bluuebunny/crossref_metadata_2025 huggingface dataset:
Tremelimumab in combination with durvalumab in first or second-line mesothelioma patients: Safety analysis from the phase II NIBIT-MESO-1 study.
Authors: Calabro Luana , Morra Aldo , Giannarelli Diana , Amato Giovanni , Bertocci Erica , D'Incecco Armida , Danielli Riccardo , Brilli Lucia , Giannini Fabio , Altomonte Maresa , Di Giacomo Anna Maria , Maio Michele
Published: September 2018

8558

Background: The anti-CTLA-4 tremelimumab at two different dose-schedules of administration showed promising activity in second-line malignant mesothelioma (MM) patients (Calabrò et al., Lancet Oncol, 2013; Calabrò et al., Lancet Respir Med, 2015). These initial results and the efficacy of targeting the PD-1/PD-L1 axis in different tumor types, prompted the NIBIT-MESO-1 study aimed at investigating the efficacy and safety of tremelimumab combined with the anti-PD-L1 durvalumab in mm patients. We report the safety analysis from the fully-enrolled NIBIT-MESO-1 study. Methods: The NIBIT-MESO-1 is a phase II, open-label, single Center study. Forty mm patients received tremelimumab at 1 mg/Kg i.v. every 4 weeks (Q4W) for 4 doses, and durvalumab at 20 mg/Kg i.v. Q4W for 13 doses. Primary objective is immune-related (ir)-objective response rate; secondary are safey, ir-disease control rate, ir-progression free survival, and overall survival. Tumor assessment per ir-modified RECIST or ir-RECIST 1.1 for pleural or peritoneal MM, respectively, was performed at baseline and q12 weeks. Adverse events (AEs) were recorded according to CTC v4.0. (ClinicalTrials.gov Id: NCT02588131). Results: From October 2015 to October 2016, 40 mm patients (38 pleural and 2 peritoneal), median age 64 years (range 41-80), ECOG performance status 0 (n = 19) or 1 (n = 21) were enrolled in the study. mm histology was epithelioid (n = 32), biphasic (n = 5), sarcomatoid (n = 2) or undefined (n = 1). As of January 2017, 12 first or 28 second-line mm patients received a median of 5.5 doses of therapy (range = 1-13). Twenty-four patients (60%) experienced any grade irAEs: 5 patients (12.5%) had grade 3-4 AEs, the most frequent being hepatotoxicity (7.5%). AEs were generally manageable and reversible per protocol guidelines. Three patients (7.5%) were discontinued due to treatment-related AEs (1 trombocytopenia, 1 limbic encephalitis, 1 liver toxicity). Conclusions: The combination of tremelimumab and durvalumab is safe and manageable in mm patients. Clinical trial information: NCT02588131.
Systemic therapy use and outcomes after relapse from accelerated hemithoracic radiation and surgery for malignant pleural mesothelioma (MPM).
Authors: Soldera Sara V. , Kavanagh John , Pintilie Melania , Feld Ronald , Leighl Natasha B. , Cho John , de Perrot Marc , Bradbury Penelope Ann
Published: September 2018

8559

Background: The prognosis of patients (pts) with MPM remains poor. Accelerated hemithoracic radiation followed by extrapleural pneumonectomy and adjuvant chemotherapy in ypN2 disease (SMART) provides encouraging results. The ability to administer systemic therapy (Tx) and response rate (RR) after recurrence remains unclear. We therefore examined subsequent lines of Tx and outcomes following relapse after SMART. Methods: A retrospective analysis of pts diagnosed with recurrent MPM following SMART was conducted at a single institution. OS was determined from date of relapse to death and was estimated using the Kaplan-Meier method. Potential prognostic variables were tested utilizing the log-rank test. Results: Out of 86 pts undergoing SMART from 2008 to 2016, 53 (62%) developed recurrent disease of which 36% had pathological confirmation. Two cases with initial epithelial subtype on surgical specimen relapsed with different histology (sarcomatoid and small cell). In 48% of pts, relapse was unclear at first imaging (n = 42) and a median of 98 days (range 6-966) lapsed between first suspicion and final diagnosis. The median age at relapse was 66 years (range 45-79), 47% had a performance status (PS) ≥2 (n = 45) and 64% were of epithelial subtype. After a median follow up of 7.6 mo, the median OS was 5.2 mo. PS ≥2 was associated with worse OS (2.8 vs 10.7 mo, p < 0.001). Of 42 pts followed after relapse, 36% received any Tx (19% 1 line; 12% 2 lines; 5% ≥3 lines). Tx was omitted in 62% of pts due to poor PS (26/42). First line Tx consisted of platinum doublet in 93% of pts (n = 15). Of 13 pts with response evaluable disease, RR was 15% (0 CR, 15% PR). Of note, 0/13 pts had neoadjuvant Tx and 3/13 pts had adjuvant Tx (10, 13 and 38 mo lapsed between end of adjuvant Tx and start of Tx in the relapsed setting). 6/15 pts discontinued Tx due to toxicity, 5/15 due to progression and median number of cycles was 4. Conclusions: Pts with relapsed MPM following SMART have poor prognosis and low RR to first line Tx. Poor performance status at relapse is a poor prognostic factor. Earlier detection, novel diagnostic markers of relapse and consideration of maintenance strategies should be investigated in future studies.
Longitudinal monitoring of circulating tumor DNA and peripheral T cell repertoire in patients with small cell lung cancer.
Authors: Iams Wade Thomas , Almodovar Karinna , Meador Catherine , York Sally Jane , Horn Leora , Raymond Chris , Hernandez Jennifer , Shaffer Tristan , DiPasquo Dan , Lim Lee , Lovly Christine Marie
Published: September 2018

8571

Background: Advances in the treatment of small cell lung cancer (SCLC), an aggressive disease with poor prognosis, will require the development of diagnostic methods during treatment that are more sensitive and descriptive than are currently available. The emergence of “liquid biopsy” technologies coupled with comprehensive genomic information about common mutations in SCLC prompted us to implement a blood-based assay for simultaneous sequencing of circulating, cell-free tumor DNA (cfDNA) and determination of the peripheral a and b T cell receptor repertoire in patients with SCLC. Methods: Our SCLC assay uses targeted hybrid capture and next generation sequencing of cfDNA extracted from patient plasma to detect somatic mutations in 14 frequently mutated genes in SCLC. We also sequenced rearranged T cell receptor α and β genes, each with 5000 unique α and β CDR3 open reading frames per microgram of gDNA. Over 26 months we followed 27 patients with SCLC (16 with extensive stage and 11 with limited stage disease) and examined cfDNA from 141 plasma samples and T cell repertoire from 41 samples. Results: We detected somatic, disease-associated mutations in 85% of patient samples (23/27) with allele frequencies of cfDNA ranging from ≤0.5% to ≥85%. The most commonly mutated genes were TP53 (17/27 patients) and RB1 (10/27 patients) . We detected 87 unique genomic alterations in 12 different genes (in addition to TP53 and RB1 these included PTEN, NOTCH1-4, MYC, MYCL1, PIK3CA, KIT, and BRAF). The observed mutant allele frequencies in longitudinal samples tracked with treatment response, including cases in which cfDNA allele frequencies increased before clinical evidence of relapse. Longitudinal monitoring of T cell repertoire demonstrated both variability between patients and sequential changes during therapy, including one case of decreased T cell numbers accompanying disease relapse. Conclusions: As the field of immuno-oncology matures, we anticipate that coupled determination of T cell repertoire together with cfDNA monitoring will merge into a clinically useful “molecular image” of each patient’s disease status and real-time host immune response.
Efficacy of the addition of cisplatin to single-agent first-line chemotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC): A joint analysis of the multicenter, randomized phase III MILES-3 and MILES-4 studies.
Authors: Gridelli Cesare , Morabito Alessandro , Cavanna Luigi , Luciani Andrea , Maione Paolo , Bonanno Laura , Piazza Elena , Leo Silvana , Cinieri Saverio , Ciardiello Fortunato , Burgio Marco Angelo , Ferrara Domenica , Cortinovis Diego , Rosetti Francesco , Montanino Agnese , Manzo Anna , Daniele Gennaro , Perrone Francesco , Gallo Ciro , Piccirillo Maria Carmela
Published: September 2018

9002

Background: The role of platinum in first line treatment of elderly patients with advanced NSCLC is still debated. We tested its efficacy in two parallel phase 3 trials. Methods: Advanced NSCLC patients, > 70 years, ECOG performance status 0-1, were eligible. In MILES-3 (started in 2011) patients with any tumor histology were randomly assigned 1:1 to cisplatin/gemcitabine (C 60 mg/m² d1, G 1000mg/m² dd1,8) or gemcitabine (G 1200 mg/m² dd1,8). In MILES-4 (started in 2013 with a factorial design) patients with non-squamous histology were randomly assigned 1:1:1:1 to CG, G, cisplatin/pemetrexed (C 60 mg/m² d1, P 500 mg/m² d1) or pemetrexed (P 500 mg/m² d1). Six cycles were planned. In each trial, to have 80% power in detecting a HR of death 0.75 (corresponding to 3-month prolongation of median survival), with 0.05 two-tailed α, 382 events were required. The two trials were closed prematurely because of slow accrual but a joint analysis allowed to properly perform the final analysis, according to IDMC advice. Analysis was based on intention-to treat and adjusted by possible confounding factors. Results: From Mar 2011 to Aug 2016, 531 patients (MILES-3: 299, MILES-4: 232) were assigned to cisplatin-doublet (n = 263) or single-agent chemotherapy (n = 268). Median age was 75, 79% were male, 70% had non-squamous histology. Median number of cycles was 4 and 3 with and without cisplatin, respectively. With a median follow-up of 2 years, 384 deaths and 448 progression-free survival (PFS) events were reported. With and without cisplatin, median OS was 9.6 vs 7.5 months (HR 0.86, 95% CI: 0.70-1.04, p = 0.14); median PFS was 4.6 vs 3.0 months (HR 0.76, 95% CI: 0.63-0.92, p = 0.005); response rate was 15.5% vs 8.5% (p = 0.02). Significantly more severe hematologic toxicity and fatigue were reported with cisplatin. Conclusions: Although improving PFS and response rate, addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival of elderly patients with advanced NSCLC. QOL data will be reported separately. Partially supported by AIFA (grant FARM8KAJZK) and Eli Lilly. Clinical trial information: NCT01405586 and NCT01656551.
A randomized, controlled, open label phase II study of erlotinib (E) with or without the MET antibody emibetuzumab (Emi) as first-line treatment for EGFRmt non-small cell lung cancer (NSCLC) patients who have disease control after an 8-week lead-in treatment with erlotinib.
Authors: Scagliotti Giorgio V. , Moro-Sibilot Denis , Kollmeier Jens , Favaretto Adolfo G. , Cho Eun Kyung , Grosch Heidrun , Kimmich Martin , Girard Nicolas , Tsai Chun-Ming , Hsia Te-Chun , Brighenti Matthew , Schumann Christian , Wang Xuejing Aimee , Wijayawardana Sameera R. , Gruver Aaron M , Wallin Johan , Mansouri Kambiz , Wacheck Volker , Chang Gee-Chen
Published: September 2018

9019

Background: MET expression is a mechanism of resistance to EGFR inhibition in EGFRmt NSCLC and correlated with poor prognosis. Emi (LY2875358) is a humanized IgG4 monoclonal bivalent MET antibody that blocks ligand dependent and independent HGF/MET signaling. This Phase 2 study compared the clinical activity of Emi + E versus single agent E in 1st line EGFRmt metastatic NSCLC. Methods: Stage IV, EGFRmt NSCLC pts with disease control following an 8-week lead-in E (150 mg PO QD) treatment were randomized 1:1 to receive Emi (750 mg IV Q2W) + E or E alone. Pts were stratified by ECOG PS, ethnicity, MET expression status, and response at the end of the lead-in. The primary endpoint was PFS from randomization. Additional endpoints included safety, OS, PK, and exploratory analysis of MET-expressing populations. Results: Out of181 pts enrolled, 141 pts were randomized (Emi+E: 71; E: 70). In the ITT population, median PFS for EMI+E was 9.3 months (m) compared with 9.5 m for E (HR = 0.89: 90% CI 0.64-1.23; p = 0.534). Exploratory analysis of MET-high expressing pts (MET 3+ expression in ≥90% of tumor cells; n = 24 pts) showed a 15.3 m improvement in PFS (EMI+E: 20.7 m; E: 5.4 m [HR: 0.39; 90% CI: 0.17-0.91]). No difference in PFS was observed in the complementary population (HR: 1.1 [90% CI: 0.7-1.7]). Similar frequencies of related AEs were reported for both treatment arms. Drug-related TEAEs that were more frequent ( > 10%) for Emi+E were peripheral edema and fatigue (all grade 1 or 2). Emi serum concentrations were consistent with previously obtained PK results, and no apparent exposure-response was observed. Median OS in the ITT population was not achieved (NA) for either arm. In MET-high expressing pts, median OS was 20.6 m for E (90% CI: 8.87, NA) whereas it was not achieved for Emi+E (90% CI: NA, NA). Conclusions: No statistically significant difference in PFS was noted in the ITT population.Exploratory analysis confirmed that high MET expression is a negative prognostic marker for pts treated with E and indicated that these pts may receive clinically meaningful benefit from Emi+E. Clinical trial information: NCT01897480.
Updated survival outcomes of NEJ005/TCOG0902, a randomized phase II study of concurrent (C) versus sequential alternating (S) gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations.
Authors: Oizumi Satoshi , Sugawara Shunichi , Minato Koichi , Harada Toshiyuki , Inoue Akira , Fujita Yuka , Maemondo Makoto , Watanabe Satoshi , Ito Kazuhiko , Gemma Akihiko , Demura Yoshiki , Harada Masao , Isobe Hiroshi , Kinoshita Ichiro , Morita Satoshi , Kobayashi Kunihiko , Hagiwara Koichi , Kurihara Minoru , Nukiwa Toshihiro ,   North East Japan Study Group (NEJ) and Tokyo Cooperative Oncology Group (TCOG)
Published: September 2018

9038

Background: North East Japan Study Group (NEJ) 005/ Tokyo Cooperative Oncology Group (TCOG) 0902 study has demonstrated that first-line concurrent (C) and sequential alternating (S) combination therapies of EGFR tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant NSCLC (ASCO2014, Ann Oncol 2015). However, overall survival (OS) data were insufficient because of the lack of death events in the primary report. Methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cutoff point (November 2016) for the entire population (N = 80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 72.5% of patients had died. Median PFS was 17.5 months for the C regimen and 15.3 months for the S regimen (p = 0.13). Median OS time was 43.3 with the C regimen and 30.7 months with the S regimen (p = 0.018). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; p = 0.34). Patients who had common mutations showed no significant differences in PFS according to type of mutation. Patients with Del19 displayed relatively better OS (median: 45.3 and 33.3 months for C and S regimens) than those with L858R (31.4 and 28.9 months). No severe adverse events including interstitial lung disease have occurred during the follow-up period since the primary report. Conclusions: This updated analysis has confirmed that PFS is improved with first-line combination therapies compared to that with gefitinib monotherapy, and the C regimen in particular offers an overall survival benefit of 43 months in the EGFR-mutated setting. Our on-going NEJ009 study will clarify whether this combinational strategy can be incorporated into routine clinical practice. Clinical trial information: UMIN000002789.
Recurrent versus de novo metastatic NSCLC: Impact on outcomes.
Authors: Moore Sara , Leung Bonnie , Wu Jonn , Shokoohi Aria , Ho Cheryl
Published: September 2018

9045

Background: Metastatic non-small-cell lung (NSCLC) cancer has a poor prognosis, with a 5 year survival less than 5%. The majority of patients present with stage IV and many patients treated curatively with stage I-III will develop recurrent metastatic disease. It is unknown if the natural history differs between patients with recurrent versus de novo metastatic NSCLC. We hypothesized that de novo metastatic disease is associated with decreased overall survival compared to recurrent metastatic disease. Methods: A retrospective review was completed of all patients with NSCLC referred to the BC Cancer Agency from 2005-2012. Two cohorts were created; de novo metastatic disease and patients treated with curative intent (surgery or radiotherapy) that developed recurrent, metastatic disease. Information was collected on known prognostic and predictive factors. Overall survival was calculated from the date of diagnosis of metastatic disease. Results: A total of 9656 patients were referred, 5783 (60%) with de novo stage IV disease, and 3873 (40%) with stage I-III disease. Of patients with initial stage I-III, 1801 received curative therapy (751 surgery, 1050 radiotherapy) and 802 developed metastases. Patients in the de novo cohort were more likely to be male (52% vs 47%), have poorer performance status (ECOG≥2 50% vs 43%), and receive no palliative chemotherapy (67% vs 61%). The median overall survival in the de novo cohort was 4.7 m vs 6.9 m in the recurrent cohort (p < 0.001). De novo status was associated with shorter overall survival and this remained significant in a multivariate model that incorporated gender, ECOG and lines of palliative chemotherapy (hazard ratio 1.228[95% confidence interval 1.134-1.330], p-value < 0.001). Conclusions: In a large population based study of NSCLC, de novo metastatic status was independently associated with decreased overall survival from the time of metastatic disease diagnosis. De novo versus recurrent status should be used as a prognostic factor to inform patient decisions and ensure balanced stratification of patients in clinical trials.
Clinical comparison of ABP 215 and bevacizumab in patients with NSCLC: Pharmacokinetic results and justification for extrapolation across bevacizumab indications.
Authors: Thatcher Nick , Thomas Michael , Pan Zhiying , Goldschmidt Jerome H. , Schenker Michael , Melara Rebeca , Hanes Vladimir
Published: September 2018

9050

Background: Approval of biosimilars is based on totality of evidence (TOE) that includes demonstration of analytical, functional, and pharmacokinetic (PK) similarity, and comparable clinical efficacy, safety, and immunogenicity. The TOE supports scientific justification for extrapolation across other indications that a share common mechanism of action (MOA). The proposed biosimilar ABP 215 is similar to bevacizumab (BEV) with respect to inhibition of vascular endothelial growth factor (VEGF)-induced signaling; PK in healthy adults; and clinical efficacy, safety, and immunogenicity in patients with non-small cell lung cancer (NSCLC). The PK results from the NSCLC study are reported here. Methods: In this double-blind study, adults with non-squamous NSCLC receiving first-line chemotherapy with carboplatin and paclitaxel were randomized 1:1 to ABP 215 or BEV (15 mg/kg IV Q3W for 6 cycles). Trough (pre-dose) PK samples were collected at baseline, at weeks 4, 7, and 13, and at end of study. Clinical evaluations included efficacy, safety, and immunogenicity. Results: 642 patients (ABP 215, n = 328; BEV, n = 314) were randomized. Demographic and baseline characteristics were well balanced. The primary endpoint of risk ratio for objective response rate was 0.93 (2-sided 90% CI, 0.80-1.09), which was contained within the pre-specified equivalence margin. The incidence of adverse events was comparable between ABP 215 and BEV. During the study, 4 (1.4%) and 7 (2.5%) patients in the ABP 215 and BEV group, respectively, developed binding antibodies; no patient tested positive for neutralizing antibodies. Steady-state trough serum concentrations for both ABP 215 and BEV were reached by week 13 (median 124.9 vs 124.4 µg/mL, respectively) and were consistent between ABP 215 and BEV throughout the study. Conclusions: ABP 215 is similar to BEV in multiple analytical, functional, and clinical assessments. PK results in patients presented here provide further evidence for similarity between ABP 215 and BEV and contribute to the TOE supporting extrapolation of clinical similarity across BEV indications based on its common MOA. Clinical trial information: NCT01966003.
Primary resistance to ALK inhibitor in ALK-positive non-small-cell lung cancer.
Authors: Kang Jin , Chen Huajun , Zhou Qing , Tu Hai-Yan , Zhang Xu-Chao , Jian Su , Wang Zhen , Wang Bin-Chao , Wu Yi-Long , Yang Jin-Ji
Published: September 2018

9063

Background: Crizotinib is a standard of care in anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancers (NSCLC). Undoubtedly,the resistance to crizotinib is a current bottleneck which resists its clinical application. However, there are few reports about the primary resistance to crizotinib, especially the difference between the primary and acquired resistance. Methods: Totally,171 ALK-positive NSCLC patients treated with crizotinib were reviewed at the Guangdong General Hospital in China from October 2010 to July 2016. The status of an ALK gene rearrangement was assessed by Vysis ALK Break Apart fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), or ALK Ventana immunohistochemistry (IHC). Among 18 patients with primary resistance, 12 had tumor tissue (n = 6) or plasma (n = 6) at the baseline and meanwhile tumor tissue (n = 2) or plasma (n = 2) specimens were collected for 4 patients after primary resistance. Next generation sequencing was used to test the tissue or plasma from 16 patients with primary resistance to crizotinib. Results: Among 171 patients treated with crizotinib, 47.9% (82/171) developed acquired resistance, and 10.5%(18/171) had primary resistance. Using the specimens at the baseline, there were 6 ( 33.0%) patients with uncommon ALK fusion partners, 4 (22.2 %) with BIM deletion polymorphism, 2 (11.1%) with PTEN/mTOR mutations, and 1 (5.5 %) with a pre-existing ALK G3709A mutation.These uncommon ALK fusion partners included ZC3H8-ALK, ALK-LOC102723854 and ALK-DTNB-ASXL2. In addition, one patient was found to coexsist with KIT mutation after primary resistance. Median PFS was significantly shorter in patients with primary resistance than those with acquired resistance (2.2 vs. 10.8 months, P < 0.001). Conclusions: Uncommon ALK fusion partners, BIM deletion polymorphism, PTEN/mTOR mutation, pre-existing ALK G3709A mutation and KIT mutation might contribute to molecular mechanisms of primary resistance to crizotinib in ALK-positive NSCLC. Further investigations are warranted to overcome these primary resistances.
Cost-effectiveness analysis comparing companion diagnostic tests for EGFR, ALK and ROS-1 versus next-generation sequence (NGS) in advanced adenocarcinoma lung cancer patients.
Authors: Schluckebier Luciene , Caetano Rosangela , Aran Veronica , Ferreira Carlos G. M.
Published: September 2018

9068

Background: Success of a target therapy is directly correlated with the accuracy of its companion diagnostic test. Without a corresponding biomarker, target therapy may yield shorter survival, waste time, increase burdens and costs. As important as conducting cost-effectiveness studies for therapies, it is also valuable to compare different molecular tests. In lung cancer, the mutational status of EGFR and translocation of ALK and ROS-1 are commonly tested to offer the best intervention. Our objective is to evaluate the cost-effectiveness of a unique exam using NGS versus other routinely used tests such as the ones which involve RT-PCR and FISH. Methods: Target population is NSCLC, adenocarcinoma, and candidates to first-line therapy. Strategy 1: test EGFR mutation if EGFR test is negative, individual follow to FISH for ALK; if FISH is negative, follow to FISH for ROS-1. Strategy 2: differs from 1 since FISH for ALK and ROS are requested together. Strategy 3: all individuals are submitted to NGS (multicomplex platform which include EGFR, ALK, ROS-1 and other genes). Tests could also be classified as unknown due to the quality of tumor sample. Prevalence of biomarker, test accuracy and proportion of unknown results were used to calculate each decision tree branch. Sensitivity and specificity was obtained from literature review using Sanger as reference standard for RT-PCR tests and NGS. The study was analyzed from a healthcare-payer perspective based on Brazilian private sector. Costs were based on data from diagnostic companies, ANS and AMB-CBHPM 2016. Results: The use of NGS added 24% extra cases correct identified as well as extra costs (US$ 800.76; PPP 2015) attributed to the molecular testing. The ICER comparing NGS with sequential tests was US$ 3,381.82/correct case detected. Comparing strategy 2:1, the ICER was US$937.86/correct case detected. Conclusions: this study is part of an effort to integrate companion diagnostics discussions on precision medicine and covered drugs in the Brazilian health system. These findings can also subsidy cost-effectiveness studies that incorporates subsequent treatments and survival.
A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms.
Authors: Tarhini Ahmad A. , Lee Sandra J. , Hodi F. Stephen , Rao Uma N. M. , Cohen Gary I , Hamid Omid , Hutchins Laura Fulper , Sosman Jeffrey Alan , Kluger Harriet M. , Sondak Vernon K. , Koon Henry B. , Lawrence Donald P. , Kendra Kari Lynn , Minor David R. , Lee Carrie B. , Albertini Mark R , Flaherty Lawrence E. , Petrella Teresa M. , Kirkwood John M.
Published: September 2018

9500

Background: In the U.S., 3 regimens have regulatory approval as adjuvant therapy for high-risk melanoma, including high-dose interferon-alfa (HDI) and ipilimumab 10 mg/kg (ipi10). Ipilimumab 3 mg/kg (ipi3) has regulatory approval for metastatic inoperable melanoma. The toxicity of ipi is dose- dependent, and following the recent approval of adjuvant ipi10, it has become urgent to evaluate the relative safety and efficacy of adjuvant ipi at the 2 dose levels that have been tested in E1609. Methods: E1609 randomized patients (pts) with resected high-risk melanoma (stratified by stages IIIB, IIIC, M1a, M1b) to ipi10 or ipi3 versus HDI. Co-primary endpoints were RFS and OS. The current analysis investigates the relative safety and preliminary, non-comparative RFS of the ipi arms as of 3/2/17. Results: E1609 was activated on 5/25/11 and completed adult pt accrual on 8/15/14. Accrual to ipi10 was suspended due to toxicity between 9/23-11/16/2013. Final adult pt accrual was 1670 including 511 ipi10, 636 HDI and 523 ipi3 pts. Treatment related adverse events (AEs) were reported among 503 ipi10 and 516 ipi3 pts. Worst degree (Gr 3+) AEs were experienced by 57% ipi10 and 36.4% ipi3 pts and were mostly immune related (Table 1). AEs led to discontinuation of treatment in 271 (53.8 %) of 503 ipi10 and in 180 (35.2 %) of 512 ipi3 pts during the initial 4 dose induction phase. Gr5 AEs considered at least possibly related were 8 with ipi10 and 2 with ipi3. At a median follow-up of 3.1 years, an unplanned RFS analysis of ipi3 and ipi10 on concurrently randomized pts showed no difference between the 2 arms. Three-year RFS rate was 54% (95% CI: 49, 60) with ipi10 and 56% (50, 61) with ipi3. Conclusions: Adjuvant therapy of pts with high-risk melanoma is associated with significantly more toxicity at ipi10 compared to ipi3. An unplanned RFS analysis of concurrently randomized pts on the 2 ipi arms showed no difference in RFS. Clinical trial information: NCT01274338. [Table: see text]
A randomized multicenter phase 3 trial of adjuvant fotemustine versus surveillance in high risk uveal melanoma (UM) patients (FOTEADJ).
Authors: Piperno-Neumann Sophie , Rodrigues Manuel Jorge , Servois Vincent , Pierron Gaëlle , Gastaud Lauris , Negrier Sylvie , Levy-Gabriel Christine , Lumbroso Livia , Cassoux Nathalie , Bidard Francois-Clement , Michielin Olivier , Lacour Jean-Philippe , Durando Xavier , Mariani Pascale , Plancher Corine , Asselain Bernard , Armanet Sebastien , Mosseri Veronique , Desjardins Laurence
Published: September 2018

9502

Background: Up to 30% of UM patients will develop metastases, with a median survival of 12 months in the metastating setting. Prognostic factors combine clinical features of the primary tumor (diameter, thickness, retinal detachment, extra-scleral extension) and genetic factors (monosomy 3, 8 q gain and class 1 /2 gene expression profiling).The genomic analysis is feasible by fine needle aspiration biopsies before radiotherapy for small UM or on enucleated eyes. Methods: Multicenter randomized phase 3 trial with adjuvant fotemustine, 6 cycles, 100 mg/m2 versus surveillance for 3 years (liver tests/3 months, liver MRI or CT/6 months, whole body CT/12 months) in patients with high risk of recurrence, defined by clinical criteria (diameter > 15 mm with extra scleral extension and/or retinal detachment or diameter > 18 mm) or genomic high risk signature by array-CGH (monosomy 3 or deletion of 3p associated with gain of chromosome 8). The primary objective was 5-year Metastasis Free Survival (MFS). With an expected increase of 5-year MFS from 50 to 70%, 302 patients and 99 events were required to achieve an 95%-power with a 5% type I error rate. Secondary objectives were overall survival (OS), safety (NCI-CTC v3), quality of life (QLQ-C30). Interim analyses were planned for safety and after 50 events, disclosed to an independent safety monitoring board. Results: The trial was stopped for futility after 244 patients had been recruited between June 2009 and January 2016. No unexpected toxicity was found in the chemotherapy group. The study was amended to go on with intensive surveillance in new high risk patients. Ninety-one metastases and 43 deaths were reported, with no treatment-related death. With a median follow-up of 3 years, the 3-year MFS is 60.3% in the chemo group and 60.7% in the surveillance group (HR 0.97 [0.64-1.47]). The 3-year OS is 79.4% [73.2-85.7], with no difference between the 2 groups of patients. Conclusions: FOTEADJ is the first adjuvant randomized phase 3 trial based on genomic analysis in high risk UM patients. Despite negative results, it shows the feasibility of multicenter adjuvant studies in this rare cancer and provides genomic data in small tumors for future trials. Clinical trial information: NCT02843386.
Primary results from a randomized (1:1), open-label phase II study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected stage IIIB- IV melanoma.
Authors: Chesney Jason Alan , Puzanov Igor , Ross Merrick I. , Collichio Frances A. , Milhem Mohammed M. , Chen Lisa , Kim Jenny J. , Garbe Claus , Hauschild Axel , Andtbacka Robert Hans Ingemar
Published: September 2018

9509

Background: T is a HSV-1-based oncolytic virus designed to selectively replicate in tumors and produce GM-CSF to stimulate antitumor immune responses. I is an anti-CTLA-4 Ab that blocks inhibition of activated T cells. This is the first randomized study to evaluate the addition of an oncolytic virus to a checkpoint inhibitor. Methods: The 1o endpoint was ORR by immune-related response criteria. Key 2o endpoints: duration of response, disease control rate (DCR), PFS, OS, and safety. Prior treatment was allowed but not required. Pts had unresected stage IIIB-IV melanoma with measurable/injectable tumor(s) and no evidence of immunosuppression. T was given at approved dosing until no injectable tumors, disease progression (PD), or intolerance. I was started at w6 in T+I and at w1 in I at 3 mg/kg IV q3w x 4. Primary analysis occurred 6 m after last pt enrolled. Results: 198 pts were randomized: 98 T+I; 100 I. Characteristics were similar: 54% stage IIIB-IVM1a, 46% IVM1b/c. Median follow up time was 68 w (T+I) and 58 w (I). ORR was 38.8% (T+I) and 18.0% I, P = 0.002, Odds ratio (OR) 2.9. 89% T+I and 83% I pts remain in response. Unconfirmed visceral lesion response was 35.5% T+I vs 13.6% I. OS is immature. Of 190 pts (safety set: 95 T+I, 95 I), most common adverse events (AEs) for T+I, I (%) were fatigue (59, 42), chills (53, 3), and diarrhea (42, 35). 28% T+I and 18% I pts had gr ≥3 tx-related AE. There were 3 deaths (all unrelated) in T+I: 1 myocardial infarction and 2 PD. Conclusions: The study met the 1o endpoint. ORR was significantly higher for T+I vs I; responses were not limited to injected lesions. Toxicity of T+I combination was tolerable with no unexpected AEs. Clinical trial information: NCT01740297. [Table: see text]
A phase Ib/II dose-escalation study evaluating triple combination therapy with a BRAF (encorafenib), MEK (binimetinib), and CDK 4/6 (ribociclib) inhibitor in patients (Pts) with BRAF V600-mutant solid tumors and melanoma.
Authors: Ascierto Paolo Antonio , Bechter Oliver , Wolter Pascal , Lebbe Celeste , Elez Elena , Miller Wilson H. , Long Georgina V. , Omlin Aurelius Gabriel , Siena Salvatore , Calvo Emiliano , Pickard Mike , Gollerkeri Ashwin , Wollenberg Lance , Germa Caroline , Dummer Reinhard
Published: September 2018

9518

Background: The benefits of BRAF + MEK inhibition (dual combo) in pts with BRAF V600-mutant ( BRAFV600) melanoma are known. Preclinical data supports inhibiting CDK 4/6 and BRAF + MEK (triple combo) to improve antitumor activity. We report safety and preliminary efficacy from a phase 1b/2 study (NCT01543698) of encorafenib (ENCO; a selective BRAF kinase inhibitor), binimetinib (BINI; a MEK inhibitor), and ribociclib (RIBO; a CDK 4/6 inhibitor). Methods: Phase 1b of this open-label, multicenter study enrolled pts with confirmed BRAFV600advanced solid tumors. Escalating doses of RIBO 100 mg-600 mg QD for 3 wk on/1 wk off were administered with ENCO 200 mg QD + BINI 45 mg BID in successive cohorts (6 pts each) until the maximum tolerated or recommended phase 2 dose (RP2D) was reached. Due to potential pharmacokinetic interactions with RIBO, the ENCO dose was lower than the dual combo RP2D (450 mg QD). Dose escalations followed an adaptive Bayesian model. In phase 2, the triple combo was tested in pts with BRAFV600melanoma naïve to prior BRAF inhibitor treatment; the primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: In phase 1b (n = 21), no dose-limiting toxicities were reported and the triple combo RP2D was ENCO 200 mg QD + BINI 45 mg BID + RIBO 600 mg QD. ENCO AUC was slightly lower than at the dual combo RP2D. In phase 2 (n = 42), 59.5% pts had an ECOG PS of 0 and 43% of pts had elevated lactate dehydrogenase. The most common (≥5%) grade 3/4 toxicities were neutropenia (26.2%), increased alanine transaminase (14.3%), diarrhea (7.1%), and anemia (7.1%). Ten pts (23.8%) discontinued treatment due to an AE, of which 4 were increased transaminases. The confirmed ORR was 52.4%, including 4 complete responses, 18 partial responses, and 15 pts with stable disease. Median duration of exposure in phase 2 was 9.1 mo (range, 0.0-21.6). Median progression-free survival was 9.0 mo (95% confidence interval, 7.0-11.1). Conclusions: Triple therapy with ENCO + BINI + RIBO in this small trial of pts with high disease burden was associated with responses in over half of pts and some evidence of increased toxicity. Clinical trial information: NCT01543698.
ENCORE 601: A phase II study of entinostat (ENT) in combination with pembrolizumab (PEMBRO) in patients with melanoma.
Authors: Johnson Melissa Lynne , Gonzalez Rene , Opyrchal Mateusz , Gabrilovich Dmitry , Ordentlich Peter , Brouwer Susan , Sankoh Serap , Schmidt Emmett V. , Meyers Michael L. , Agarwala Sanjiv S.
Published: September 2018

9529

Background: Entinostat is an oral, class I selective histone deacetylase inhibitor shown preclinically to enhance immune checkpoint inhibitor activity by regulation of immune suppressor cells in the tumor microenvironment. ENCORE 601 is designed to evaluate safety and efficacy of ENT in combination with PEMBRO. Phase 1b identified ENT 5 mg PO weekly and PEMBRO 200 mg IV every 3 weeks as the recommended Phase 2 dose for further investigation. Methods: Phase 2 of ENCORE 601 employs a Simon 2-stage design to assess activity across 3 cohorts: 1) NSCLC not previously treated with a PD-1/L1 blocking antibody, 2&3) NSCLC & melanoma previously progressing on or after a PD-1/L1 blocking antibody. Patients were enrolled irrespective of PD-L1 expression levels. The primary endpoint is ORR as assessed by irRECIST. Results of the first stage of Cohort 3 are reported. Criteria for advancing to Stage 2 are ≥2 responses out of 13 evaluable patients. Results: Stage 1 enrollment has been completed (n = 13). All patients received a prior PD-1 inhibitor; in addition, 7 patients received prior ipilimumab and 2 patients received a prior BRAF inhibitor. 9 patients are still on treatment; 4 patients have discontinued due to progression. To date, 1 confirmed and 1 unconfirmed objective response have been observed. The confirmed response (PR) was in a patient who was previously treated with ipilimumab/nivolumab for 6 months (best response of SD with subsequent progression on therapy). Treatment-related AEs occurred in 5 patients (most common being nausea and fatigue occurring in 2 patients); one patient experienced Gr3/4 events (fatigue and rash). Blood samples and pre-treatment biopsies were obtained in all patients along with paired post-treatment biopsies in 8 patients. Evaluation of PD-L1 expression, gene expression, myeloid and lymphoid compartments in blood and tumor samples is in progress. Of note, the patient with a confirmed PR converted from a PD-L1 negative, non-inflamed gene signature to PD-L1 positive, inflamed after 2 weeks of treatment. Conclusions: ENT combined with PEMBRO demonstrates acceptable safety and encouraging preliminary activity in melanoma patients refractory to checkpoint inhibitors. Clinical trial information: NCT02437136.
Phase II multicenter, single arm, open label study of nivolumab (NIVO) in combination with ipilimumab (IPI) as first line in adult patients (pts) with metastatic uveal melanoma (MUM): GEM1402 NCT02626962.
Authors: Piulats Josep M. , De La Cruz-Merino Luis , Curiel Garcia Maria Teresa , Berrocal Alfonso , Alonso-Carrión Lorenzo , Espinosa Enrique , López Castro Rafael , Rodriguez-Abreu Delvys , Luna Fra Pablo , Martin-Algarra Salvador
Published: September 2018

9533

Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults. Overall Survival (OS) at 5 years(y) is 62% due high incidence of liver metastasis, fatal within 4-9 months(m) from diagnosis. No standard treatment exists for MUM. NIVO+IPI combination has shown efficacy in metastatic cutaneous melanoma. However, MUM pts were excluded in these trials. Methods: GEM1402 is a phase-2 trial evaluating NIVO+IPI in untreated adult pts with MUM; is being conducted in 10 centers in Spain, leading by the Spanish Melanoma Group. Eligible pts had histologically-confirmed MUM, ECOG-PS 0/1, and no prior systemic treatment for MUM. Treatment consisted in NIVO (1mg/kg, iv, q3 weeks [wk]) and 4 doses of IPI (3mg/kg iv q3wk) followed by NIVO (3mg/kg q2wk) until progressive disease (PD), toxicity or withdrawal. Primary endpoint is OS and secondary progression free survival (PFS), Overall Response Rate (ORR) (per RECIST 1.1) and safety. Radiologic evaluations q6wk. Interim analysis (n = 19) was planned per protocol to assess safety and ORR. Intention to treat analysis includes pts with PD at first radiological evaluation. Safety population includes all pts receiving at least one dose of study treatment. Results:19 pts enrolled from April to July 2016: Median age 62y (43y-82y), 63% male, liver M1 84% pts and extra-liver M1 42% pts, 31% elevated baseline LDH. 11 pts completed cycle 2 and 8 pts stopped after 1 dose (6 PD, 2 toxicity). Treatment-related adverse events were reported in 12 pts and lead to end of treatment in 2 pts. Grade ≥3 toxicities were seen in 7 pts (36.8%): diarrhea, transaminitis, dermatological events, anemia, acute thyroiditis. All G3/4 were resolved following the toxicity guideline. One G5 acute thyroiditis related to NIVO+IPI was reported. ORR was observed in 15.8% and disease stabilization in 47.4%. With a median follow-up of 4.6m, PFS was 4.99m. Median OS was not reached at time of this analysis. Conclusions: Combination of NIVO+IPI is feasible for MUM. In this INTERIM ANALYSIS, ORR did not reach yet 20%, but PFS seems promising. The clinical trial is ongoing. Final results will be updated. Clinical trial information: 2015-004429-15.
Efficacy and safety of single agent pan-HER inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer (sSCC).
Authors: Bossi Paolo , Cavalieri Stefano , Perrone Federica , Miceli Rosalba , Ascierto Paolo Antonio , Locati Laura D. , Bergamini Cristiana , Granata Roberta , Alfieri Salvatore , Resteghini Carlo , Galbiati Donata , Busico Adele , Paielli Nicholas , Patuzzo Roberto , Maurichi Andrea , Gallino Gianfranco , Ruggeri Roberta , Mariani Luigi , Palla Marco , Licitra Lisa
Published: September 2018

9543

Background: In recurrent/metastatic skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. We investigated the role of pan-HER inhibitor dacomitinib within a phase II trial in this setting. Methods: Patients (pts) with diagnosis of sSCC not amenable to curative approaches were included. Oral dacomitinib was started at a dose of 30 mg daily for 15 days, followed by 45 mg daily. Primary endpoint was response rate (RR). Tumor samples were analyzed through Next Generation Sequencing methods (pgm, Ion torrent) using a custom panel targeting 36 genes associated with sSCC. Results: Forty-two pts (33 M, 9 F; median age 77 years, range 45-92) were treated. ECOG PS was 0 in 58%, 1 in 40% and 2 in 2%. One fifth of the pts had distant metastasis. Most pts (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). Among evaluable pts, overall RR was 28% (complete response CR 2%, partial response PR 26%), disease control rate 86%. Median duration of response was 11 months (range 1-26+). Median treatment duration was 4 months (range 1-26+). Reason for discontinuation were disease progression in 69%, adverse events (AEs) in 19%, non drug-related death in 5%; 3 pts are still on treatment. Median PFS and OS were 6 and 12 months, respectively. Most pts (93%) had at least one AE, mainly consisting in diarrhea and skin rash (71% each), fatigue (36%) and stomatitis (31%). G3/G4 AEs occurred in 36% of pts (diarrhea and skin rash 17% each). Tumor material was available from 7 responding (R: 6 PR, 1 CR) and 15 non-responding (NR: 13SD, 2PD) pts. Frequent TP53 (60%), NOTCH1/2 (60%) and FAT1 (40%) mutations were observed. NR pts showed a higher occurrence of HRAS/BRAF/NRAS mutations (40%) than R ones (28%). Moreover, HER3 (27%) CASP8 (27%), KMT2C (33%) and DCLK1 (27%) mutations were restricted to NR pts. Conclusions: In sSCC dacomitinib showed activity, similar to what observed with anti-EGFR monoclonal antibody cetuximab and panitumumab (RR 28% and 31%); safety profile was comparable to previous experiences in other diseases. Molecular pt selection could improve therapeutic ratio. Clinical trial information: NCT02268747.
KEYNOTE-029: Efficacy and safety of pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma.
Authors: Carlino Matteo S. , Atkinson Victoria , Cebon Jonathan S. , Jameson Michael B. , Fitzharris Bernie M. , McNeil Catriona M. , Hill Andrew G , Ribas Antoni , Atkins Michael B. , Thompson John A. , Hwu Wen-Jen , Hodi F. Stephen , Menzies Alexander M. , Guminski Alexander David , Kefford Richard , Shu Xinxin , Ibrahim Nageatte , Homet Moreno Blanca , Long Georgina V.
Published: September 2018

9545

Background: We previously showed that standard-dose pembro plus reduced-dose ipi has manageable safety and robust antitumor activity in patients (pts) with advanced melanoma. Here, we present more mature data, including 1-y landmark PFS and OS estimates. Methods: In the phase 1 KEYNOTE-029 expansion cohort (NCT02089685), pts with advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro alone for up to 2 y. Primary end point was safety. Efficacy end points were ORR, PFS, and DOR per RECIST v1.1 by independent central review and OS. Results: 153 pts were enrolled between Jan 13, 2015, and Sep 17, 2015. Median age was 60 y, 66% were male, 25% had elevated LDH, 56% had stage M1c disease, 36% were BRAFV600mutant, and 13% received ≥1 prior therapy. As of Oct 17, 2016, median follow-up was 17 mo, and 64 (42%) pts remained on pembro. 110 (72%) pts received all 4 ipi doses. There were no treatment-related (TR) deaths. TRAEs occurred in all pts, were grade 3/4 in 69 (45%), and led to discontinuation of pembro and ipi in 17 (11%), ipi alone in 11 (7%), and pembro alone after ipi completion or discontinuation in 19 (12%). PD occurred in 1/11 pts who discontinued ipi alone and 4/17 pts who discontinued ipi and pembro. Of the 11 pts who discontinued ipi alone for a TRAE, 0 experienced recurrence of the same TRAE during pembro monotherapy and 2 discontinued pembro for a different TRAE (both elevated lipase). Immune-mediated AEs occurred in 90 (59%) pts and were grade 3/4 in 39 (25%). With 7 mo additional follow-up, there were 6 additional responses for an ORR of 61% (95% CI, 53%-69%); the CR rate increased from 10% to 15%. Median DOR was not reached (range, 1.6+ to 18.1+ mo), with 86/93 responders (92%), including 23/23 (100%) with CR, alive and without subsequent PD at cutoff. Median PFS and OS were not reached; 1-y estimates were 69% for PFS and 89% for OS. Conclusions: Pembro 2 mg/kg plus 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust, durable antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685.