bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of PET staging in limited-stage SCLC.
Authors: Xanthopoulos Eric , Grover Surbhi , Corradetti Michael Nino , Fernandes Annemarie Therese , Kim Miranda , Simone Charles B. , Christodouleas John Paul , Evans Tracey L. , Stevenson James , Langer Corey J. , Apisarnthanarax Smith , Rengan Ramesh
Published: March 2020

7098

Background: Although PET/CT has been established for the initial staging of NSCLC, it is still unproven for SCLC. This study examines clinical outcome in patients with limited-stage SCLC staged with and without PET/CT. Methods: An institutional database was reviewed to identify all patients that presented with limited-stage SCLC and treated definitively with concurrent chemoradiation. Overall survival and associations were assessed by the Kaplan-Meier approach, log-rank tests and Cox modeling. Results: From 01/04 – 08/10, 54 consecutive limited-stage SCLC patients were treated with concurrent chemoradiation at the University of Pennsylvania. 40 patients underwent PET staging; 14 underwent CT staging only; all had MR of the brain. Patient characteristics were well distributed, including age (p = 0.35), race (p = 0.21), sex (p = 0.93), dose (45 Gy, p = 0.89), and fractions per day (p = 0.89). PET-staged patients had median survival of 32 vs 15 months in patients without PET (p = 0.03). Survival rate was 57% vs 29% at 24 months. Median time to distant failure of 29 vs 11 months (p = 0.05). Median time to local failure was 41 vs 12 months (p = 0.03). Median followup was 38 months in the 19 surviving PET-staged patients and 40 in the 2 surviving non-PET patients (p = 0.59). Lack of PET-staging (OR = 0.92, p = 0.04) and race (OR = 1.02, p = 0.03) associated with increased distant failure on multivariate Cox analysis. Only PET-staging (OR = 0.93, p = 0.04) associated with increased overall survival on univariable Cox modeling. Conclusions: Median and overall survival of PET-staged SCLC patients compared favorably with those who were not. These findings are presumably due primarily to identification of CT-occult distant disease by PET. This study underscores the value of PET in staging patients with SCLC.
Amrubicin and carboplatin with pegfilgrastim in patients with extensive-stage small-cell lung cancer (ES-SCLC): A phase II study of the Sarah Cannon Research Institute (SCRI).
Authors: Shipley Dianna , Hainsworth John D. , Mekhail Tarek , Zubkus John D. , Flora Douglas B. , Daniel Davey B. , Waterhouse David Michael , Gravenor Donald , Burris Howard A. , Greco Frank A. , Spigel David R.
Published: March 2020

7100

Background: Amrubicin is a novel anthracycline associated with high objective response rates (ORR) in patients (pts) with relapsed SCLC. Amrubicin improved the ORR and progression-free survival (PFS) in relapsed SCLC vs. topotecan, but not overall survival (OS) in a phase III study. Amrubicin with cisplatin/carboplatin for elderly Japanese pts was safe and active. We conducted a multicenter phase II study evaluating amrubicin and carboplatin in newly diagnosed ES-SCLC. Methods: Eligible pts had untreated ES-SCLC, measurable/evaluable disease (RECIST v. 1.1) and an ECOG PS <2. Pts received 4 cycles of amrubicin 30 mg/m2 on days 1-3 and carboplatin AUC=5 both IV day 1 every 21 days with restaging every 6 weeks. Pegfilgrastim 6 mg sq was administered on day 4 of each cycle. The primary endpoint was 1-year OS. Secondary endpoints included ORR, PFS, OS, and toxicity. Results: 78 pts were enrolled from 3/2010 to 7/2011. Baseline characteristics included: median age 65 yrs (range 45-84); 56% female. 64% completed 4 cycles of treatment. Eleven (14%) pts showed complete responses and 47 (60%) pts partial responses, for an ORR of 74% (95% confidence interval 65%-82%). Twelve (15%) pts had stable disease. Median PFS and OS were 5.3 and 9.5 months, respectively. The 1-year OS was 36%. Grade 3/4 myelosuppression was the most common toxicity (thrombocytopenia 44%, neutropenia 34%, febrile neutropenia 12%, anemia 26%), but was manageable. Severe non-hematologic toxicities (>5%) included hypokalemia 17%, fatigue 13%, dehydration 10%, hyponatremia 10%, pneumonia 9%, and nausea/vomiting 8%. 1 pt died from sepsis and another from aspiration pneumonia. Conclusions: First-line ES-SCLC treatment with amrubicin and carboplatin induced several complete responses and is considered highly active. Myelosuppression was managed effectively with growth factor support. These results are comparable to historical data with platinum-doublet chemotherapy. A larger randomized study would be required to best assess this regimen’s impact on survival.
Multiplex testing for driver mutations in squamous cell carcinomas of the lung.
Authors: Paik Paul K. , Hasanovic Adnan , Wang Lu , Rekhtman Natasha , Ladanyi Marc , Kris Mark G.
Published: March 2020

7505

Background: While the majority of lung adenocarcinomas (ADCL) harbor an identifiable driver mutation, targeted therapies for squamous cell lung carcinomas (SQCLC) have lagged in development due to a paucity of druggable oncogenic events. Three targets, which together occur in up to 50% of SQCLC, have been recently identified (FGFR1 amplification, DDR2 mutations, PIK3CA mutations/PTEN loss). Comprehensive molecular analysis of SQCLC tumors by The Cancer Genome Atlas is ongoing, with new therapeutic targets on the horizon. Methods: We have instituted prospective, multiplex testing of SQCLC tumors (Squamous Cell Lung Cancer Mutation Analysis Program, “SQ-MAP”). Tests include FISH for FGFR1 amplification (defined as FGFR1:CEP8 ≥ 2 in >10% of cells), IHC for loss of PTEN expression, and Sequenom MassARRAY for PIK3CA mutations (and others, below). We are also incorporating targeted exon sequencing (Agilent SureSelect/Ion Torrent) of a panel of over 80 lung cancer oncogenes and tumor suppressors in preparation for future studies. All tests were performed on formalin-fixed paraffin-embedded samples and with Institutional Review Board/Biospecimen Utilization Committee approval. Results: 40 SQCLC patient specimens have been processed through SQ-MAP over 3 months. 8 samples were excluded (insufficient tissue in 4, reclassification to ADCL in 4). Data are available for 28 patients. PTEN IHC was performed on 15 samples to date. Molecular results are summarized in the table. Events were non-overlapping. Results for the ≥80 gene sequencing component will be described. Based on SQ-MAP, accrual to 2 approved clinical trials (FGFR1 inhibition; PI3K inhibition) has begun, with a third planned (DDR2 mutations). Conclusions: Actionable defects were detected in 60% (95% CI: 37-75%) of SQCLC specimens. Mutation data for ≥80 other oncogenes and tumor suppressors will be available shortly (including DDR2). SQ-MAP serves as a platform supporting both personalized care and research. [Table: see text]
A randomized phase III trial of single-agent pemetrexed (P) versus carboplatin and pemetrexed (CP) in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2.
Authors: Lilenbaum Rogerio , Zukin Mauro , Pereira Jose Rodrigues , Barrios Carlos H. , De Albuquerque Ribeiro Ronaldo , Beato Carlos Augusto de Mendonça , Neron do Nascimento Yeni , Murad Andre , Franke Fabio A. , Precivale Maristela , de Lima Araujo Luiz Henrique , Baldotto Clarissa Serodio Da Rocha , Vieira Fernando Meton , Small Isabele Avila , Ferreira Carlos G. M.
Published: March 2020

7506

Background: No standard of care exists for patients with advanced NSCLC and PS 2 and clinical practice ranges from supportive care to combination chemotherapy. Methods: In a Brazilian multicenter phase III randomized trial, advanced NSCLC patients, with any histology at first, amended to non-squamous only, PS 2, no prior chemotherapy, and adequate organ function, were randomized to P alone (500 mg/m2) or CP (AUC 5 + same P) administered every 3 weeks for 4 cycles. Stratification factors included stage (IIIB vs. IV); age (≥70 vs. <70); and weight loss (≥5 kg vs. <5kg). The primary endpoint was overall survival and the study was powered to demonstrate an improvement in median survival from 2.9 to 4.3 months based on a prior CALGB trial. Results: A total of 217 patients were enrolled from 8 centers in Brazil and 1 in the US from April 2008 to July 2011. Twelve patients were ineligible and excluded. The 2 arms (P=102; CP=103) were balanced for patient characteristics. 14 patients had squamous and another 12 had unknown histology. The response rates were P = 10% and CP = 24% (p=0.019). In the ITT population, the median PFS was P = 3.0 mo and CP = 5.9 mo (HR=0.46, 95% CI 0.34; 0.63, p<0.001) and median OS was P = 5.6 mo vs. CP = 9.1 mo (HR=0.57, 95% CI 0.41; 0.79, p=0.001). 1-year survival rates were 22% and 39% respectively. Similar results were seen when squamous patients were excluded from the analysis. Grade ¾ anemia (5.5%; 12%) and neutropenia (2.8%; 5.6%) were more frequent in CP. There were 4 treatment-related deaths in the CP arm. 30% of patients in each arm received 2nd line therapy Conclusions: Combination chemotherapy with CP significantly improves survival, with acceptable safety, in eligible patients with advanced NSCLC and PS 2, and represents a new standard.
Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement.
Authors: Shaw Alice Tsang , Camidge D Ross , Engelman Jeffrey A. , Solomon Benjamin J. , Kwak Eunice Lee , Clark Jeffrey W. , Salgia Ravi , Shapiro Geoffrey , Bang Yung-Jue , Tan Weiwei , Tye Lesley , Wilner Keith D. , Stephenson Patricia , Varella-Garcia Marileila , Bergethon Kristin , Iafrate A. John , Ou Sai-Hong Ignatius
Published: March 2020

7508

Background: Chromosomal rearrangements of the ROS1 receptor tyrosine kinase gene define a new molecular subset of NSCLC. In cell lines, ROS1 rearrangements lead to expression of oncogenic ROS1 fusion kinases and sensitivity to ROS kinase inhibition. We examined the efficacy and safety of crizotinib, a small molecule tyrosine kinase inhibitor of MET, ALK and ROS, in patients with advanced, ROS1-rearranged NSCLC. Methods: Patients with advanced NSCLC harboring ROS1 rearrangement, as determined using a break-apart FISH assay, were recruited into an expansion cohort of a phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg BID. The objective response rate (ORR) was determined based on RECIST 1.0. The disease control rate (DCR; stable disease [SD] + partial response [PR] + complete response [CR]) was evaluated at 8 weeks. Results: Thirteen patients within the ROS expansion cohort received crizotinib and all were evaluable for response. The median age was 47 yrs (range 31–72), and all but one of the patients were never-smokers. All patients had adenocarcinoma histology. 12/13 patients were tested for ALK rearrangement and all were negative. The median number of prior treatments was 1 (range 0–3). To date, the ORR is 54% (7/13), with 6 PRs and 1 CR, with 6 responses achieved by the first restaging scan at 7–8 wks. There was 1 additional unconfirmed PR at the time of data cut-off. The DCR at 8 wks was 85% (11/13). Median duration of treatment was 20 wks (range 4+–59+). All responses are ongoing, and 12 patients continue on study. One patient had disease progression at first restaging and was discontinued from the study. The pharmacokinetics and safety profile of crizotinib in this group of patients were similar to that observed in patients with ALK-positive NSCLC. Conclusions: Crizotinib demonstrates marked antitumor activity in patients with advanced NSCLC harboring ROS1 rearrangements. Like ALK, ROS defines a distinct subpopulation of NSCLC patients for whom crizotinib therapy may be highly effective. This study represents the first clinical validation of ROS as a therapeutic target in cancer.
Response to EGFR tyrosine kinase inhibitor (TKI) retreatment after a drug-free interval in EGFR-mutant advanced non-small cell lung cancer (NSCLC) with acquired resistance.
Authors: Heon Stephanie , Nishino Mizuki , Goldberg Sarah B. , Porter Jennifer , Sequist Lecia V. , Jackman David Michael , Johnson Bruce E.
Published: March 2020

7525

Background: Patients (pts) with advanced NSCLC and sensitizing EGFR mutations who initially respond to gefitinib or erlotinib eventually develop acquired resistance to the TKIs. Anecdotal and retrospective reports suggest that EGFR-TKI resistant cancers can respond again to gefitinib or erlotinib after an interval off the TKI. This retrospective study was undertaken to investigate the impact of EGFR-TKI retreatment after a drug-free interval in EGFR mutant NSCLC with acquired resistance to gefitinib or erlotinib. Methods: Pts with stage IV or relapsed NSCLC with sensitizing EGFR mutations and acquired resistance to EGFR-TKI seen at the DFCI/MGH between 8/00 and 8/11 who were retreated with single agent gefitinib or erlotinib after an EGFR-TKI-free interval were identified from a prospective trial. The objective tumor response (CR, PR, SD, PD) was determined using RECIST 1.1. Results: 19 pts were eligible and had adequate scans for radiographic assessments after the reinstitution of an EGFR-TKI. The response rate and median PFS to the initial course of gefitinib (n=4) or erlotinib (n=15) were 16/19 (84%) and 9.8 months (95% CI, 7.8-11.3) respectively. All pts were retreated with erlotinib after 1 to 4 intervening systemic regimens. The median interval from EGFR-TKI discontinuation to erlotinib retreatment was 11 months (range, 2-46). 4 of the 19 pts (21%) had PD as the best response to erlotinib retreatment, 14 (74%) had SD for at least 1 month, and 1 (5%) had a PR. The median PFS was 4.4 months (95% CI, 3.0-6.7). 3 pts remained on erlotinib without progression for 6 months. 3 pts had their tumors rebiopsied before (n=2) or during (n=1) erlotinib retreatment; 1 of the 3 had EGFR T790M in association with the initial sensitizing EGFR mutation, and another had a secondary PIK3CA mutation. Conclusions: Our findings suggest that erlotinib retreatment is an option for EGFR mutated NSCLC with acquired resistance to EGFR-TKI after a drug-free interval and progression on intervening therapy. Additional advanced NSCLC pts without a documented EGFR mutation who fulfill the clinical definition of acquired resistance are undergoing review to expand our cohort.
First-line dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor, for patients with EGFR-mutant lung cancers.
Authors: Kris Mark G. , Mok Tony , Ou Sai-Hong Ignatius , Martins Renato , Kim Dong-Wan , Goldberg Zelanna , Zhang Hui , Taylor Ian , Letrent Stephen P. , Janne Pasi Antero
Published: March 2020

7530

Background: Dacomitinib irreversibly inhibits EGFR, HER2 and HER4, and showed superior activity vs. reversible EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer models, including resistant forms. This open-label Phase II study evaluates dacomitinib as 1st-line treatment (tx) for patients (pts) with lung cancers. Pts with sensitizing EGFR deletions/mutations in exons 19 or 21 are reported here. Methods: Pts had stage IIIB/IV adenocarcinoma, no prior systemic tx, had smoked <10 pack years (none within 15 years of enrollment) or had known EGFR mutation. Pts received dacomitinib orally once daily continuously at 45 mg, or 30 mg with the option to escalate to 45 mg; evaluation was every 28 days. Endpoints included progression-free survival rate at 4 months (PFS at 4M, primary); PFS, and partial response (PR) rate. Results: 92 pts enrolled; 47 had EGFR mutation in exons 19 (n=25) or 21 (n=22), 33 were female and 27 Asian. 34/46 evaluable pts with EGFR exon 19 or 21 mutations had a PR (PR rate = 74%; 95% CI: 59–86; exon 19 = 72%; exon 21 = 76%). PR rates and preliminary PFS were not significantly different for exons 19 and 21. Preliminary PFS at 4M was 96% (95% CI: 84–99), preliminary PFS rate at 1 year was 77% (95% CI: 61–87) and preliminary median PFS was 17 months (95% CI: 13–24). Median tx duration was 13.1 months. For pts with EGFR wild-type lung cancers, PR and PFS at 4M rates were 7% (n=14; 95% CI: 0–34) and 33% (n=14; 95% CI: 11–58), respectively, and for pts with EGFR unknown lung cancers, 46% (n=22; 95% CI: 24–68) and 68% (n=24; 95% CI: 45– 83), respectively. 7 pts had lung cancers with non-sensitizing EGFR mutations; 2 had a PR and 3 SD. For all 92 pts, common side effects included dermatitis acneiform (grade 3/4 = 17%/0) and diarrhea (14%/0). 3/46 pts with EGFR exon 19 or 21 mutations discontinued tx due to drug-related toxicity. Conclusions: 74% of pts in this cohort with EGFR exon 19 or 21 mutant lung cancers experienced PRs with 1st-line dacomitinib; preliminary PFS rate was 77% at 1 year; preliminary median PFS was 17 months; further research is planned in this pt population. As dacomitinib is well tolerated, with preclinical activity against HER2, a cohort of pts with HER2 mutant lung cancers is recruiting.
A randomized discontinuation phase II trial of ridaforolimus in non-small cell lung cancer (NSCLC) patients with KRAS mutations.
Authors: Riely Gregory J. , Brahmer Julie R. , Planchard David , Crinò Lucio , Doebele Robert Charles , Mas Lopez Luis Alberto , Gettinger Scott N. , Schumann Christian , Li Xiaoyun , Atkins Barbara McCormick , Ebbinghaus Scot , Rosell Rafael
Published: March 2020

7531

Background: Mutations in KRAS are present in ~25% of patients with advanced NSCLC. Preclinical data support the role of mammalian target of rapamycin (mTOR) in KRAS mediated oncogenesis. Ridaforolimus is an inhibitor of mTOR which has been shown to have efficacy in advanced endometrial cancer and soft tissue sarcoma. Everolimus, another mTOR inhibitor was previously evaluated in unselected patients with advanced NSCLC and found to have a response rate <5%. We hypothesized that by enrichment for patients with NSCLC and KRAS mutations, treatment with ridaforolimus would be associated with prolonged stable disease relative to available standard treatments for NSCLC. Methods: Patients with stage IIIB/IV non-small cell lung cancer with KRAS mutation who had received prior chemotherapy for NSCLC began treatment with oral ridaforolimus 40 mg once daily on a 5 day/week schedule. After 8 weeks, patients with >30% tumor shrinkage remained on ridaforolimus and patients with >20% tumor growth discontinued treatment. Patients with stable disease were randomized 1:1 to placebo or ridaforolimus. The primary endpoint of the study was progression-free survival (PFS) after randomization. Results: 79 patients were enrolled (40 women, median age 58 [range 28-85]). The overall response rate (CR+PR) at 8 weeks was 1/79 (1%, 95% CI 0-7%).  28 patients with stable disease at 8 weeks were randomized to ridaforolimus or placebo.  Median PFS based on investigator assessment from randomization was significantly longer with ridaforolimus (4 months) than placebo (2 months, p=0.013, HR 0.36).  Median OS from randomization was 18 months in the ridaforolimus treated arm and 5 months in the placebo treated group, (HR 0.46, p=0.09).  The most common grade ≥3 adverse events were fatigue (10%), mucositis/stomatitis (10%), pneumonia (10%), dyspnea (9%), diarrhea (6%), and hyperglycemia (6%). Conclusions: In patients with KRAS mutant NSCLC who had stable disease after 8 weeks of ridaforolimus, ridaforolimus was associated with prolonged progression-free survival.  Further evaluation of ridaforolimus in this patient population is warranted.
GAIN-(L): Efficacy and biomarker findings of RG7160 (GA201), a novel, dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with first-line cisplatin and pemetrexed in metastatic nonsquamous NSCLC.
Authors: Spicer James F. , Felip Enriqueta , Bosquée Lionel , Gregorc Vanesa , Lopez Calderero Iker , Martinez Pablo , Montes Ana , Sorlini Cristina , Ott Marion Gabriele , Golding Sophie , Mariconti Luisa , Longauer Banholzer Maria , Passioukov Alexandre , Carlile David , Manenti Luigi , Paz-Ares Luis
Published: March 2020

7544

Background: GA201, a humanized, engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, has shown promising clinical activity in phase I and in the neoadjuvant treatment of head and neck cancer. This phase Ib study (NCT01185847) aimed to determine the safety, pharmacokinetics (PK), activity and recommended phase II dose (RP2D) of GA201 in combination with chemotherapy in non-squamous NSCLC. Methods: Successive cohorts received GA201 1000 mg or 1400 mg (IV d1, d8 then 2-weekly (q2W)) in combination with chemotherapy at standard doses. Data cut off was 7 months after enrolling the last patient. Results: 14 patients (4 female) with performance status 0-1 were enrolled. No maximum tolerated dose was reached. Most common adverse events (AEs – all grades) included rash (100%), hypomagnesaemia (71%), infusion-related reactions (64%), mucosal inflammation (57%) and anemia (50%). AEs of ≥ grade 3 included rash (71%), skin fissure (21%), dry skin (14%), paronychia (14%), and asthenia (14%). Median timeto improvement of rash grade 3 was 11 days. AEs led to dose reduction for 4 patients and discontinuation for 1 patient. There were 6 confirmed partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with stable disease >=9 weeks. Duration of response ranged between 5 and 42 weeks (3 patients still ongoing). Preliminary biomarker analysis shows a correlation between tumor-infiltrating CD16+ immune cells and target lesion shrinkage at first tumor assessment [R(spear)=-0.65 (p=0.02)]; no apparent correlation between EGFR H-score and response was found. PK data supports 1400 mg as the RP2D (d1, d8 then q2W). Conclusions: The RP2D of GA201 in combination with chemotherapy was established to be 1400 mg. The incidence of EGFR associated rash was high and guidelines to reduce its severity were implemented with a noted improvement in tolerability. Promising antitumor activity was observed. Biomarker data support the mode of action of GA201 via ADCC. A randomized phase II trial of this combination is ongoing and fully recruited.
FGFR1 amplification and EGFR mutation in Chinese squamous cell lung cancer.
Authors: Wei Zhigang , Wang Jie , Bai Hua , An Tongtong , Wang Zhijie , Zhuo Minglei , Wu Meina , Yang Lu
Published: March 2020

7545

Background: Squamous cell lung cancer (SCC) lacks for effective targeted therapies. FGFR1 amplification has emerged as a potential biomarker. This study aimed to explore clinicopathologic characteristics of FGFR1 amplification in Chinese SCC patients and further explore the correlation between FGFR1 amplification and EGFR mutations. Methods: One hundred seventy-seven SCC patients were included in this retrospective study. Gene copy number of FGFR1 and EGFR mutations were detected by fluorescence in situ hybridization (FISH) and denaturing high-performance liquid chromatography (DHPLC), respectively. Results: FGFR1 amplifications were detected in 24.9% (44/177) Chinese SCC patients. FGFR1 amplification in SCC was more common in male (28.0%, 40/143) and smokers (28.7%, 39/136) than female (11.8%, 4/34, p=0.049) and nonsmokers (12.2%, 5/41, p=0.032). FGFR1 amplification and EGFR mutations were mutually exclusive (p=0.006), fourty-one of 139(29.4%) patients with wild-type EGFR had FGFR1 amplification, while 3 of 38 (7.9%) patients with EGFR mutation had FGFR1 amplification. Conclusions: FGFR1 amplification was common in Chinese squamous cell lung cancer, and mutually exclusive with EGFR mutations.
N0821: A phase II first-line study of a combination of pemetrexed (P), carboplatin (C), and bevacizumab (B) in elderly patients with good performance status (PS < 2).
Authors: Dy Grace K. , Molina Julian R. , Qi Yingwei , Ansari Rafat H. , Thomas Sachdev P. , Ross Helen J. , Meyers Jeffrey P , Adjei Araba , Mandrekar Sumithra J. , Adjei Alex A. ,   North Central Cancer Treatment Group
Published: March 2020

7555

Background: In a retrospective exploratory analysis of E4599, patients (pts) > 70 yo had a higher frequency of and more severe toxicities without apparent survival benefit from the addition of B to C+paclitaxel. We hypothesized that in this pt population, B will have better safety and efficacy profile when used in combination with C+P. Methods: Pts >/= 70 yo with previously untreated stage IIIB/IV (TNM 6th ed) nonsquamous NSCLC, ECOG PS 0-1, measurable disease and adequate organ function were eligible. C at AUC 6, P at 500 mg/m2 and B at 15 mg/kg were administered on day 1 of each 21-day cycle for up to 6 cycles followed by maintenance P+B in patients with CR, PR or SD. The primary endpoint was 6-month progression-free survival (PFS) rate. The treatment would be considered promising based on a single arm one-stage binomial design if 34 or more successes out of 55 patients were observed. This design had an exact significance level of 0.05 at 93% power to detect a true success rate of at least 70%. Polymorphisms in VEGFA, FPGS, GGH, SLC19A1 and TYMS in germline DNA were correlated with treatment outcome. Results: 58 eligible pts were enrolled; 29 males/29 females. Median age was 75. Median treatment cycles received was 6. Grade 3 or higher adverse events (AE) were reported in 49 (85%) pts. There were no treatment-related deaths. The most common grade 3/4 AEs(regardless of attribution) were hypertension (10%), fatigue (28%), dehydration (9%), neutropenia (43%) and thrombocytopenia (21%). There were 3 (5%) grade 3/4 hemorrhagic events. 8 (14%) had grade 4 neutropenia and 3 (5%) had grade 4 thrombocytopenia. Grade 3/4 ischemic/thromboembolic events occurred in 6 pts (10%). Thirty-four out of the first 54 (63%, 95% CI: 48.7-75.7%) evaluable pts met the primary endpoint (4 pts were lost to follow-up prior to 6 months). The confirmed ORR was 37.9% (95% CI: 25.5-51.6%). Median time to treatment failure was 4.8 months (95% CI: 3.9-6.4). Median PFS was 7.1 months (95% CI: 5.9-11.7), median OS was 13.7 months (95% CI: 9.4-15.7). Results of SNP analysis will be presented. Conclusions: C+P+B followed by maintenance P+B is an active and tolerable first-line regimen for elderly patients with good PS.
Final overall survival and updated biomarker analysis results from the randomized phase III ICOGEN trial.
Authors: Sun Yan , Shi Yuankai , Zhang Li , Liu Xiaoqing , Zhou Caicun , Zhang LI , Wang Dong , Li Qiang , Zhang Shucai , Qin Shukui , Hu Chunhong , Zhang Yiping , Chen Jianhua , Song Yong , Feng Ji Feng , Cheng Ying , Zhang Helong , Wu Yi Long , Xu Nong , Zhou Jianying
Published: March 2020

7559

Background: A total of 399 pretreated patients with advanced NSCLC were randomly assigned to receive gefitinib or icotinib in the phase III ICOGEN trial, the first head-to-head phase III trial of EGFR-TKIs. The results of the primary endpoint, PFS, have been reported previously. This report represents the final OS and biomarker analysis results. Methods: EGFR mutation was evaluated by using Scorpion ARMS (QIAGEN, n=152). Overall survival was analyzed by Cox proportional-hazards model analysis at 82% maturity. Results: Median OS was 13.3 months for icotinib and 13.9 months for gefitinib (hazard ratio [HR] = 0.90; 95% CI, 0.79 to 1.02; P = .109). The EGFR mutation rate was 43% in the icotinib group and 59% in the gefitinib group. Compared to wild type patients, patients with EGFR mutation had longer PFS (median, 6.2m vs. 2.3m; P=.00001) as well as OS (median, 20.5m vs. 7.7m; P=.00001). There were no significant differences in PFS or OS between the two treatment groups in EGFR mutation-positive subgroup (median PFS, 7.8m vs. 5.3m for icotinib and gefitinib, respectively, P =.3162; median OS, 20.9m vs. 20.2m for icotinib and gefitinib, respectively, P =.7611.) or in EGFR mutation-negative subgroup (median PFS, 2.3m vs. 2.2m for icotinib and gefitinib, respectively, P =.1531; median OS, 7.8m vs. 6.9m for icotinib and gefitinib, respectively, P =.7885.). Conclusions: There is no statistically significant difference between icotinib and gefitinib in PFS or OS when given to NSCLC patients. This suggests that icotinib can provide similar OS benefits to gefitinib in advanced NSCLC patients. Moreover, EGFR mutation status is the strongest predictor in identifying which patients are most likely to benefit from icotinib.
Difference in incidence and pattern of salvage treatment after failure to first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and standard cytotoxic chemotherapy in pts with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations: Okayama Lung Cancer Study Group experience.
Authors: Kato Yuka , Ichihara Eiki , Hotta Katsuyuki , Hisamoto Akiko , Takigawa Nagio , Nogami Naoyuki , Kozuki Toshiyuki , Kudo Kenichiro , Tabata Masahiro , Shinkai Tetsu , Tanimoto Mitsune , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: March 2020

7576

Background: EGFR-TKI (E) therapy yielded a better PFS than standard cytotoxic chemotherapy (C) therapy and a comparable OS in untreated pts with EGFR-mt tumors, suggesting each of the treatments is now crucial for such subpopulation. But, it has not been fully evaluated yet which of each should be initiated first, and to what degree both of two are actually administered in early line setting in the treatment course. We here investigated a potential difference in incidence and pattern of delivery of subsequent crossover therapy after failure to each of the treatments in pts with EGFR-mt tumors. Methods: Consecutive 79 pts with advanced EGFR-mt NSCLC were retrospectively assessed who underwent E therapy (n = 39) or standard C therapy (n = 40) in the 1st-line setting between 2007 and 2011. Results: In E group 16 (41%) of 39 pts were still on 1st-line E therapy. Nine (39%) of the remaining 23 could not receive standard C therapy after failure to E therapy due to symptomatic CNS metastasis(mets) in 6, skeletal events in 2, and patient refusal in 1, whilst in C group only one (3%) of 40 failed to receive subsequent E therapy because of relapse (carcinomatous lymphangitis) (χ2-test; p < .001). Also, at the time of relapse to the 1-st line therapy, PS deteriorated more frequently in E group (8/23 vs. 7/40; p = .042) and, relapse with symptomatic CNS mets seemed frequently observed in E group (6/23 vs. 4/40; p = .093). Multivariate analysis revealed type of regimens undergone in the 1st-line setting (E vs. C) correlated with failure of administration of subsequent crossover therapy (odd ratio: 3.224, 95%CI: .1.032 – 5,417, p = .004). Conclusions: It seems that pts with EGFR-mt tumors who were treated with 1st-line C had better opportunity to receive post-progression E therapy than those treated with 1st-line E had chance to receive subsequent C therapy, possibly due to difference in PS deterioration rate and relapse pattern.
KIF5B-RET: Discovery of a novel fusion oncogene in lung adenocarcinomas by a systematic screen for tyrosine kinase fusions and identification of patients for a RET targeted therapy trial.
Authors: Suehara Yoshiyuki , Arcila Maria E. , Drilon Alexander Edward Dela Cruz , Ito Tatsuo , Wang Lu , Hasanovic Adnan , Khanin Raya , Rizvi Naiyer A. , Ladanyi Marc
Published: March 2020

7578

Background: The mutually exclusive pattern of major targetable driver oncogenes in lung adenocarcinomas (ADC) suggests that other similar driver oncogenes may exist. We therefore performed a systematic screen for tyrosine kinase (TK) fusions in cases without known driver oncogenes by measuring aberrantly high RNA expression of kinase domain (KD) exons relative to more 5’ exons. Methods: We studied 74 patients whose lung ADC lacked mutations in KRAS, EGFR, BRAF, HER2, and ALK fusions. A NanoString-based assay was designed to query the transcripts of 90 TKs at two points: 5’ to the KD and within or 3’ to the KD. Tumor RNAs were hybridized to the NanoString probes and analyzed for outlier 3’ to 5’ expression ratios. The assay was validated on samples with known ALK and ROS fusions. Presumed novel fusion events were followed up by rapid amplification of cDNA ends (RACE) and confirmatory RT-PCR. Results: The NanoString assay identified aberrant 5’ to 3’ ratios in ROS and RET in 2 cases, respectively, out of 74. RACE analysis isolated a novel GOPC-ROS fusion in the former and a novel KIF5B-RET fusion in the latter, both confirmed by RT-PCR. Further screening by RT-PCR for KIF5B-RET identified one more positive sample in the study set that had not been detected by NanoString. At the RNA level, both fusions joined exon 15 of KIF5B to exon 12 of RET, thus retaining a portion of the dimerization domain of KIF5B and the entire KD of RET, analogous to RET fusions in papillary thyroid carcinoma (TC). One KIF5B-RET patient was a 60 y.o. female never smoker, the other, a 73 y.o. male former smoker. Conclusions: The novel KIF5B-RET fusion described here and also recently reported by Ju YS et al. (Genome Res, Dec 22, 2011) defines a new subset of lung ADC with a potentially targetable driver oncogene. Based on these genetic data and the preclinical activity of the RET inhibitor XL184 (Exelixis) in papillary TC and its known activity in medullary TC with RET mutations, we have initiated prospective testing for KIF5B-RET as part of our lung ADC screening panel in anticipation of a planned phase 2 trial with XL184 in patients with KIF5B-RET or related variant RET fusions.
Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI).
Authors: Gian Victor , Rubin Mark S. , Shipley Dianna , Burris Howard A. , Kaplan Joseph , Kosloff Rebecca A. , Shih Kent C. , Smith Frederick P. , Quinn Raven , Greco Frank A. , Hainsworth John D. , Spigel David R.
Published: March 2020

7587

Background: Erlotinib is an oral epidermal growth factor receptor kinase inhibitor used in the treatment of advanced non-small-cell lung cancer (NSCLC). Resistance develops in patients (pts) who initially respond to erlotinib leading to progressive disease (PD). Sorafenib is an oral inhibitor of vascular endothelial and platelet-derived growth factor receptors and Raf kinases which play important roles in PD. This randomized phase II study evaluated the role of sorafenib and continued erlotinib or sorafenib alone in pts with progressive NSCLC following initial benefit with erlotinib. Methods: Eligible pts had IIIB/IV NSCLC, an ECOG PS 0-2, and had received ≤2 lines of therapy with the last being single-agent erlotinib. Pts must have PD following clinical benefit (complete/partial response/stable disease) from erlotinib for >8 weeks. Pts were randomized 1:1 to continue erlotinib at the dose administered at the time of PD with the addition of sorafenib 400 mg orally twice daily (Arm A) or to sorafenib alone (Arm B). Cycles were 28 days with restaging every 2 cycles. The primary endpoint was progression-free survival (PFS). Results: 52 pts were enrolled from 2/2008 to 3/2011 (A 24; B 28). Baseline characteristics were balanced between arms and included: median age 65 years (41-87); 65% female; 69% adenocarcinoma/large cell; and 96% PS <2. 41% of pts were either never smokers or smoked <100 cigarettes/lifetime. Pts received a median of 8 weeks of treatment per arm (0.6–67 weeks). The median PFS was 3.1 (95% CI 1.7-3.7) and 2.3 (1.7-3.6) months for A and B, respectively (p=.84). There were no grade 3/4 hematologic toxicities in either arm except grade 3 anemia in 1 pt (A). Severe nonhematologic toxicities in >5% included: fatigue 17%(A)/7%(B); diarrhea 17%/0; dehydration 13%/7%; hand-foot skin reaction 8%/8%, and anorexia 4%/7%. Conclusions: Sorafenib has modest activity when used in combination with erlotinib or as a single agent in pts with PD following benefit with erlotinib alone. Additional study to identify potential subsets of refractory pts who might derive the greatest benefit from sorafenib are warranted.
Survival outcome segregated by KRAS mutation status in newly diagnosed stage IV non-small cell lung cancer (NSCLC) patients (pts) treated with first-line chemotherapy.
Authors: Brady Anna K. , McNeill Jonathan D , Judy Brendan , Evans Tracey L. , Cohen Roger B. , Langer Corey J. , Vachani Anil , Aggarwal Charu
Published: March 2020

7595

Background: KRAS mutations (MT) form a distinct subset of NSCLC, generally considered to have poor prognosis. Although KRAS MT is a well-establised prognostic and predictive marker in colorectal cancer, its role in NSCLC remains ambiguous. Pts with KRAS MT NSCLC do not respond well to epidermal growth factor receptor (EGFR) directed tyrosine kinase inhibitor therapy, but little is known about the ability of KRAS MT to predict outcome after first-line chemotherapy in newly diagnosed advanced or recurrent NSCLC. Methods: We analyzed outcomes of consecutive pts with newly identified Stage IV non- squamous NSCLC treated at University of Pennsylvania (Penn) between 05/2008 and 7/2010 and then compared survival based on KRAS status [MT vs wild type (WT)] using chi square, Kaplan-Meier methods, and Cox regression models. Results: Of 106 consecutive new pts with Stage IV non squamous NSCLC treated at Penn, 49 (46%) underwent molecular analysis for KRAS MT. Fifteen (34%) were KRAS MT. Of 34 KRAS WT pts, 6 were positive for EGFR MT. The median age of all 49 pts was 61 years; 83% were Caucasian, 45% male and 60% had a >10 pack year smoking history. Median duration of follow up is 16.4 mos. Majority of pts (92%) had adenocarcinoma histology. Most pts (88%) had ECOG PS 0-1 at presentation. Forty three pts received first line platinum-based combination chemotherapy (platinum and pemetrexed in 31 pts). KRAS MT was associated with smoking (p=0.04), but not with gender or age. Overall survival (OS) of pts with KRAS MT was similar to KRAS WT pts [median OS 15.6 vs. 19.0 mos; HR 1.24 (95% CI 0.57-2.67)]. Univariate analyses demonstrated superior OS among women compared to men (HR 0.40, 95% CI 0.20-0.85) in the entire pt cohort. Conclusions: In our population of stage IV non squamous NSCLC, pts with KRAS MT had similar OS to those with KRAS WT tumors. OS was slightly higher in KRAS WT pts, but this may have been confounded by the inclusion of 6 EGFR MT pts in this cohort. The potential prognostic or predictive role of KRAS MT in NSCLC pts undergoing chemotherapy requires further prospective study.
A large retrospective analysis of the activity of pemetrexed (PEM) in patients (pts) with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) prior to crizotinib (CRIZ).
Authors: Scagliotti Giorgio , Kim Dong-Wan , Shaw Alice Tsang , Ou Sai-Hong Ignatius , Riely Gregory J. , Gettinger Scott N. , Besse Benjamin , Thomas Michael , Salgia Ravi , Wilner Keith D. , Bartlett Cynthia Huang , Polli Anna , Gandara David R.
Published: March 2020

7599

Background: Retrospective small cohort studies suggest ALK+ NSCLC may be particularly sensitive to PEM. Methods: PROFILE 1005 (NCT00932451; Pfizer) is a large phase 2 multi-center, single-arm study of CRIZ in previously treated ALK+ NSCLC. Eligibility criteria included pts with progressive disease from the PEM arm of companion trial PROFILE 1007. We retrospectively assessed objective response rate (ORR) and time to progression (TTP; 1st dose to objective progression) in pts who received PEM prior to CRIZ. ORR with CRIZ post-PEM was assessed. Results: Of the 439 ALK+ pts enrolled as of June 2011, 369 (84.1%) received prior PEM (single agent or combination; any line advanced/metastatic) with a cumulative ORR of 18.7%. In pts who received PEM combinations 1st-line (1L; n=120) or 2nd-line (2L; n=60), ORR was 24.2% and 16.7%; and median TTP was 6.9 months (mo; 95% CI: 6.0–7.4) and 6.9 mo (95% CI: 4.8–8.8), respectively. In pts who received 2L single-agent PEM (n=80), ORR was 12.5% and median TTP was 5.3 mo (95% CI: 3.0–6.6). In pts treated with PEM 3rd-line (3L) or later (n=138), ORR was 16.7%. By line of PEM treatment, ORR was lower and TTP shorter than that reported in small ALK+ cohorts evaluating multiple lines of treatment. In 2L, previously reported ORR and median PFS with single-agent PEM in adenocarcinoma NSCLC were 12.8% (n=158) and 3.5 mo (n=283), and comparable to our findings. Pts who received 2L single-agent PEM (n=80) subsequently achieved higher ORR with CRIZ (54%; 95% CI: 42–65). Similar analyses in the 1L and 3L groups are ongoing. Conclusions: This retrospective study in predominantly never-smokers with ALK+ NSCLC reports lower ORR and shorter TTP with PEM than that reported in smaller retrospective ALK+ NSCLC cohorts. This finding may be in part due to the inclusion of crossover pts from PROFILE 1007. This analysis and previous reports observed a tendency to a higher response rate and better PFS or TTP with PEM than in unselected populations in 2L, which may not be specifically related to ALK status but to a higher sensitivity to cytotoxic agents in never-smokers. Results from an ongoing phase 3 trial (PROFILE 1007) will provide additional information.
CALGB 50401: A randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma.
Authors: Leonard John , Jung Sin-Ho , Johnson Jeffrey L. , Bartlett Nancy , Blum Kristie A. , Cheson Bruce D. ,   Alliance for Clinical Trials in Oncology
Published: March 2020

8000

Background: Lenalidomide (L) and rituximab (R) are active as single agents in follicular (FL) and other B-cell lymphomas, although combination strategies have not been previously assessed in a randomized fashion. Methods: CALGB 50401 is a randomized phase II study, initially designed to evaluate 3 regimens: R alone (375 mg/m2 weekly x 4), L alone (15 mg cycle 1, then escalated to 20 mg cycles 2-12, administered days 1-21 q 28 days x 12 cycles) or the combination of L+ R (other 2 arms combined). The R alone arm was discontinued due to slow accrual with 3 enrolled subjects. Eligibility included recurrent FL, prior therapy with rituximab alone or in combination, and TTP of ≥ 6 months from last rituximab dose. Prophylactic ASA or LMW heparin was recommended for patients at high risk for thrombosis. Results: Of 94 pts registered to L or LR, 89 (45 L and 44 LR) received at least one dose and had adequate data for analysis. Baseline characteristics include median age 63 (range 34-85) and 60% with intermediate- or high-risk FLIPI. Grade 3-4 adverse events (AE) were most commonly neutropenia (16% L,19% LR), fatigue (9% L, 14% LR) and thrombosis (16% - 7 pts L, 4% - 2 pts LR, p=0.158), and overall were seen in 49% (L) and 52% (LR) with 9% grade 4 in each arm. The full regimen was completed in 33% (L) and 59% (LR) of patients, with the difference due to more progressions or non-responders in the L group. In both arms about 19% of subjects discontinued therapy early due to AEs and dose intensity was over 80%. Objective response rates are L - 49% (13% CR) and LR - 75% (32% CR). With a median follow-up of 1.5 years (range 0.1- 3.6 years), median EFS is 1.2 years (L) and 2.0 years (LR), p=0.0063, log-rank test. Conclusions: Lenalidomide + rituximab is more active than lenalidomide alone in patients with recurrent FL with similar toxicity. A trend toward lower thrombosis risk with LR may relate to greater anti-tumor efficacy. The LR regimen warrants further study in FL including as a backbone for addition of novel agents in relapsed and frontline settings.
Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM).
Authors: Lonial Sagar , Baz Rachid C. , Wang Michael , Talpaz Moshe , Liu Guohui , Berg Deborah , Gupta Neeraj , Di Bacco Alessandra , Hui Ai-Min , Richardson Paul Gerard Guy
Published: March 2020

8017

Background: MLN9708 is the first oral proteasome inhibitor to enter clinical investigation in MM. This study (NCT00932698) assessed safety, MTD, and response rate with twice-weekly oral MLN9708 in pts with relapsed and/or refractory MM, and characterized plasma pharmacokinetics (PK) and blood pharmacodynamics. Methods: Pts aged ≥18 yrs with measurable MM received MLN9708 on d 1, 4, 8, and 11 of 21-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD (2.0 mg/m2), pts were enrolled to relapsed and refractory [RR], bortezomib-relapsed [VR], proteasome-inhibitor [PI] naïve, and carfilzomib [CZ] expansion cohorts. Results: 57 pts (53% M) were enrolled, 37 to the expansion cohorts (16 RR, 14 VR, 6 PI naïve, 1 CZ). Median age was 65 yrs (range 50-86). Median number of prior lines of therapy was 4 (range 1-28); 88%, 84%, 61%, and 5% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 3 cycles (range 1-24) to date (data cut-off Dec 1, 2011); 7 (12%) have received ≥13 cycles. Drug-related AEs were seen in 89% of pts, including fatigue (46%), thrombocytopenia (40%), and nausea (30%); 63% had drug-related grade ≥3 AEs, including thrombocytopenia (33%), neutropenia (14%), fatigue (9%), and rash (7%). Only 6 (11%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 7 pts discontinued due to AEs. 2 pts died on study, due to PD and an unrelated cardiac disorder. Of 46 response-evaluable pts, 6 have achieved ≥PR, with 1 sCR (PI naïve cohort) and 5 PRs (2 in dose-escalation, 1 in RR, 2 in VR cohorts), and 1 VR pt has achieved MR, with duration of disease control of up to 18.6 mo. PK analyses showed MLN2238 (biologically active hydrolysis product) has linear plasma PK (0.8-2.23 mg/m2), Tmax of 0.5-1.25 hr, and terminal half-life of 4-6 d. A dose-dependent increase in whole blood 20S proteasome inhibition was observed. Conclusions: Current data suggest MLN9708 has clinical activity in heavily pretreated MM pts, with durable responses/disease control, and is generally well tolerated with infrequent low-grade PN.
Retreatment with brentuximab vedotin in CD30‑positive hematologic malignancies: A phase II study.
Authors: Bartlett Nancy , Brice Pauline , Chen Robert W. , Fanale Michelle A. , Gopal Ajay K. , Matous Jeffrey , Rosenblatt Joseph David , Grove Laurie E. , Forero-Torres Andres
Published: March 2020

8027

Background: Brentuximab vedotin comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, MMAE. In pivotal phase 2 studies in patients (pts) with relapsed/refractory Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL), objective response rates were 75% and 86% and median durations of response were 6.7 and 12.6 mo, respectively. A phase 2 study was initiated to investigate if pts who have previously responded to brentuximab vedotin could achieve another remission with retreatment (ClinicalTrials.gov #NCT00947856). Methods: Pts had a CD30-positive hematologic malignancy, achieved an objective response (per Cheson 2007) with prior brentuximab vedotin treatment, and experienced relapse after discontinuing treatment. Brentuximab vedotin was administered IV 1.8 mg/kg every 21 days; antitumor activity was assessed by the investigator. Results: 14 HL pts and 8 sALCL (5 ALK-negative) pts were enrolled (median age 34 yr, range 16–72). Pts had received a median of 4 prior chemotherapy regimens (range 2–12). Median time since the previous brentuximab vedotin treatment was 6.9 mo (range 1–44). Median number of retreatment cycles was 7 (range 1+ to 32+). Adverse events (AEs) in >25% of pts were nausea (41%), fatigue (36%), peripheral sensory neuropathy (36%), and diarrhea (27%). The most common Grade 3/4 AEs were anemia, fatigue, and hyperglycemia (3 pts each). Of the 11 pts who had pre-existing peripheral neuropathy, 3 (27%) had worsening with retreatment. Best clinical responses in pts with HL were 3 CR, 5 PR, 3 SD, 3 PD. Among pts with sALCL, 5 achieved a CR, 1 had PD, and 2 were not yet evaluated. Of the 8 pts with CR in retreatment, previous best responses to brentuximab vedotin treatment were 4 PR and 4 CR. Median duration of retreatment response was 10.8 mo (range 0+ to 10.8), and in pts who achieved CR, the median duration of response was not reached (range 0+ to 10.5 mo); 11 pts remain on retreatment. Conclusions: Retreatment with brentuximab vedotin was generally well tolerated. Objective responses were observed (13 of 20; 65%) in this heavily pretreated population. Enrollment to the phase 2 retreatment study is ongoing.