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L. Bazhenova
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.03 - Updated Efficacy/Safety Data From the Phase 2 NP28761 Study of Alectinib in ALK+ NSCLC (ID 1261)
17:07 - 17:18 | Author(s): L. Bazhenova
- Abstract
- Presentation
Background:
ALK gene rearrangements occur in approximately 3–6% of patients with non-small-cell lung cancer (NSCLC). Crizotinib has demonstrated efficacy in ALK+ NSCLC, however many patients experience systemic and/or central nervous system (CNS) disease progression within one year of treatment. Alectinib, a CNS-penetrant and highly selective ALK inhibitor, has shown preclinical activity in the CNS (Ou, et al. JTO 2013) and clinical efficacy in crizotinib-naïve (Ohe, et al. ASCO 2015) and pre-treated (Ou, et al. ASCO 2015; Gandhi, et al. ASCO 2015) ALK+ NSCLC patients. We will present updated efficacy and safety outcomes from the phase II NP28761 study (NCT01871805).
Methods:
North American patients ≥18 years of age with ALK+ NSCLC (by FDA-approved FISH test), disease progression following first-line crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included investigator-assessed ORR; progression-free survival (PFS); quality of life (QoL); CNS response rate; disease control rate (DCR); and safety.
Results:
At data cut-off (24 October 2014), 87 patients were enrolled in the intent-to-treat population. Median age was 54 years; 74% had received prior chemotherapy; 60% of patients had baseline CNS metastases, of whom 65% (34/52) had prior brain radiation therapy. Median follow-up was 20.7 weeks. ORR by IRC was 48% (95% CI 36–60); median PFS was 6.3 months (Table 1). In patients with measurable CNS lesions at baseline (n=16), IRC CNS ORR was 69% (95% CI 41–89) and CNS DCR was 100% (complete response, 13%; partial response, 56%; stable disease, 31%). In patients with measurable or non-measurable CNS disease (n=52), IRC CNS ORR was 39% (95% CI 25–53) and 11 patients (21%) had complete CNS responses. The most common grade ≥3 AEs were elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%) and aspartate aminotransferase (5%); no GI toxicities leading to treatment withdrawal were reported. Clinically meaningful improvements were seen in EORTC QLQ-C30 items, including Global Health Status. Figure 1
Conclusion:
Alectinib (600mg twice daily) was well tolerated and demonstrated clinical efficacy in patients with ALK+ NSCLC disease who had progressed on prior crizotinib. A clinical benefit with alectinib was also observed in patients with CNS lesions at baseline. These data are preliminary; updated efficacy and safety data from a cut-off date of 27 April 2015 will be presented.
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ORAL33.06 - Brigatinib (AP26113) Efficacy and Safety in ALK+ NSCLC: Phase 1/2 Trial Results (ID 2125)
17:39 - 17:50 | Author(s): L. Bazhenova
- Abstract
- Presentation
Background:
Brigatinib (AP26113), an investigational oral tyrosine kinase inhibitor with FDA breakthrough therapy designation for the treatment of patients with crizotinib-resistant advanced ALK+ NSCLC, has preclinical activity against both rearranged ALK and clinically identified crizotinib-resistant mutant ALK.
Methods:
This is an ongoing phase 1/2, single-arm, open-label, multicenter study in patients with advanced malignancies (N=137; NCT01449461). Patients received escalating total daily doses of brigatinib from 30–300 mg during phase 1. Daily regimens of 90 mg, 180 mg, or 90 mg for 7 days followed by 180 mg were evaluated in phase 2. Safety is reported for all treated patients; antitumor efficacy (ORR and PFS per RECIST v1.1) is reported for ALK+ NSCLC patients.
Results:
Seventy-nine (58%) patients had ALK+ NSCLC. Median age was 54 (29–83) years, 49% were female, 90% had prior crizotinib, and 47% had ≥2 prior chemotherapy regimens. As of February 17, 2015, 45/79 (57%) ALK+ NSCLC patients remained on study, with median time on treatment of 12.6 months (1 day to 35.5 months; n=79); ORR/PFS for evaluable ALK+ NSCLC patients was 74%/13.4 months (additional data shown in Table). In a post hoc independent radiological review of patients with brain metastases at baseline (as of January 19, 2015), 8/15 (53%) patients with measurable brain lesions ≥10 mm had an intracranial response (≥30% decrease in sum of longest diameters of target lesions) and 9/30 (30%) patients with only nonmeasurable lesions had disappearance of all lesions. Treatment-emergent AEs in ≥30% of total patients, generally grade 1/2, included nausea (52%), fatigue (42%), diarrhea (40%), headache (33%), and cough (32%). Early-onset pulmonary events, which occurred ≤7 days after treatment initiation and included dyspnea, hypoxia, and new pulmonary opacities on chest CT consistent with pneumonia or pneumonitis, were reported in 13/137 (9%) patients overall (6/44 [14%] at 180 mg qd; 2/50 [4%] at 90 mg qd [maintained or escalated to 180 mg qd after 7 days]).Response and PFS With Brigatinib All Evaluable ALK+ NSCLC Patients n=78 Prior Crizotinib n=70 No Prior Crizotinib n=8 Response, n(%) OR (CR+PR) 58(74) 50(71) 8(100) [95% CI] [63–84] [59–82] [63–100] CR 7(9) 4(6) 3(38) PR 51(65) 46(66) 5(63) SD 11(14)[a] 11(16)[a] 0 PD 6(8) 6(9) 0 Termination before scan 3(4) 3(4) 0 Median duration of response,[b] mo 11.2[c] 9.9[d] Not reached[e] Median PFS,[b] mo 13.4 13.4 Not reached [a]Includes non-CR/non-PD for 4 patients with no measurable disease at baseline [b]Kaplan-Meier estimate [c]n=55 evaluable [d]n=48 evaluable [e]n=7 evaluable
Conclusion:
Brigatinib has promising antitumor activity in ALK+ NSCLC patients with (71% ORR; PFS 13.4 months) or without (100% ORR) prior crizotinib, including patients with brain metastases (53% ORR in patients with measurable brain lesions). Early-onset pulmonary events were less frequent when starting at 90 vs 180 mg qd. A pivotal global phase 2 trial (ALTA) of brigatinib 90 mg qd vs 90 mg qd for 7 days followed by 180 mg qd in crizotinib-resistant ALK+ NSCLC is ongoing.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-086 - TIGER-3: A Phase 3 Open-Label, Randomized Study of Rociletinib vs Chemotherapy in NSCLC (ID 949)
09:30 - 09:30 | Author(s): L. Bazhenova
- Abstract
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) that has demonstrated efficacy against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X, a Phase I/II dose-ranging trial, has provided evidence that rociletinib is associated with durable response and is well tolerated in patients with NSCLC and positive T790M status following progression on a TKI.[1 ]Efficacy has also been noted for patients with T790M negative status in TIGER-X.[2] TIGER-3 is designed to investigate single agent rociletinib vs chemotherapy in patients who have failed EGFR therapy and platinum-based doublet chemotherapy, which is a setting of acquired resistance and high unmet need for targeted therapeutic options. TIGER-3 will evaluate patients with T790M positive and negative status based on tumor biopsies and plasma, and biomarkers of response and/or resistance.
Methods:
Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC, with radiological progression on the most recent therapy will be enrolled in this phase 3, randomized, open-label study (NCT02322281). Patients must have documented evidence of a tumor with ≥1 EGFR activating mutations excluding exon 20 insertion, and prior treatment with an EGFR TKI and platinum-containing doublet chemotherapy. Patients will be randomized 1:1 to receive rociletinib twice daily (500 mg) or single agent cytotoxic chemotherapy (investigator choice specified before randomization) until disease progression according to RECIST 1.1. Patients will be stratified by presence or absence of brain metastases, ECOG performance status (0 vs 1), and race (Asian vs non-Asian). The primary endpoint is progression-free survival (PFS). Secondary endpoints include safety, objective response rates, duration of response, disease control rate, and overall survival. Kaplan-Meier methodology will assess time to event variables. The stratified log-rank and the hazard ratio will be used for comparing PFS distributions. Serial assessment of safety will be carried out based on standard adverse event reporting. Planned enrolment is 600 patients; enrolment has been open since March 2015. Sequist LV J Clin Oncol. 2014 Soria J-C EORTC-NCI-AACR 2014
Results:
Not applicable
Conclusion:
Not applicable
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-101 - Randomized Phase 3 Trial of Docetaxel+Plinabulin Compared to Docetaxel in Advanced Non-Small Cell Lung Cancer with at Least 1 Large Lung Lesion (ID 1498)
09:30 - 09:30 | Author(s): L. Bazhenova
- Abstract
Background:
Plinabulin (BPI-2358) is a marine derived tubulin binding agent, which inhibits existing tumor vasculature and directly induces cancer cell apoptosis via the Ras-JNK pathway. Additional effect of inducing dendritic cell maturation is also observed. Phase 1/2 randomized clinical trial of Docetaxel + Plinabulin (DP) compared to Docetaxel (D) alone failed to show improvement in OS in an ITT analysis. The median OS was 8.6 months in DP, and 7.5 months in D arm. (HR 0.97, P=0.90). However, post hoc subset analysis showed improvement in OS in patient with pulmonary tumors >3 cm regardless of number of prior therapy for metastatic disease. In this population, OS was 11.47 (7.13, 16.73) months vs. 7.10 (4.06, 10.60) in DP vs D arm (HR 0.76 and P=0.36). Mechanistically it is postulated that those patients are more dependent on angiogenesis. This phase 3 protocol is designed to test the hypothesis generated from the subset analysis.
Methods:
This is a randomized phase 3, open label clinical trial comparing DP at 75 mg/m2 of D on day1 and 30 mg/m2 of P on days 1 and 8 to D alone at 75 mg/m2 on day 1 in a 21-day cycle. Randomization stratified by ECOG performance status and region. Study population: patients with metastatic with non small cell lung cancer ( NSCLC), who has failed one line of chemotherapy and have at least one lung lesion larger than 3 cm. Primary endpoint of the study is to compare overall survival (OS) between two arms. Secondary endpoints are Progression free survival (PFS), overall response rate (ORR), duration of response (DOR), and adverse event profile. Planned number of subjects 550 (440 from China and 110 from the US). Primary outcome analysis is planned after 434 death events which will provide a 0.85 power to detect a statistically significant treatment effect using a two-sided log-rank test at a significance level of α = 0.05.
Results:
Not applicable, trial in progress.
Conclusion:
not applicable
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-088 - Surrogate or Not: The Role for Cell Free Circulating DNA in Detecting EGFR Mutations Present in Tumor Tissue (ID 499)
09:30 - 09:30 | Author(s): L. Bazhenova
- Abstract
Background:
Identification of molecular drivers such as EGFR in non-small cell lung cancer (NSCLC) has increased our capability to deliver personalized cancer therapy. EGFR tyrosine kinase inhibitors (TKI) are very effective in patients with EGFR sensitive mutations, but resistance ultimately develops. Determining mechanisms of secondary resistance requires post progression biopsies which carry non-trivial complication risks for patients and thus are not suitable means for serial monitoring. Cell free circulating DNA (cfcDNA) could represent an alternative method to detect molecular mechanisms of secondary resistance.
Methods:
Single institution observational study of 13 patients with EGFR mutant Stage IV lung adenocarcinoma. Two 8-10 ml tubes of blood were collected from patients who progressed on erlotinib. Patient samples were tested for T790M mutations using the Biocept Selector assay as well as MET using FISH amplification. Results from these “liquid-biopsies” were then compared to results obtained on standard tissue biopsy.
Results:
13 patients with secondary resistance were enrolled, all 13 had adenocarcinoma. Median age was 61 with an age range 52-76, male to female ratio 7:6, 8/13 (62%) had deletion 19, 5/13 (38%) had an L858R mutation. Median duration of EGFR TKI therapy prior to cfcDNA sample collection was 16 months, range 5.2-64.4 months. 9/13 patients underwent a post-progression tissue biopsy with 8/13 found to have the T790M mutation, 1/13 with c-MET amplification, and 1/13 with both. 11/13 patients were found to have T790M in cfcDNA. Average concentration of T790M clone in cfcDNA was 4% with a range from .004-27.6% (from 3mL of blood). Average copy number of T790M in cfcDNA was 2310 with a range from 7-20507 (from 3mL of blood). Average copy number of the EGFR gene in cfcDNA was 39404 with a range from 4308-169628 (from 3mL of blood). Among the 10 patient thus far whose post-progression biopsies and cfcDNA sampling was completed, the sensitivity and positive predictive value (PPV) of Selector was 88% and 88% respectively. Concordance was 80% between cfcDNA and tissue. 7/9 patients with tissue confirmed T790M were switched to third generation TKI with 6/7 currently with stable disease after an average of 7 months (5-9). 1/7 passed away after one month on the next generation TKI due to disease progression.
Conclusion:
Biocept’s blood based assay detecting T790M and MET amplifications from cfcDNA is highly concordant with mutations present in tumor tissue and therefore a non-invasive surrogate for determining mutational status of patients’ who progress on TKI therapy.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-057 - Randomized Phase 2 Study of Plinabulin and Docetaxel in Patients with Advanced Non-Small Cell Lung Cancer - Mechanism-Based Efficacy Analyses (ID 1505)
09:30 - 09:30 | Author(s): L. Bazhenova
- Abstract
Background:
Plinabulin (N), a tubulin binding agent, which depolarizes microtubules, resulting in tumor vasculature obliteration, apoptosis via JNK pathway and maturation of dendritic cells. A multicenter randomized phase 2 study was performed to compare overall survival (OS) between plinabulin/docetaxel (DN) and docetaxel (D). Results of Intent-to-treat (ITT) analyses have been presented at ASCO 2014. The primary objective of OS prolongation was not met, however, exploratory mechanism based analysis revealed improvement in outcomes in patients with large tumors.
Methods:
From November 2008 to July 2011 172 patients with advanced NSCLC who progressed after at least one chemotherapy were enrolled. Patients were treated with D 75mg/m[2] on day 1 and N 30 mg/[2] on days 1 and 8. A second cohort of N 20 mg/m[2] was also enrolled. This exploratory analysis is based on 105 patients (50 DN arm and 55 D arm) receiving 30 mg/m[2] dose, which was selected for an ongoing Phase 3 study and explains the population chosen for future investigation.
Results:
Median OS was 8.7 months (m) (CI 6.6-12.6) in DN arm and 7.5 m (6.3-10.5) in D arm (p=0.899, HR=0.97). PFS was 2.8 m and 3.5 m and ORR was 14.0% vs 14.5% respectively. Among clinical parameters, lesion size (Table 1) and presence of pulmonary disease were identified to impact OS. The OS in patients with pulmonary disease was 11.3 m (6.7-15.1) in DN and 6.7 m (6-9.8) in D, respectively (p=0.29, HR=0.76) regardless of lesion size. Table 1: Exploratory Analysis of Overall Survival by Tumor Size
CI = confidence interval; D = docetaxel; DN, docetaxel + plinabulin; ITT = intent-to-treat; OS = overall survival (Months).Patients Tumor size Median OS Months (95% CI) Hazard Ratio P-value DN (30mg/m[2]) D ITT 1 and 2 prior chemo-therapy All 8.68 (6.33, 12.63) N=50 7.47 (6.17, 10.60) N=55 0.972 0.8993 ≤ 3 cm 6.45 (3.73, NA) N=16 6.47 (5.6, 22.43) N=19 0.934 0.8687 > 3 cm 8.98 (6.60, 12.63) N=34 7.47 (4.77, 11.60) N=36 0.967 0.8990 > 5 cm 8.98 (4.57, 19.23) N= 20 6.70 (4.07, 12.93) N=21 0.750 0.4176 > 7 cm 7.32 (4.57, 19.23) N= 8 5.03 (2.93, 6.70) N= 10 0.507 0.1936
Conclusion:
Mechanism-based exploratory analyses of Phase 2 results have identified advanced NSCLC patients with lung lesion size >3 cm to have benefited from plinabulin. A Phase 3 to confirm this observation is on-going.
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PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)
- Event: WCLC 2015
- Type: Plenary
- Track: Plenary
- Presentations: 1
- Moderators:T. Mok, F.R. Hirsch
- Coordinates: 9/09/2015, 10:45 - 12:15, Plenary Hall (Bellco Theatre)
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PLEN04.01 - A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent Cetuximab in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): SWOG S0819 (ID 3612)
10:45 - 10:57 | Author(s): L. Bazhenova
- Abstract
- Presentation
Background:
This abstract is under embargo until September 9, 2015 and will be distributed onsite on September 9 in a Late Breaking Abstract Supplement.
Methods:
Results:
Conclusion:
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