Langer, Corey J.

9065 Background: BRG is a potent and selective ALK inhibitor with preclinical and clinical activity against wild-type ALK and a broad range of mutants associated with clinical CRZ resistance, including G1202R. Herein we examine the association between BRG efficacy and ALK mutation status using plasma specimens from the initiation of BRG treatment (baseline [BL]) and the end of BRG treatment (EOT) in CRZ-resistant ALK+ NSCLC pts enrolled in the BRG Ph1/2 or pivotal Ph2 (ALTA) trials. Methods: Plasma samples were analyzed using the Resolution Bioscience ctDx Lung Panel v3.0. BRG activity was described using the confirmed objective response rate (cORR) (RECIST v1.1). Data are reported as of May 31, 2016 for the Ph1/2 (NCT01449461) and ALTA (NCT02094573) trials. Results: Of 291 CRZ-resistant ALK+ NSCLC pts enrolled in the Ph1/2 (N = 69) and ALTA (N = 222) trials, evaluable plasma samples were obtained from 67 pts at BL. cORR to BRG in these pts was 49% (33/67). An ALK fusion was detected in plasma in 45% (30/67) of these pts (cORR 57% [17/30]), of whom 33% (10/30) had secondary ALK mutations (cORR 50% [5/10]) and 67% (20/30) did not (cORR 60% [12/20]). Best responses in pts with secondary ALK mutations were: 2 CR (ALK amplification [Amp] copy number [CN] = 10; T1151M); 3 PR (L1196M; E1408V; Amp CN = 6); 4 SD (L1196M; E1419K; F1174C; C1156Y+S1206F+G1269A); 1 PD (T1151R+C1156Y+E1161D+F1174L). Of 67 pts with evaluable plasma at BL, 35 discontinued BRG therapy, of whom 20 had evaluable samples collected at EOT. No new mutations were detected at EOT in 75% (15/20) of pts. Complex mutation patterns were associated with resistance in the remaining 25% (5/20): High-level ALK-Amp (CN = 58); ALK-Amp (CN = 14)+MET-Amp (CN = 6); ALK-S1206F+S1206C+Amp (CN = 6); ALK-G1202R+L1196M+L1198Q; ALK-G1202R+BRAF-V600E+KRAS-G12D. Conclusions: ALK fusions were detected in plasma in < 50% of CRZ-resistant ALK+ NSCLC pts. BRG had substantial activity in ALK fusion–positive pts with a range of CRZ-resistance mutations. Neither primary nor secondary resistance to BRG was associated with any single plasma ALK mutation. The therapeutic implications of complex secondary resistance patterns associated with BRG require further exploration. Clinical trial information: NCT01449461, NCT02094573.

BACKGROUNDExisting data supporting the use of proton‐beam therapy (PBT) for limited‐stage small cell lung cancer (LS‐SCLC) are limited to a single 6‐patient case series. This is the first prospective study to evaluate clinical outcomes and toxicities of PBT for LS‐SCLC.METHODSThis study prospectively analyzed patients with primary, nonrecurrent LS‐SCLC definitively treated with PBT and concurrent chemotherapy from 2011 to 2016. Clinical backup intensity‐modulated radiotherapy (IMRT) plans were generated for each patient and were compared with PBT plans. Outcome measures included local control (LC), recurrence‐free survival (RFS), and overall survival (OS) rates and toxicities.RESULTSThirty consecutive patients were enrolled and evaluated. The median dose was 63.9 cobalt gray equivalents (range, 45‐66.6 cobalt gray equivalents) in 33 to 37 fractions delivered daily (n = 18 [60.0%]) or twice daily (n = 12 [40.0%]). The concurrent chemotherapy was cisplatin/etoposide (n = 21 [70.0%]) or carboplatin/etoposide (n = 9 [30.0%]). In comparison with the backup IMRT plans, PBT allowed statistically significant reductions in the cord, heart, and lung mean doses and the volume receiving at least 5 Gy but not in the esophagus mean dose or the lung volume receiving at least 20 Gy. At a median follow‐up of 14 months, the 1‐/2‐year LC and RFS rates were 85%/69% and 63%/42%, respectively. The median OS was 28.2 months, and the 1‐/2‐year OS rates were 72%/58%. There was 1 case each (3.3%) of grade 3 or higher esophagitis, pneumonitis, anorexia, and pericardial effusion. Grade 2 pneumonitis and esophagitis were seen in 10.0% and 43.3% of patients, respectively.CONCLUSIONSIn the first prospective registry study and largest analysis to date of PBT for LS‐SCLC, PBT was found to be safe with a limited incidence of high‐grade toxicities. Cancer 2017;123:4244–4251. © 2017 American Cancer Society.

Purpose We conducted a phase II study of combination of the anti–insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non–small-cell lung cancer (NSCLC). Patients and Methods Patients were randomly assigned (2:1) to paclitaxel 200 mg/m2, carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI10, PCI20) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI10-20 patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigator's discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI20 was enrolled on completion of the randomized study. Results A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI10 and 50 patients received PCI20 in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI20/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship. Conclusion These data suggest that PCI20 is safe and effective in patients with NSCLC.

Purpose Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC. Patients and Methods Patients were randomly assigned to IP (irinotecan 60 mg/m2 on days 1, 8, and 15; cisplatin 60 mg/m2 day 1, every 4 weeks) or EP (etoposide 100 mg/m2 on days 1 through 3; cisplatin 80 mg/m2 day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. Results Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia. Conclusion This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.

Purpose Elderly patients often have comorbidities and other characteristics that make the selection of treatment daunting. Methods We have reviewed the available evidence in the literature to gauge the results of therapy for elderly lung cancer patients. Results The beneficial results achieved with adjuvant chemotherapy in the general population with early non–small-cell lung cancer (NSCLC) cannot be automatically extrapolated to the elderly, who are at higher risk of toxicity. Retrospective analyses of combined chemoradiotherapy in locally advanced NSCLC patients suggest equivalent therapeutic benefit for younger and older patients, despite heightened toxicity. There have been no elderly-specific phase III trials for locally advanced NSCLC. For advanced NSCLC, on the basis of evidence-based data, single-agent chemotherapy remains the standard of care for nonselected elderly patients. However, retrospective analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with increased but acceptable toxicity for elderly patients. In limited-disease small-cell lung cancer (SCLC), sequential chemoradiotherapy is clearly less toxic compared with a standard concurrent approach, but our assessment of treatment is hindered by the absence of prospective elderly-specific trials. Although prophylactic cranial irradiation has emerged as a standard strategy, it should be omitted in patients with cognitive impairment. In extensive SCLC, etoposide in combination with either cisplatin or carboplatin has emerged as standard treatment; hematopoietic support may be necessary. Conclusion With the exception of advanced NSCLC, prospective elderly-specific studies are lacking. Available data suggest that outcomes in the fit elderly mirror results observed in younger patients, although toxicity is generally worse.

Purpose Appropriate therapy for Eastern Cooperative Oncology Group (ECOG) performance status (PS) -2 patients with advanced non–small-cell lung cancer (NSCLC) remains challenging. PS-2 patients on ECOG 1594 had a median survival (MS) of only 4.1 months and 1-year overall survival (OS) of 19%. Three percent had grade 5 toxicity. Patients and Methods ECOG 1599, the first PS 2–specific, US cooperative group trial for treatment-naïve advanced NSCLC, randomly assigned patients to dose-attenuated carboplatin/paclitaxel (the least toxic regimen in ECOG 1594) or gemcitabine/cisplatin (which yielded an MS of 7.9 months in PS-2 patients). Patients received either carboplatin (area under the concentration-time curve, 6) and paclitaxel 200 mg/m2 every 3 weeks (CbP) or gemcitabine 1 g/m2 days 1 and 8 and cisplatin 60 mg/m2 day 1 every 3 weeks (CG). Results One hundred three patients were enrolled; 100 proved eligible. Median age was 66 years; 46% had at least 5% weight loss; 88% had stage IV or recurrent disease. Median number of cycles administered was three per arm. CbP featured more grade 3 neutropathy (10% v 0%) and more grade ≥ 3 neutropenia (59% v 33%), whereas CG yielded more grade ≥ 3 thrombocytopenia (33% v 14%), more grade ≥ 3 fatigue (22% v 14%), and more grade ≥ 1 creatinine elevations (43% v 6%). One grade 5 toxicity, confined to the CbP arm, occurred. Response rate, time to progression, MS, and 1-year OS rates for CG and CbP, were 23%, 4.8 months, 6.9 months, and 25%, and 14%, 4.2 months, 6.2 months, and 19%, respectively. Conclusion Platinum-based combination chemotherapy for PS-2 patients with NSCLC is feasible with acceptable toxicity, but survival in these patients remains inferior to that of PS-0 to -1 patients.