Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer.

BACKGROUND: 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 AND METHODS: 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). RESULTS: 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. CONCLUSION: 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. CLINICAL TRIALS NUMBER: NCT02143466.

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.

Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients.

Osimertinib was the first third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to receive FDA and EMA approval for metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) patients that have acquired the EGFR T790M resistance mutation. Clinical trials have demonstrated the efficacy of osimertinib in this patient population and clinical trials of other third-generation EGFR TKI are currently under way. Additional challenges in this patient population, such as the upfront efficacy of osimertinib, validation of T790M in liquid biopsies as a dynamic predictive marker of efficacy, along with combination with immune checkpoint inhibitors are being explored, representing an extraordinary time of development for EGFR-mutant NSCLC.

Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.

Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.

Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508).

BACKGROUND: Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. METHODS: Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). RESULTS: Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4-7.1) in arm A versus 7 months (95% CI 5.7-7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65-1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. CONCLUSIONS: The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. CLINICALTRIALS.GOV IDENTIFIER: NCT00955305.

Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials.

BACKGROUND: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. METHODS: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. RESULTS: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0-18.2] with dacomitinib and 9.6 months (95% CI 7.4-12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458-1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6-41.5) with dacomitinib versus 23.2 months (95% CI 16.0-31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431-1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. CONCLUSIONS: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). CLINICAL TRIALS NUMBER: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).

Analysis of liver-directed therapies in U.S. cancer patients.

BACKGROUND: The liver is a common site of primary and metastatic cancer. Liver-directed therapies are commonly used to treat cancer involving the liver. We report on the patterns, predictors, and outcomes of liver-directed therapies in hospitalized cancer patients in the United States. METHODS: Data were obtained from all U.S. states that contributed to the Nationwide Inpatient Sample maintained by the Agency for Healthcare Research and Quality between 2006 and 2010. Univariate and multivariate testing was used to identify factors significantly associated with patient outcome. RESULTS: For the 5-year period of interest, 12,540 patient discharges were identified. Mean age in the sample was 60 years. Primary liver lesions (n = 8840) made up 26.9% of the sample; the remaining cases were metastases. Most procedures were performed in large (79%) urban (98%) hospitals and in patients with insurance (97.9%). The most common intervention was partial hepatectomy (42.7%), followed by open (9.9%), percutaneous (7.2%), and laparoscopic (5.04%) ablation of liver lesions; embolization (9.8%); and liver transplantation (2.64%). The incidence of in-hospital mortality was very low (2.4%), and the complication rate was 12.2%. Complications such as acute liver necrosis, ascites, hepatic coma, hepatorenal syndrome, liver abscess, and high number of comorbid illnesses (>8) accounted for 60% of the in-hospital mortality. CONCLUSIONS: The low rate of morbidity and mortality associated with liver-directed therapies in hospitalized cancer patients supports the continuing utility of such procedures in the management of primary and metastatic liver cancer. The patterns of health disparities observed with respect to the use of liver-directed therapies are concerning.

A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies.

BACKGROUND: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination. METHODS: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m(-2). Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria. RESULTS: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m(-2) were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m(-2). Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m(-2) and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients. CONCLUSION: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.

Nivolumab plus chemotherapy in first-line metastatic non-small-cell lung cancer: results of the phase III CheckMate 227 Part 2 trial.

BACKGROUND: In CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression. PATIENTS AND METHODS: Seven hundred and fifty-five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy. Primary endpoint was OS with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC. OS in all randomized patients was a hierarchically tested secondary endpoint. RESULTS: At 19.5 months' minimum follow-up, no significant improvement in OS was seen with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC [median OS 18.8 versus 15.6 months, hazard ratio (HR) 0.86, 95.62% confidence interval (CI) 0.69-1.08, P = 0.1859]. Descriptive analyses showed OS improvement with nivolumab plus chemotherapy versus chemotherapy in all randomized patients (median OS 18.3 versus 14.7 months, HR 0.81, 95.62% CI 0.67-0.97) and in an exploratory analysis in squamous NSCLC (median OS 18.3 versus 12.0 months, HR 0.69, 95% CI 0.50-0.97). A trend toward improved OS was seen with nivolumab plus chemotherapy versus chemotherapy, regardless of the tumor mutation status of STK11 or TP53, regardless of tumor mutational burden, and in patients with intermediate/poor Lung Immune Prognostic Index scores. Safety with nivolumab plus chemotherapy was consistent with previous reports of first-line settings. CONCLUSIONS: CheckMate 227 Part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in patients with metastatic nonsquamous NSCLC. Descriptive analyses showed prolonged OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations, suggesting that this combination may benefit patients with untreated metastatic NSCLC.

Innovative Clinical Trials: The LUNG-MAP Study.

Although the proportion of patients with squamous cell carcinoma of the lung has declined over the last two decades, the disease is still fatal for tens of thousands of patients each year. The treatment of non-small cell lung cancer has advanced rapidly over the past decade, providing novel, targeted therapeutic options to patients, but has mostly been limited to the adenocarcinoma histology. Efforts are currently underway to bring squamous cell carcinoma of the lung into this new era of targeted therapy. This article reviews the rationale and trial design for the "LUNG-MAP: S1400 Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer" study. This multi-institutional, multi-cooperative group trial aims to individualize treatment for patients with metastatic squamous cell carcinoma to one of five arms based on the genomic profile of the tumor. The goal of this clinical trial is to rapidly identify new active drugs and bring them as soon as possible through a registration process for patients with squamous cell lung cancer by utilizing a novel trial design and involving all key stakeholders in drug development in a national effort. This could serve as a paradigm for drug development for malignancies with wide molecular heterogeneity.

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis.

Mcl-1 is a unique antiapoptotic Bcl2 family member with a short half-life due to its rapid turnover through ubiquitination. We discovered that Ku70, a DNA double-strand break repair protein, functions as a deubiquitinase to stabilize Mcl-1. Ku70 knockout in mouse embryonic fibroblast (MEF) cells or depletion from human lung cancer H1299 cells leads to the accumulation of polyubiquitinated Mcl-1 and a reduction in its half-life and protein expression. Conversely, expression of exogenous Ku70 in Ku70(-/-) MEF cells restores Mcl-1 expression. Subcellular fractionation indicates that Ku70 extensively colocalizes with Mcl-1 in mitochondria, endoplasmic reticulum and nucleus in H1299 cells. Ku70 directly interacts with Mcl-1 via its C terminus (that is, aa 536-609), which is required and sufficient for deubiquitination and stabilization of Mcl-1, leading to suppression of apoptosis. Purified Ku70 protein directly deubiquitinates Mcl-1 by removing K48-linked polyubiquitin chains. Ku70 knockdown not only promotes Mcl-1 turnover but also enhances antitumor efficacy of the BH3-mimetic ABT-737 in human lung cancer xenografts. These findings identify Ku70 as a novel Mcl-1 deubiquitinase that could be a potential target for cancer therapy by manipulating Mcl-1 deubiquitination.

A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer.

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, 73.5 Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63 Gy 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.