacci 3 + 3 design; maximum number = 18) then an expanded cohort (n = 15). Oral selumetinib was administered twice daily (starting dose 50 mg) commencing 7 days prior to thoracic radiotherapy, then with radiotherapy (6-6.5 weeks; 60-66 Gy/30-33 fractions). The primary objective was to determine the recommended phase II dose (RP2D) of selumetinib in combination with thoracic radiotherapy. RESULTS: 21 patients were enrolled (06/2010-02/2015). Median age: 62y (range 50-73). M:F ratio 12(57%):9(43%). ECOG PS 0:1, 7(33%):14(67%). Stage III 16(76%); IV 5(24%). Median GTV 64 cm3 (range 1-224 cm3). 15 patients comprised the expanded cohort at starting dose. All 21 patients completed thoracic radiotherapy as planned and received induction chemotherapy. 13 (62%) patients received the full dose of selumetinib.In the starting cohort no enhanced radiotherapy-related toxicity was seen. Two patients had dose-limiting toxicity (1x grade 3 diarrhoea/fatigue and 1x pulmonary embolism). Commonest grade 3-4 adverse events: lymphopaenia (19/21 patients) and hypertension (7/21 patients). One patient developed grade 3 oesophagitis. No patients developed grade ≥3 radiation pneumonitis. Two patients were alive at the time of analysis (24 and 26 months follow-up, respectively). Main cause of first disease progression: distant metastases ± locoregional progression (12/21 [57.1%] patients). Six patients had confirmed/suspected pneumocystis jiroveci pneumonia. CONCLUSION: We report poor outcome and severe lymphopenia in most patients treated with thoracic radiotherapy and selumetinib at RP2D in combination, contributing to confirmed/clinically suspected pneumocystis jiroveci pneumonia. These results suggest that this combination should not be pursued in a phase II trial.ClinicalTrials.gov reference: NCT01146756.

A prospective cohort study on the safety of checkpoint inhibitors in older cancer patients - the ELDERS study.

OBJECTIVE: Older cancer patients are underrepresented in the pivotal trials of checkpoint inhibitors (CPIs). This study aimed to investigate the impact of an ageing immune system on CPI-related toxicity and provide evidence for the role of geriatric assessments with CPI. METHODS: The ELDERS study is a prospective observational study with two cohorts: older (70+ years of age) and younger (<70 years of age). Patients with advanced/metastatic non-small-cell lung cancer or melanoma starting single-agent CPI were eligible. The older cohort was assessed for frailty with Geriatric-8 (G8) screening, which when positive (<15 points) was followed by a holistic set of geriatric assessments. Primary endpoint was the incidence of grade 3-5 immune-related adverse events (irAEs). RESULTS: One hundred and forty patients were enrolled with 43% being pretreated and pembrolizumab represented 92% of treatments on study. The older cohort had a significantly higher comorbidity burden (P < 0.001) and polypharmacy (P = 0.004). While 50% of older patients had a positive G8 screening, 60% on this frail subgroup had a performance status score of 0 or 1. There was no significant difference in the incidence of irAEs grade 3-5 between older and younger cohorts (18.6% versus 12.9%; odds ratio 1.55, confidence interval 95% 0.61-3.89; P = 0.353). Exposure to systemic steroids due to irAEs was numerically longer for older patients (22 versus 8 weeks; P = 0.208). A positive G8 screening predicted hospital admissions (P = 0.031) and risk of death (P = 0.01). CONCLUSIONS: The use of CPI in older patients was not associated with more high-grade toxicity. The G8 screening identified a subgroup with higher risk of AEs and its implementation should be considered in the context of CPI.

Toxicity with small molecule and immunotherapy combinations in non-small cell lung cancer.

Treatment stratification in stage IV NSCLC is guided by identification of oncogene driver mutations. Actionable mutations with current licenced therapeutic agents include epidermal growth factor receptor (EGFR), rearrangements of anaplastic lymphoma kinase (ALK), ROS-1 and BRAF V600. Alongside progress with small molecule therapy, developments in immune checkpoint inhibitors (CPIs) have transformed the landscape of stage III and stage IV NSCLC. The success of CPIs has led to evaluation with small molecule therapy in both concurrent and sequential settings. In this review we summarise recent results of combination CPIs and tyrosine kinase inhibitors (TKIs) in stage IV NSCLC, detailing significant toxicity and its potential mechanisms with both concurrent and sequential approaches. As more therapeutic targets are being discovered it is becoming increasingly important for clinicians to correctly sequence therapy for delivery of safe and effective treatment. In addition to stage IV disease we suggest that comprehensive molecular profiling of key NSCLC drivers, particularly in stage III disease, will help to inform optimal treatment sequencing and minimise potential toxicity.

Choice of second-line systemic therapy in stage IV small cell lung cancer (SCLC) - A decision-making analysis amongst European lung cancer experts.

OBJECTIVES: Stage IV small cell lung cancer (SCLC) is associated with short survival and progression after first-line systemic therapy frequently occurs within months. Although topotecan is approved for second-line treatment, its efficacy is limited, and treatment heterogeneity exists. MATERIAL AND METHODS: The decision-making patterns for second line treatment of 13 European medical oncologists with expertise in SCLC were analyzed. RESULTS: The two criteria most relevant to decision-making were the performance status and the interval of recurrence since first-line treatment. With an interval of less than 3 months since the end of first-line chemotherapy, 62 % of the experts recommended cyclophosphamide, doxorubicin and vincristine (CAV) for fit patients and 54 % recommended topotecan for unfit patients. For an interval of more than 6 months, a clear consensus for a re-challenge with a platinum doublet was achieved (92 %). However, there was no consensus on the second-line therapy with an interval of 3-6 months since the end of first-line therapy. CONCLUSION: Real world practice may differ from recommendations in general guidelines and cannot always be directly derived from trial results as other factor such as habits, patient's preference, convenience or costs have to be factored in.

Treatment of brain metastases in small cell lung cancer: Decision-making amongst a multidisciplinary panel of European experts.

BACKGROUND: Brain metastases (BM) are common in patients with small cell lung cancer (SCLC). In recent years, the role of whole brain radiotherapy (WBRT) for brain metastases in lung cancer is being reevaluated, especially in the context of new systemic treatments available for SCLC. With this analysis, we investigate decision-making in SCLC patients with BM among European experts in medical oncology and radiation oncology. METHODS: We analyzed decision-making from 13 medical oncologists (selected by IASLC) and 13 radiation oncologists (selected by ESTRO) specialized in SCLC. Management strategies of individual experts were converted into decision trees and analyzed for consensus. RESULTS AND CONCLUSION: In asymptomatic patients, chemotherapy alone is the most commonly recommended first line treatment. In asymptomatic patients with limited volume of brain metastases, a higher preference for chemotherapy without WBRT among medical oncologists compared to radiation oncologists was observed. For symptomatic patients, WBRT followed by chemotherapy was recommended most commonly. For limited extent of BM in symptomatic patients, some experts chose stereotactic radiotherapy as an alternative to WBRT. Significant variation in clinical decision-making was observed among European SCLC experts for the first line treatment of patients with SCLC and BM.

Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts.

Somatic mutations in RAS and related pathway genes such as NF1 have been strongly implicated in the development of cancer while also being implicated in a diverse group of developmental disorders named the 'RASopathies', including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFC), and capillary malformation-arteriovenous syndrome (CM-AVM). It remains unclear why (i) there is little overlap in mutational subtype between Ras-driven malignancies associated with sporadic disease and those associated with the RASopathy syndromes, and (ii) RASopathy-associated cancers are usually of different histological origin to those seen with sporadic mutations of the same genes. For instance, germline variants in KRAS and NRAS are rarely found at codons 12, 13 or 61, the most common sites for somatic mutations in sporadic cancers. An exception is CS, where germline variants in codons 12 and 13 of HRAS occur relatively frequently. Given recent renewed drug interest following early clinical success of RAS G12C and farnesyl transferase inhibitors, an improved understanding of this relationship could help guide targeted therapies for both sporadic and germline cancers associated with the Ras pathway.

EPAC-lung: pooled analysis of circulating tumour cells in advanced non-small cell lung cancer.

INTRODUCTION: We assessed the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a pooled analysis of individual patient data. METHODS: Nine European NSCLC CTC centres were asked to provide reported/unreported pseudo-anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 to March 2017. We used Cox regression models, stratified by centres, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinicopathological models using likelihood ratio (LR) statistics and c-indices. RESULTS: Seven out of nine eligible centres provided data for 550 patients with prognostic information for overall survival. CTC counts of ≥2 and ≥ 5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: hazard ratio [HR] = 1.72, p < 0·001; ≥5 CTCs: HR = 2.21, p < 0·001) and overall survival (≥2 CTCs: HR = 2·18, p < 0·001; ≥5 CTCs: HR = 2·75, p < 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinicopathological models (log-transformed CTCs p < 0·001; ≥2 CTCs p < 0·001; ≥5 CTCs p ≤ 0·001 for both survival end-points), whereas moderate improvements were observed with the use of c-index models. There was some evidence of between-centre heterogeneity, especially when examining continuous counts of CTCs. CONCLUSIONS: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC and also reveal some evidence of between-centre heterogeneity. CTC count improves prognostication when added to full clinicopathological predictive models.

Prognostic value of circulating tumour cells in limited-stage small-cell lung cancer: analysis of the concurrent once-daily versus twice-daily radiotherapy (CONVERT) randomised controlled trial.

BACKGROUND: The clinical significance of circulating tumour cells (CTCs) in limited-stage small-cell lung cancer (LS-SCLC) is not well defined. We report a planned exploratory analysis of the prevalence and prognostic value of CTCs in LS-SCLC patients enrolled within the phase III randomised CONVERT (concurrent once-daily versus twice-daily chemoradiotherapy) trial. PATIENTS AND METHODS: Baseline blood samples were enumerated for CTCs using CellSearch in 75 patients with LS-SCLC who were enrolled in the CONVERT trial and randomised between twice- and once-daily concurrent chemoradiation. Standard statistical methods were used for correlations of CTCs with clinical factors. Log-rank test and Cox regression analyses were applied to establish the associations of 2, 15 and 50 CTC thresholds with progression-free survival (PFS) and overall survival (OS). An optimal CTC count threshold for LS-SCLC was established. RESULTS: CTCs were detected in 60% (45/75) of patients (range 0-3750). CTC count thresholds of 2, 15 and 50 CTCs all significantly correlate with PFS and OS. An optimal CTC count threshold in LS-SCLC was established at 15 CTCs, defining 'favourable' and 'unfavourable' prognostic risk groups. The median OS in <15 versus ≥15 CTCs was 26.7 versus 5.9 m (P = 0.001). The presence of ≥15 CTCs at baseline independently predicted ≤1 year survival in 70% and ≤2 years survival in 100% of patients. CONCLUSION: We report the prognostic value of baseline CTC count in an exclusive LS-SCLC population at thresholds of 2, 15 and 50 CTCs. Specific to LS-SCLC, ≥15 CTCs was associated with worse PFS and OS independent of all other factors and predicted ≤2 years survival. These results may improve disease stratification in future clinical trial designs and aid clinical decision making. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00433563.

Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small-cell lung cancer.

Background: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes. Patients and methods: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. Results: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17). Conclusions: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.

KRAS: Reasons for optimism in lung cancer.

Despite being the most frequent gain-of-function genetic alteration in human cancer, KRAS mutation has to date offered only limited potential as a prognostic and predictive biomarker. Results from the phase III SELECT-1 trial in non-small cell lung cancer (NSCLC) recently added to a number of historical and more contemporary disappointments in targeting KRAS mutant disease, including farnesyl transferase inhibition and synthetic lethality partners such as STK33. This narrative review uses the context of these previous failures to demonstrate how the knowledge gained from these experiences can be used as a platform for exciting advances in NSCLC on the horizon. It now seems clear that mutational subtype (most commonly G12C) of individual mutations is of greater relevance than the categorical evaluation of KRAS mutation presence or otherwise. A number of direct small molecules targeted to these subtypes are in development and have shown promising biological activity, with some in the late stages of preclinical validation.

Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms.

Despite the unheralded success of immune checkpoint blockade in delivering durable responses for some patients with non-small-cell lung cancer (NSCLC), the majority of patients do not respond. PD-L1 tumour expression and pre-existing tumour T-cell infiltration have been correlated with improved clinical outcomes to anti-PD-1/anti-PD-L1. However, patients with tumours that are negative for PD-L1 expression can also respond to treatment. Strategies to combine other treatment modalities like radiotherapy (RT) with immune checkpoint inhibitors are being investigated as means of improving the response rates to PD-1/PD-L1 antibody blockade. RT induces immunogenic changes in cancer cells, can adaptively upregulate tumour cell PD-L1 expression and can improve the efficacy of anti-PD-1/anti-PD-L1 therapy. How we design future clinical trials in NSCLC also depends on practical considerations of delivering these treatment combinations, such as RT dose, fractionation and field volume, as well as scheduling with immune checkpoint blockade. Here, we review reasons for resistance to anti-PD-1/anti-PD-L1 and how RT may be utilised in combination with these drugs to enhance their effect by building better translational research platforms.

Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Crizotinib: from discovery to accelerated development to front-line treatment.

Non-small-cell lung cancer (NSCLC) is associated with a poor prognosis and low survival rates, providing a strong rationale for the development of new treatment options. The discovery of ALK gene rearrangements in a subset of NSCLC specimens and the identification and development of the first-in-class ALK inhibitor crizotinib provided a personalised treatment option for patients with advanced ALK-positive NSCLC. Crizotinib demonstrated rapid and durable responses in advanced ALK-positive NSCLC patients in phase I and II studies, leading to accelerated FDA approval. Subsequent evaluation in phase III studies showed that crizotinib improved progression-free survival compared with platinum-based doublet chemotherapy in previously untreated patients and compared with pemetrexed or docetaxel in previously treated patients. Crizotinib was shown to have an acceptable safety profile and also to improve quality of life and symptom scores. Overall, crizotinib has been shown to provide a valuable first- and second-line treatment option and is now the first-line standard of care for patients with advanced ALK-positive NSCLC.

Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study.

BACKGROUND: Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, 'liquid biopsies' such as circulating tumour cells (CTCs) are minimally invasive and easier to obtain. Here, we present a clinical case study of a NSCLC patient with advanced metastatic disease, a never smoker whose primary tumour was EGFR and ALK wild-type. We demonstrate for the first time, tumorigenicity of their CTCs to generate a patient CTC-derived eXplant (CDX). PATIENTS AND METHODS: CTCs were enriched at diagnosis and again 2 months later during disease progression from 10 ml blood from a 48-year-old NSCLC patient and implanted into immunocompromised mice. Resultant tumours were morphologically, immunohistochemically, and genetically compared with the donor patient's diagnostic specimen. Mice were treated with cisplatin and pemetrexed to assess preclinical efficacy of the chemotherapy regimen given to the donor patient. RESULTS: The NSCLC CDX expressed lung lineage markers TTF1 and CK7 and was unresponsive to cisplatin and pemetrexed. Examination of blood samples matched to that used for CDX generation revealed absence of CTCs using the CellSearch EpCAM-dependent platform, whereas size-based CTC enrichment revealed abundant heterogeneous CTCs of which ∼80% were mesenchymal marker vimentin positive. Molecular analysis of the CDX, mesenchymal and epithelial CTCs revealed a common somatic mutation confirming tumour origin and showed CDX RNA and protein profiles consistent with the predominantly mesenchymal phenotype. CONCLUSIONS: This study shows that the absence of NSCLC CTCs detected by CellSearch (EpCAM(+)) does not preclude CDX generation, highlighting epithelial to mesenchymal transition and the functional importance of mesenchymal CTCs in dissemination of this disease.