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We evaluated whether tissue tumor mutational burden (tTMB) and STK11 , KEAP1 , and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR / ALK alterations in the phase III KEYNOTE-042 trial. This retrospective exploratory analysis assessed prevalence of tTMB and STK11 , KEAP1 , and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [ STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [ KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [ KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11 , KEAP1 , or KRAS mutation status. • Pembrolizumab monotherapy is a standard first-line treatment of patients with PD-L1-positive advanced/metastatic NSCLC. • We assessed clinical utility of potential biomarkers among patients receiving pembrolizumab versus chemotherapy. • tTMB ≥175 mutations/exome was associated with improved outcomes among patients receiving pembrolizumab versus chemotherapy. • tTMB has potential clinical utility as a biomarker for pembrolizumab in first-line PD-L1-positive advanced/metastatic NSCLC. • Pembrolizumab improved overall survival versus chemotherapy regardless of STK11 , KEAP1 , or KRAS mutation status. [ABSTRACT FROM AUTHOR]

A phase II study investigating intercalated combinations of eribulin and erlotinib in 21- and 28-day regimens in unselected patients with previously treated advanced non-small-cell lung cancer. Combination treatment demonstrated modest activity; the addition of erlotinib did not appear to improve outcomes in an unselected population. The 28-day regimen is suitable for further investigation.Background This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. Patients and methods Eligible patients were randomized to eribulin mesylate 2.0 mg/m2 on day 1 with erlotinib 150 mg on days 2–16 (21-day regimen) or eribulin mesylate 1.4 mg/m2 on days 1 and 8 with erlotinib 150 mg on days 15–28 (28-day regimen). The primary end point was objective response rate (ORR). Results One hundred and twenty-three patients received ≥1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%–24%] and 17% (95% CI 8%–29%), and disease control rates were 48% (95% CI 35%–61%) and 63% (95% CI 50%–75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. Conclusion Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier NCT01104155. [ABSTRACT FROM AUTHOR]

Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs. Other rare side-effects, such as hepatic impairment and interstitial lung disease, should be identified early and managed carefully. Patients with uncommon EGFR mutations, such as G719X, S768I, and L861Q, may require special selection of EGFR TKIs. The combination of erlotinib plus bevacizumab has been accepted in certain parts of the world as an alternative front-line treatment. This review article summarizes the studies leading to the establishment of EGFR TKIs in EGFR-mutant lung cancer patients. The side-effect profiles of the current EGFR TKIs in these large trials are listed, and the management of uncommon EGFR mutations is discussed. Finally, the potential role of combination front-line treatment is discussed. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. Patients and methods: Patients with advanced NSCLC previously treated with ≥ 1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m² in Japan, 75 mg/m² at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. Results: A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P=0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P=0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. Conclusion: S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: This phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel–carboplatin (CP) plus motesanib or bevacizumab.Patients and methods: Chemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs).Results: ORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma Cmax and Cmin values were consistent with its pharmacokinetic properties observed in previous studies.Conclusions: The efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study. [ABSTRACT FROM AUTHOR]

Background Although osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) is approved for first-line (1L) treatment of EGFR -mutated metastatic non-small cell lung cancer (NSCLC) and second-line (2L) treatment of pts who acquired the EGFR T790M mutation during 1L therapy with other TKIs, treatment options after progression on TKIs are limited; platinum-doublet chemotherapy (PT-DC) remains the standard therapy, including for pts with no T790M mutation. Nivolumab (NIVO), a fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody, is approved worldwide for the treatment of advanced NSCLC on or after prior chemotherapy. CheckMate 722 (NCT02864251) will compare the efficacy and safety of NIVO + PT-DC vs PT-DC alone in pts with EGFR -mutated metastatic or recurrent NSCLC progressed on 1L or 2L EGFR TKI therapy. Methods This open-label phase 3 trial is enrolling ∼500 adults with confirmed stage IV or recurrent EGFR -mutated NSCLC progressed on prior EGFR TKI therapy. Patients are eligible if they progressed on 1L first- or second-generation TKIs with no T790M mutation or 1L or 2L osimertinib regardless of T790M status. Pts with CNS metastases that are adequately controlled and/or treated during screening are eligible. Pts are randomized 1:1 to NIVO (360 mg Q3W) + PT-DC (pemetrexed 500 mg/m2 Q3W + cisplatin 75 mg/m2 or carboplatin AUC 5 or 6 Q3W), or PT-DC alone; pts without disease progression after 4 cycles will receive NIVO + pemetrexed or pemetrexed, respectively, until disease progression or unacceptable toxicity. Randomization is stratified by programmed death ligand-1 status (≥ 1% or < 1%/not evaluable), presence or absence of brain metastases, smoking history and prior osimertinib treatment. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, objective response rate, duration of response, and PFS rates at 9 and 12 months. Results The estimated primary completion date is September 2019. [ABSTRACT FROM AUTHOR]