Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION.

BACKGROUND: Tepotinib, a MET inhibitor approved for the treatment of MET exon 14 (METex14) skipping NSCLC, demonstrated durable clinical activity in VISION (Cohort A + C; N = 313): objective response rate (ORR) 51.4% (95% CI: 45.8, 57.1); median duration of response (mDOR) 18.0 months (95% CI: 12.4, 46.4). We report outcomes in Asian patients from VISION (Cohort A + C) (cut-off: November 20, 2022). METHODS: Patients with advanced METex14 skipping NSCLC, detected by liquid or tissue biopsy, received tepotinib 500 mg (450 mg active moiety) once daily. PRIMARY ENDPOINT: objective response (RECIST 1.1) by independent review. Secondary endpoints included: DOR, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: Across treatment lines in 106 Asian patients (39.6% female, 43.4% smoking history, 79.2% adenocarcinoma, 47.2% treatment-naive), ORR was 56.6% (95% CI: 46.6, 66.2), mDOR 18.5 months (10.4, ne), mPFS 13.8 months (10.8, 22.0), and mOS 25.5 months (19.3, 36.4). Consistent efficacy observed, regardless of baseline characteristics. HRQoL remained stable during treatment. Treatment-related adverse events (TRAEs) occurred in 95.3% of patients (39.6% Grade ≥3). Most common TRAEs: peripheral edema (62.3%), creatinine increase (38.7%). CONCLUSIONS: Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian patients with METex14 skipping NSCLC. CLINICAL TRIAL REGISTRATION: NCT02864992.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Clinicopathological features and resistance mechanisms in HIP1-ALK-rearranged lung cancer: A multicenter study.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.

Camrelizumab in different PD-L1 expression cohorts of pre-treated advanced or metastatic non-small cell lung cancer: a phase II study.

BACKGROUND: This phase II study evaluated camrelizumab in different PD-L1 expression cohorts of patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC; NCT03085069, registered March 21, 2017). METHODS: Patients who progressed during/after chemotherapy were enrolled and divided into four cohorts based on PD-L1 tumor proportion score (TPS). Patients with EGFR/ALK alterations and PD-L1 TPS ≥ 50% were also eligible. All enrolled patients received camrelizumab at 200 mg IV Q2W. The primary endpoint was objective response rate. RESULTS: A total of 146 patients were enrolled. As of data cutoff on Aug 20, 2020, the median follow-up was 29.5 months (95% CI 27.4-30.8). Objective response rate was 17.8% (95% CI 12.0-25.0) and improved with the increasing PD-L1 TPS (TPS < 1%, 12.2% [95% CI 5.7-21.8]; ≥ 1-< 25%, 19.4% [95% CI 7.5-37.5]; ≥ 25-< 50%, 36.4% [95% CI 10.9-69.2]; ≥ 50%, 23.3% [95% CI 9.9-42.3]). No response was observed in the five patients harboring EGFR mutations. Median progression-free survival was 3.2 months (95% CI 2.0-3.4), and patients with positive PD-L1 TPS had longer progression-free survival. Median overall survival was 14.8 months (95% CI 10.2-18.7). Treatment-related adverse events (TRAEs) of any grade occurred in 87.7% of patients, and 21.2% had grade ≥ 3 TRAEs. CONCLUSION: Camrelizumab showed improved efficacy compared with historical data of the second-line chemotherapy in pre-treated advanced/metastatic NSCLC. Patients with positive PD-L1 expression derived greater benefit from camrelizumab. Camrelizumab has a manageable safety profile.

Subsequent treatments beyond progression on osimertinib in EGFR-mutated NSCLC and leptomeningeal metastases.

BACKGROUND: Despite the reported efficacy of osimertinib, central nervous system (CNS) progression is still frequent in EGFR-mutated NSCLC. This study aimed to reveal site-specific resistant mechanisms to osimertinib and investigate subsequent treatments for leptomeningeal metastases (LM). METHODS: EGFR-mutated NSCLC with LM who progressed on osimertinib were included. Molecular analysis of cerebrospinal fluid (CSF) at osimertinib progression was performed. Subsequent treatments of LM were collected and analyzed. RESULTS: A total of 246 patients were identified. Only those with LM as a progression site on osimertinib were included (n=81). In 58 CSF-plasma pairs, more alterations were uniquely detected in CSF (77%) than in plasma (7%). These mechanisms led to 22 patients receiving matched targeted therapy. Among them, 16 (72.7%) had a clinical response. The median overall survival was 7.2 months. For non-matched therapy (n=59), the osimertinib combination had a longer median overall survival than the regimen switch in CNS-only progression (15.3 vs. 7 months, p=0.03). Finally, serial monitoring by CSF revealed the potential evolution of LM. CONCLUSIONS: Private resistant mechanisms in CSF might match osimertinib-resistant LM for targeted therapy. Besides, continuing osimertinib with intensification strategy might prolong survival, especially for those with CNS-only progression. Prospective  exploration is needed.

A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

Retrospective study on bevacizumab in the treatment of non-small cell lung cancer with brain metastases.

BACKGROUND: Bevacizumab was demonstrated to have efficacy in patients with non-small cell lung cancer (NSCLC) and brain metastases. However, cerebral toxicities were a major concern. This study aims to investigate the efficacy and risk factors of toxicity of bevacizumab in brain metastases. METHODS: All patients with advanced NSCLC hospitalized in our institute were screened and only those, who underwent bevacizumab administration after the diagnosis of brain metastases, were included. RESULTS: Fifty-one patients, who were treatment naïve or pretreated prior to bevacizumab regimens, were enrolled. Regardless of treatment lines, the objective response rate (ORR) was 62.7% (32/51), progression free survival (PFS) and overall survival were 6.2 months (95%CI, 5.0-7.4) and 14.0 months (95%CI, 9.6-18.4), respectively, and intracranial PFS was 7.8 months (95%CI, 7.1-8.5). For 41 patients with measurable brain metastatic lesions, the intracranial ORR was 46.3% (19/41). Ten patients (19.6%, 10/51) experienced cerebral toxicities (seven cases of grade 1 and three cases of grade 3), including cerebral or intratumoral hemorrhage and ischemic stroke. Cardiovascular disease was the risk factor contributing to cerebral toxicities (OR 16.645; 95%CI, 2.443-113.430; P = 0.004). CONCLUSIONS: This retrospective study shows that bevacizumab has efficacy and favorable toxicity in patients with NSCLC and brain metastases and cardiovascular disease might be a risk factor for cerebral toxicity.

Characterization of PD-L1 expression in Chinese non-small cell lung cancer patients with PTEN expression as a means for tissue quality screening.

The goal of this study is to evaluate PD-L1 prevalence and its association with major clinical characteristics in Chinese non-small cell lung cancer (NSCLC) patients to inform the clinical development of anti-PD1/PD-L1 agents in this population. We used phosphatase and tensin homolog (PTEN) expression through IHC as a surrogate tissue quality marker to screen surgical NSCLC samples in tissue microarray (TMA; 172 cases) or whole-section (268 cases) format. The samples were then analyzed with a clinically validated PD-L1 IHC assay. The results were correlated with baseline characteristics and clinical outcomes. PTEN IHC showed that 108 TMA samples and 105 whole-section samples qualified for PD-L1 IHC. With a clinically relevant cutoff, 41.7% of the TMA samples were PD-L1 positive. PD-L1 level was much lower in EGFR-mutant patients and seemed to be a favorable prognostic factor for both overall survival (OS) and recurrence-free survival (RFS). These findings were confirmed in the whole-section samples except that their survival data were not mature enough for correlation analysis. In summary, PD-L1 expression was detected in approximately 40% of PTEN-qualified Chinese NSCLC samples, negatively correlated with EGFR mutation and seemed to be a favorable prognostic factor for both OS and RFS. Notably, the different results from PTEN-qualified and PTEN-disqualified samples underscore the importance of tissue quality control prior to biomarker testing.

Crizotinib in advanced non-small-cell lung cancer with concomitant ALK rearrangement and c-Met overexpression.

OBJECTIVE: Crizotinib can target against mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK), which has been considered as a multi-targeted tyrosine kinase inhibitor (TKI). The objective of this study was to explore the efficacy of crizotinib in advanced non-small-cell lung cancer (NSCLC) with concomitant ALK rearrangement and c-Met overexpression. METHODS: Totally, 4622 advanced NSCLC patients from two institutes (3762 patients at the Guangdong Lung Cancer Institute from January 2011 to December 2016 and 860 cases at the Perking Cancer Hospital from January 2015 to December 2016) were screened for ALK rearrangement with any method of IHC, RACE-coupled PCR or FISH. C-Met expression was performed by IHC in ALK-rearranged patients, and more than 50% of cells with high staining were defined as c-Met overexpression. The efficacy of crizotinib was explored in the ALK-rearranged patients with or without c-Met overexpression. RESULTS: Sixteen patients were identified with c-Met overexpression in 160 ALK-rearranged cases, with the incidence of 10.0% (16/160). A total of 116 ALK-rearranged patients received the treatment of crizotinib. Objective response rate (ORR) was 86.7% (13/15) in ALK-rearranged patients with c-Met overexpression and 59.4% (60/101)in those without c-Met overexpression, P = 0.041. Median PFS showed a trend of superiority in c-Met overexpression group (15.2 versus 11.0 months, P = 0.263). Median overall survival (OS) showed a significant difference for ALK-rearranged patients with c-Met overexpression group of 33.5 months with the hazard ratio (HR) of 3.2. CONCLUSIONS: C-Met overexpression co-exists with ALK rearrangement in a small population of advanced NSCLC. There may be a trend of favorable efficacy of crizotinib in such co-altered patients.

Supraclavicular lymph node incisional biopsies have no influence on the prognosis of advanced non-small cell lung cancer patients: a retrospective study.

BACKGROUND: Supraclavicular lymph node (SCLN) biopsies play an important role in diagnosing and staging lung cancer. However, not all patients with SCLN metastasis can have a complete resection. It is still unknown whether SCLN incisional biopsies affect the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: Patients who were histologically confirmed to have NSCLC with SCLN metastasis were enrolled in the study from January 2007 to December 2012 at Guangdong Lung Cancer Institute. The primary endpoint was OS, and the secondary endpoints were complications and local recurrence/progression. RESULTS: Two hundred two consecutive patients who had histologically confirmed NSCLC with SCLN metastasis were identified, 163 with excisional and 39 with incisional biopsies. The median OS was not significantly different between the excisional (10.9 months, 95% CI 8.7-13.2) and incisional biopsy groups (10.1 months, 95% CI 6.3-13.9), P = 0.569. Multivariable analysis showed that an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 (HR = 2.75, 95% CI 1.71-4.38, P < 0.001) indicated a worse prognosis. Having an epidermal growth factor receptor (EGFR) mutation (HR = 0.58, 95% CI 0.40-0.84, P = 0.004) and receiving systemic treatment (HR = 0.36, 95% CI 0.25-0.53, P < 0.001) were associated with a favorable OS. Neither the number (multiple vs. single) nor site (bilateral vs. unilateral) of SCLNs was associated with an unfavorable OS, and SCLN size or fixed SCLNs did not affect OS. CONCLUSIONS: SCLN incisional biopsies did not negatively influence the prognosis of NSCLC patients. It was safe and feasible to partly remove a metastatic SCLN as a last resort in advanced NSCLC.

Distribution and prognosis of uncommon metastases from non-small cell lung cancer.

BACKGROUND: According to the literature and our experience, the most common sites of non-small cell lung cancer (NSCLC) metastases include the brain, bone, liver, adrenal glands, contralateral lung and distant lymph nodes. Metastases to other organs are relatively rare. There have been numerous case reports and a few small case series of uncommon metastases derived from NSCLC. METHODS: We defined all organs except the common metastatic sites mentioned above as uncommon sites of metastasis. Patients with uncommon metastases among 2,872 consecutive NSCLC patients with stage IV disease at the Guangdong Lung Cancer Institute (GLCI) from 2006 to 2012 were included in this study. The diagnosis of uncommon metastases was based on pathology or imaging studies. RESULTS: Uncommon metastases were diagnosed in 193 cases at anatomical sites such as the soft tissue, kidney, pancreas, spleen, peritoneum, intestine, bone marrow, eye, ovary, thyroid, heart, breast, tonsil and nasal cavity. Uncommon metastases were identified as independent poor prognostic factors through a multivariate analysis with a HR (hazard ratio) of 1.29 [95% confidence interval (CI) 1.09-1.52, P < 0.01]. Those patients who received systemic therapy plus local treatment had a better survival rate than did those who received systemic therapy only (P < 0.01); all patients received best supportive care. CONCLUSIONS: Metastases to the above mentioned sites are infrequent. The presentation of uncommon metastases tends to indicate a poor outcome, and selected patients may benefit from local treatment.

Do-not-resuscitate orders among advanced-stage Chinese lung cancer patients who died in hospital.

PURPOSE: Do-not-resuscitate (DNR) orders are an important part of end-of-life care (EOL) for patients with incurable advanced lung cancer. The aim of this study was to investigate the clinical factors related to the acceptance of DNR orders by Chinese patients. METHODS: This study was a retrospective analysis involving patients with advanced-stage (IIIB or IV) lung cancer who died in hospital at our center from August 2004 through August 2014. The patients' clinical characteristics and DNR forms were reviewed. RESULTS: Of the 348 patients enrolled, 260 (74.7 %) provided DNR orders signed only by surrogates. The signing rate of DNR orders increased annually. The median interval from signing a DNR order to death was 1 day (range, 0-72 days). Patients with poor performance status (PS) (≥2) 1 week prior to death (OR, 3.395; 95 % CI, 1.536-7.502, P = 0.003) and relatively longer overall survival (OS) (>3 months) (OR, 2.464; 95 % CI, 1.566-4.472, P < 0.001) were more likely to sign DNR orders. CPR was performed on 10.3 % (27/260) of patients with DNR orders, and was withheld in 22.7 % (20/88) of patients without DNR orders. CONCLUSIONS: The DNR order-signing rate has been increasing annually among terminal patients with lung cancer in China. DNR orders, all of which were signed by surrogates, were more likely to be accepted by patients with slowly deteriorating disease and longer OS. More effort should be taken to help patients and medical professionals establish a sensible understanding of EOL care, including DNR orders, at earlier points during the disease course.

Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial.

BACKGROUND: Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. METHODS: The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapy-naive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. FINDINGS: Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65-1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5-5·7 in the gefitinib group and 4·6-5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. INTERPRETATION: Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting. FUNDING: AstraZeneca.

Multiple primary malignancies involving lung cancer.

BACKGROUND: The incidence of multiple primary malignancies (MPM) has increased sharply in recent decades. However, the clinical characteristics and prognosis of MPM patients involving lung cancer were not fully elucidated. This retrospective study was designed to explore the clinical characteristics and prognosis of MPM patients involving lung cancer in the People's Republic of China. METHODS: Of 5405 lung cancer cases diagnosed at the Guangdong Lung Cancer Institute between 2005 and 2013, we analyzed 185 patients (3.4 %) with MPM involving lung cancer. RESULTS: Among 185 patients with MPM involving lung cancer, 10 (5.4 %)had three malignancies and 175 (94.6 %) had two malignancies. 10 patients with three malignancies were excluded from the analysis to avoid misunderstanding. Of 175 accompanying malignancies, 64 (36.6 %) were synchronous MPM patients and 111 (63.4 %) were metachronous MPM patients; 49 (28.0 %) were lung cancer first MPM patients and 126 (72.0 %) were other cancer first MPM patients. The most frequent accompanying malignancy was colon cancer (25/175), followed by rectal cancer (18/175), esophageal cancer (17/175), and thyroid cancer (13/175). Metachronous MPM patients showed significantly better overall survival (OS) than synchronous MPM, with a median OS of 72.8 (range 12.2-391.0) and 12.9 (range 0.8-86.3)months, respectively (P < 0.001). Cox regression analysis revealed that time of occurrence and stage were independent factors for OS. CONCLUSIONS: Colorectal cancer, esophageal cancer, and thyroid cancer were the tumors that most frequently accompanying lung cancer. Metachronous MPM patients showed significantly better OS compared with synchronous MPM patients.

Venous thromboembolism risk factors in Chinese non-small cell lung cancer patients.

PURPOSE: Certain clinicopathological factors contribute to the development of venous thromboembolism (VTE) in lung cancer. The aim of the current study was to assess the incidence of and the potential risk factors associated with the development of VTE in Chinese lung cancer patients. METHODS: Patients with lung cancer in our center were screened for VTE from January 2004 to July 2013. One VTE case was matched with two controls according to gender, pathology, clinical stage, and anticancer therapy. RESULTS: Among the 4,726 patient records screened, 61 (1.3 %) VTE cases with non-small cell lung cancer (NSCLC) were identified, including 58 (95.1 %) with adenocarcinoma and 59 (96.7 %) with advanced stage tumors (IIIb and IV). Serous effusion (OR 2.089, 95 % CI 1.022-4.270, P = 0.043), fever (OR 8.999, 95 % CI 1.688-47.968, P = 0.010), increased leukocytes (OR 4.136, 95 % CI 1.957-8.738, P < 0.001), hyponatremia (< 130 mmol/L, OR 5.335, 95 % CI 1.366-20.833, P = 0.016), and increased alanine aminotransferase (ALT) (OR 3.879, 95 % CI 1.514-9.936, P = 0.005) were associated with an increased risk of VTE. Patients with poor performance status (PS) (≥ 2 vs. < 1) (HR 1.574, 95 % CI 1.112-2.228, P = 0.010) and serous effusion (HR 1.571, 95% CI 1.114-2.215, P = 0.010) tended to have a poor prognosis. There was no difference in overall survival between VTE (median 15.2 months, 95 % CI 11.6-18.9) and control patients (median 16.3 months, 95 % CI 14.1-18.4, P = 0.184; HR 1.273, 95 % CI 0.890-1.820, P = 0.185). CONCLUSIONS: Clinical characteristics such as serous effusion, fever, increased leukocytes, hyponatremia, and increased ALT are potential risk factors for VTE in NSCLC. Poor PS and serous effusion imply poor prognosis for NSCLC patients, most of which have adenocarcinomas and advanced stage.

Insight into early-phase trials for lung cancer in the United States.

INTRODUCTION: Few data have been published comparing early-phase trials for lung cancer between China and the United States (US). This study was to investigate the differences of phase 1 trials for lung cancer between these two countries. METHODS: In 2014, a cross-sectional survey was conducted to compare phase 1 trials for lung cancer between the Guangdong Lung Cancer Institute (GLCI), the University of Wisconsin Carbone Cancer Center (UWCCC), and the University of Texas MD Anderson Cancer Center (MDACC). RESULTS: We found that the GLCI had a lower percentage of phase 1 lung cancer trials than the MDACC in December 2014 (23.8% [5/21] vs. 59.8% [28/47], P = 0.006) and the UWCCC in September 2014 (16.7% [3/18] vs. 34.8% [8/23], P = 0.345). Descriptive analyses were performed for early-phase trials conducted by the Cancer Therapy Evaluation Program at the National Cancer Institute (CTEP/NCI), the MDACC, and the Chinese Thoracic Oncology Group (CTONG). There were 149 ongoing early-phase trials in the Department of Investigational Cancer Therapeutics (Phase 1 program) at the MDACC in October 2014. In contrast, no phase 1 trials had been initiated by the CTONG since its establishment in 2007. CONCLUSIONS: These data suggest that a significantly higher percentage of phase 1 trials for lung cancer were conducted in the US than in China. Early-phase oncology trials with robust preclinical data had a higher chance of being approved by the Investigational Drug Branch at the CTEP/NCI. Given the importance of early-phase oncology trials in developing innovative cancer medicines, such studies should be highly encouraged and strategically funded in China.

Lung cancer treatment disparities in China: a question in need of an answer.

BACKGROUND: Substantial progress has been made in the treatment of malignancies in the People's Republic of China in recent years. The goal of this study was to identify the extent to which national treatment guidelines are being used to customize patient care in lung cancer and to analyze the reasons for treatment disparities. METHODS: Patient characteristics and treatments were investigated retrospectively for the period from October 2004 to January 2013 using the outpatient database of the Guangdong Lung Cancer Institute (GLCI) in China. RESULTS: A total of 2,535 outpatients with lung cancer were studied in this retrospective analysis. The treatment disparity was 45.3%. Overall, 20.6% of patients with stage I non-small cell lung cancer (NSCLC) were overtreated, and 20.1% of stage II patients were undertreated. Only 19.6% of stage IIIA patients and 30.7% of stage IIIB patients underwent the recommended combination of chemotherapy and radiotherapy, respectively. For advanced NSCLC, the greatest treatment disparity appeared in the second-line setting and beyond. Patients who were positive for epidermal growth factor receptor (EGFR) and receiving EGFR tyrosine kinase inhibitors experienced significant prolongation of survival compared with patients who were EGFR negative or whose EGFR mutation status was unknown (hazard ratio: 0.79; p = .037). The treatment disparities were significantly larger among patients aged younger than 65 years and in patients from developing regions compared with patients aged 65 years and older and from developed regions, respectively (p < .001, p = .046). The difference in treatment disparity was statistically significant between GLCI and other hospitals (p < .001). CONCLUSION: This retrospective study of a large number of patients from an outpatient oncology database demonstrated large disparities in the treatment of lung cancer in China. It is important to develop a new guideline for recommendations that are based on resource classification.

A randomized phase II clinical trial of nab-paclitaxel and carboplatin compared with gemcitabine and carboplatin as first-line therapy in locally advanced or metastatic squamous cell carcinoma of lung.

BACKGROUND: Recent advances have shown that histology and genetic biomarkers are important in patient selection, which have led to significantly better outcomes for lung cancer patients. However, most new treatments only apply to adenocarcinoma or non-squamous, and in squamous carcinoma there is little breakthrough. In a phase III trial nab-paclitaxel plus carboplatin showed superior response rate over paclitaxel and carboplatin. In subgroup analysis the squamous histology appeared to be a predictive factor to nab-paclitaxel treatment. METHODS/DESIGN: This is an open-label, randomized, active controlled phase II trial. A total of 120 untreated advanced squamous lung cancer patients are randomized at a 1:1 ratio to receive nab-paclitaxel (135 mg/m2, d1, 8, q3w) plus carboplatin (AUC 5, d1, q3w) or gemcitabine (1,250 mg/m2, d1, 8, q3w) and carboplatin (AUC 5, d1, q3w). The primary endpoint is objective response rate and the second endpoints are progression free survival, overall survival, safety and biomarkers associated with nab-paclitaxel. The treatment will continue up to six cycles or intolerable toxicity. DISCUSSION: This ongoing trial will be the first prospective randomized trial to explore the efficacy of nab-paclitaxel as the first-line treatment specifically in squamous carcinoma of lung. STUDY NUMBER: CTONG1002 TRIAL REGISTRATION: Clinicaltrials.gov reference: NCT01236716.

Mixed response to the first-line treatment of KRAS G12C inhibitor, sotorasib, in non-small cell lung cancer: A brief report.

Key Clinical Message: One Kirsten Ras (KRAS) G12C mutated non-small cell lung cancer (NSCLC) patient had improved poor performance status and obtained mixed response with the first-line KRAS-targeted treatment of sotorasib. After disease progression, partial response was achieved with chemotherapy plus immunotherapy. KRAS G12C mutated immunoenvironment in NSCLC may favor the immunotherapy. Abstract: KRAS is one of the most commonly mutated genes, which used to be untargetable. The phase II CodeBreak 100 trial revealed 6.8-month median progress-free survival (PFS) and 12.5-month overall survival (OS) in previously treated KRAS G12C-mutant NSCLC patients treated with KRAS inhibitor, sotorasib. The specimens of the brain, lymph node (LN), and blood from the patient were analyzed by next-generation sequencing. Hematoxylin and eosin staining and immunohistochemistry were performed for pathological characterization. Computed tomography (CT) and magnetic resonance imaging (MRI) scan were used for treatment response evaluation. The patient was diagnosed in a bad Eastern Cooperative Oncology Group performance status (ECOG-PS) with metastatic KRAS G12C-mutated lung adenocarcinoma who had achieved mixed response to sotorasib as the first-line treatment. Although 5-month PFS of the treatment with sotorasib was not surprising, the patient achieved significantly improved ECOG-PS score from 4 to 1. Subsequently, partial response (PR) was achieved with the treatment of pemetrexed plus pembrolizumab. This case highlights superior efficacy of first-line treatment with sotorasib for the advance untreated KRAS G12C-mutant patients. The high efficacy of the treatment with chemotherapy plus immunotherapy revealed that immunoenvironment of KRAS G12C-mutated patient may favor the immunotherapy.