Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680 ). Eligible patients with previously untreated metastatic nonsquamous non–small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non–small-cell lung cancer without EGFR/ALK alterations.

PURPOSE: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb–mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC. PATIENTS AND METHODS: This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics. RESULTS: By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1-6); 49.5% received antiprogrammed death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred in 97 patients (90.7%) and grade b % 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%) including grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit. CONCLUSION: In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing. [Media: see text]

Purpose: Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non–small-cell lung cancer (NSCLC). Patients and Methods: Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)–assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results: One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion: Alectinib showed good efficacy against CNS metastases, in addition to systemic activity, in crizotinib-refractory ALK-positive NSCLC.

Background: Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKIs) benefit Non-small cell lung cancer (NSCLC) patients, and an EGFR-TKIi erlotinib, is approved for patients with recurrent NSCLC. However, resistance to erlotinib is a major clinical problem. Earlier we have demonstrated the role of Hedgehog (Hh) signaling in Epithelial-to-Mesenchymal transition (EMT) of NSCLC cells, leading to increased proliferation and invasion. Here, we investigated the role of Hh signaling in erlotinib resistance of TGF-β1-induced NSCLC cells that are reminiscent of EMT cells. Methods: Hh signaling was inhibited by specific siRNA and by GDC-0449, a small molecule antagonist of G protein coupled receptor smoothened in the Hh pathway. Not all NSCLC patients are likely to benefit from EGFR-TKIs and, therefore, cisplatin was used to further demonstrate a role of inhibition of Hh signaling in sensitization of resistant EMT cells. Specific pre- and anti-miRNA preparations were used to study the mechanistic involvement of miRNAs in drug resistance mechanism. Results: siRNA-mediated inhibition as well as pharmacological inhibition of Hh signaling abrogated resistance of NSCLC cells to erlotinib and cisplatin. It also resulted in re-sensitization of TGF-β1-induced A549 (A549M) cells as well the mesenchymal phenotypic H1299 cells to erlotinib and cisplatin treatment with concomitant up-regulation of cancer stem cell (CSC) markers (Sox2, Nanog and EpCAM) and down-regulation of miR-200 and let-7 family miRNAs. Ectopic up-regulation of miRNAs, especially miR-200b and let-7c, significantly diminished the erlotinib resistance of A549M cells. Inhibition of Hh signaling by GDC-0449 in EMT cells resulted in the attenuation of CSC markers and up-regulation of miR-200b and let-7c, leading to sensitization of EMT cells to drug treatment, thus, confirming a connection between Hh signaling, miRNAs and drug resistance. Conclusions: We demonstrate that Hh pathway, through EMT-induction, leads to reduced sensitivity to EGFR-TKIs in NSCLCs. Therefore, targeting Hh pathway may lead to the reversal of EMT phenotype and improve the therapeutic efficacy of EGFR-TKIs in NSCLC patients.

BACKGROUND: Brain metastases (BM) remain an important cause of morbidity and mortality in patients with lung cancer. The current study evaluated population‐based incidence and outcomes of BM in patients with nonmetastatic lung cancer.METHODS: Patients diagnosed with nonmetastatic first primary lung cancer between 1973 and 2011 in the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) registry were used for the current analysis. Age‐adjusted odds ratios of developing BM based on various demographic characteristics and histology were calculated with 95% confidence intervals. Adjusted Cox proportional hazard ratios and log‐rank tests of Kaplan‐Meier survival curves were calculated to evaluate survival differences for non‐small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).RESULTS: The incidence of BM in patients with nonmetastatic NSCLC and SCLC was 9% and 18%, respectively. There was variation in the incidence of BM according to NCSLC histology. The incidence of BM was higher in patients aged <60 years for both NSCLC and SCLC, but there were no differences noted by race for either histological group. Female patients with NSCLC were more likely to have BM than male patients. There was variation in the proportion of BM in both patients with NSCLC and SCLC over the three 13‐year periods of diagnosis. The risk of death (hazard ratio) was found to be significantly higher for patients with NSCLC with BM, but was not significantly higher in patients with SCLC with BM.CONCLUSIONS: The incidence of BM in patients with nonmetastatic lung cancer varies according to histology, age, and sex. BM are associated with worse survival for patients with NSCLC but not those with SCLC. Cancer 2016;122:1921–7. © 2016 American Cancer Society.