Search

Abstract: Background: Cetuximab has demonstrated improved efficacy in combination with chemotherapy and radiotherapy. We evaluated the integration of cetuximab in the combined modality treatment of stage III non-small cell lung cancer (NSCLC). Methods: Patients with surgically unresectable stage IIIA or IIIB NSCLC were treated with chest radiotherapy, 73.5Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63Gy without heterogeneity corrections). Cetuximab was given weekly during radiotherapy and continued during consolidation therapy with carboplatin and paclitaxel up to a maximum of 26 weekly doses. The primary endpoint was overall survival. Baseline tumor tissue was analyzed for EGFR by fluorescence in situ hybridization (FISH). Results: Forty patients were enrolled in this phase II study. The median overall survival was 19.4 months and the median progression-free survival 9.3 months. The best overall response rate in 31 evaluable patients was 67%. No grade 3 or 4 esophagitis was observed. Three patients experienced grade 3 rash; 16 patients (69%) developed grade 3/4 neutropenia during consolidation therapy. One patient died of pneumonitis, possibly related to cetuximab. EGFR gene copy number on baseline tumor tissues, analyzed by FISH, was not predictive of efficacy outcomes. Conclusions: The addition of cetuximab to chest radiotherapy and consolidation chemotherapy was tolerated well and had modest efficacy in stage III NSCLC. Taken together with the lower incidence of esophagitis, our results support evaluation of targeted agents instead of chemotherapy with concurrent radiotherapy in this setting. [Copyright &y& Elsevier]

First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival. Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed. In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population. Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC. • Pooled analyses from four 1L NIVO + IPI studies support the durable efficacy of this regimen for advanced NSCLC treatment. • Durable responses and long-term survival benefit with NIVO + IPI were observed across histologies/PD-L1 expression levels. • Patients who had a response at 6 months with 1L NIVO + IPI had improved post-landmark survival benefit. • Responders with higher tumor burden reduction from baseline derived long-term OS benefit. [ABSTRACT FROM AUTHOR]

In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum–pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum–pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum–pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67–1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5–31.5) versus 22.5 months (95% CI 20.2–28.8) for osimertinib and platinum–pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18–1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16–0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum–pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum–pemetrexed arm. In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum–pemetrexed, which possibly reflects the high crossover rate of patients from platinum–pemetrexed to osimertinib. ClinicalTrials.gov NCT02151981 ; https://clinicaltrials.gov/ct2/show/NCT02151981. • Median OS with osimertinib was 26.8 months versus 22.5 months with platinum–pemetrexed (HR 0.87, 95% CI 0.67–1.12; P = 0.277). • The lack of a significant survival benefit could reflect high percentage (73%) of platinum–pemetrexed to osimertinib crossover. • Analysis of OS adjusted for crossover showed an HR of 0.54 (95% CI 0.18–1.60). • Among patients receiving subsequent anticancer therapy, platinum chemotherapy was the most common after osimertinib (65%). • Grade ≥3 (possibly treatment-related) adverse events were observed less frequently with osimertinib (9% versus 34% with platinum–pemetrexed). [ABSTRACT FROM AUTHOR]

Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. Patients with advanced EGFR -mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25–75 mg p.o. twice a day; continuous or intermittent), savolitinib (600–800 mg p.o. once a day), or durvalumab (3–10 mg/kg intravenous every 2 weeks). At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm—diarrhea (75%), rash (58%), nausea (47%); savolitinib arm—nausea (67%), rash (56%), vomiting (50%); durvalumab arm—rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. NCT02143466. • Patients with advanced EGFR -mutant NSCLC received osimertinib 80 mg combined with selumetinib, savolitinib or durvalumab. • Feasible dosing strategies were identified for osimertinib plus selumetinib or savolitinib. • Osimertinib plus durvalumab was not feasible due to increased reporting of interstitial lung disease. • Responses were seen in all treatment arms, warranting further analysis of the feasible combinations identified. • Osimertinib-based combinations represent a compelling approach now being investigated broadly to further improve outcomes. [ABSTRACT FROM AUTHOR]

KRAS GA are common oncogenic drivers. Effective systemic treatment of KRAS altered cancers has been largely elusive; however covalent inhibitors of G12C (AMG510, MRTX849) and SHP2 inhibitors (TNO155, RMC-4630) have recently entered the clinic in multiple tumor types. Hybrid capture-based comprehensive genomic profiling (CGP) was performed on tumor samples from 213,312 unique patients with solid or hematological malignancies. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. PD-L1 expression was determined by IHC (22C3 or SP142 antibodies) for 17% of cases. KRAS GA were detected in 22% (n = 46,182) of cases: 88% mutations (m; >99% substitutions and <0.2% indels), 8.3% amplification (a) and 3.8% both. KRASm were most common in pancreatic (83%, 8,063/9,723) gastrointestinal (GI; 39%, 13,507/35,019) and lung adenocarcinoma (LUAD; 35%, 9,159/25,968). KRASa (median 10 copies, range 6-421) was most common in esophageal adenocarcinomas (17%, 673/3,920) and testicular germ cell tumors (25%, 46/185). Co-KRASm+a was most common in pulmonary sarcomatoid carcinoma (PSC; 7.4%, 26/353). Median TMB was 3.5, 6.1, and 4.3 mut/Mb in cases with KRASm, KRASa, or KRASm+a. 124 unique KRASm were identified, most commonly G12D/V/C and G13D (26%, 21%, 14%, 6.9% of KRAS GA). G12D resulted from transitions (primarily G>A), and G12V (primarily G>T) and G12C (exclusively G>T) from transversions. G12C was most frequent in LUAD (14%, 3,613/25,968) and PSC (11%, 40/353) but uncommon in pancreatic (1.7%, 161/9,723) and GI (2.7%, 941/35,019) where G12D/V were most common. Tobacco signature (TS; 20% vs 4.5% vs 3.5%), elevated TMB (median 7.0 vs 3.5 vs 3.5 mut/Mb) and PD-L1 positivity (56% vs 29% vs 31%) were all significantly associated with G12C vs non-G12C KRASm and non-KRASm cancers (all p < 0.0001). In LUAD, TS was present in 25% G12C, 19% non-G12C KRASm and 15% non-KRASm (all p < 0.0001). Diverse KRAS GA are frequent across cancers and subtypes are associated with different solid malignancies. G12C is most common in LUAD and associated with smoking, elevated TMB and PD-L1 positivity. As multiple trials of novel therapeutic agents are currently enrolling for KRAS GA, CGP to identify these alterations is needed. The authors. Foundation Medicine. S.I. Ou: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Genentech; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Ariad; Research grant/Funding (institution): Ignyta; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Peregrine; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): TP Therapeutics; Research grant/Funding (institution): Blueprint Medicines. E.S. Sokol: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. R. Madison: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. J. Chung: Shareholder/Stockholder/Stock options: Roche; Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine. J.S. Ross: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. V.A. Miller: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche; Advisory/Consultancy: Revolution Medicines. B.M. Alexander: Leadership role, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. S.M. Ali: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche; Advisory/Consultancy: Revolution Medicines. A.B. Schrock: Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. S.S. Ramalingam: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Brystol Myers Squib; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Tesaro; Advisory/Consultancy: Takeda; Advisory/Consultancy: Nektar. [ABSTRACT FROM AUTHOR]