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S. Gadgeel
Moderator of
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 8
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.01 - Crizotinib Outcome and Post-Progression Management in ALK+ NSCLC: IFCT-1302 CLINALK (ID 1355)
16:45 - 16:56 | Author(s): M. Duruisseaux, B. Besse, J. Cadranel, M. Perol, E. Quoix, J. Mazières, R. Descourt, E. Dansin, C. Audigier-Valette, L. Moreau, J. Hureaux, R. Veillon, J. Otto, A. Madroszyk, A.B. Cortot, F. Guichard, P. Boudou-Rouquette, A. Langlais, P. Missy, F. Morin, G. Zalcman, D. Moro-Sibilot
- Abstract
- Presentation
Background:
Phase III trials have demonstrated the superiority of the ALK tyrosine kinase inhibitor (ALK-TKI) crizotinib compared to standard chemotherapy in advanced ALK positive non-small cell lung cancers (ALK+ NSCLC) in first line and second line setting. Objective response rate (ORR) with crizotinib ranged from 65 to 75% and median progression free survival (PFS) from 7.7 to 10.9 months. However a resistance to crizotinib always occurs. The French Cooperative Thoracic Intergroup (IFCT)-1302 CLINALK study aimed to describe clinical outcome and post-progression management in a large cohort of French patients with ALK+ NSCLC treated with crizotinib.
Methods:
IFCT-1302 CLINALK is a multicentric observational retrospective study. Patients with ALK+ NSCLC from centers of the IFCT network were included according to the main following criteria: advanced stage III or stage IV NSCLC, ALK immunochemistry (IHC) and/or ALK FISH positivity, crizotinib treatment in the setting of the French expanded access cohort program or as approved drug. Epidemiological and clinical data, crizotinib efficacy (objective response based on RECIST, PFS, overall survival (OS)), duration of treatment with crizotinib after disease progression and post progression outcome were collected on a case report form. The study inclusion period was from November 18 2011 to December 31 2013. The data cut-off was December 31 2014.
Results:
318 patients were included (median age 58.3, female 49.4%, caucasian 98.6%, non-smoker 55.1%, performance status 0/1 78.7%, adenocarcinoma 91.7%, stage III 14.5%, stage IV 85.5%, brain metastasis 35.9%). IHC was positive in 151/173 patients and FISH in 279/283 patients. Before crizotinib treatment, patients received platinum-based chemotherapy in 89% of cases and pemetrexed-based chemotherapy in 76.1%. Crizotinib was prescribed as first-line treatment in 17 patients (5.3%), second-line in 168 patients (52.8%), third-line in 58 patients (18.2%) and more than third-line in 75 patients (23.7%). Objective response was complete response in 1 patient (0.3%), partial response in 126 patients (40.0%), stable disease in 62 patients (19.7%) and progression in 58 patients (18.4%). ORR was 40.3 % (95%CI, 34.9-45.7). 262/318 patients presented progressive disease (82.4%) at time of analysis. Median PFS was 6.9 months (95%CI, 5.7-8.6). Median OS with crizotinib was 18.7 months (95%CI, 15.2-22.5). Median duration of treatment with crizotinib after disease progression was 56 days (29-203). Among 143 patients with subsequent treatments, crizotinib was rechallenged in 32 patients (22.4%). 58/143 patients (40.6%) were treated after crizotinib failure with another ALK-TKI, either alectinib (19/58, 32.8%) or ceritinib (40/58, 69.0%). The ALK-TKI sequence was crizotinib-alectinib in 18 patients, crizotinib-ceritinib in 39 patients and crizotinib-alectinib-ceritinib in 1 patient.
Conclusion:
This retrospective study of 318 patients with ALK+ NSCLC showed a remarkable efficacy of crizotinib, with a 18.7 months median OS, a 40.3% ORR and a 6.9 months median PFS. However, ORR and mPFS were lower than those reported in phase III trials, which may be due to less stringent selection criteria. Analysis of predictive factors of response and survival including post-progression strategies will be presented.
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- Abstract
- Presentation
Background:
There is strong interest in evaluating the outcomes of patients who have progressed after failing targeted agents. With different agents, the post-progression survival (PPS) may be either improved or shortened when a longer duration of time-to-progression (TTP) has been observed. This study evaluated the association between TTP and the duration of PPS among adult patients who received ceritinib for the treatment of advanced anaplastic lymphoma kinase-positive (ALK+) NSCLC.
Methods:
Patients experiencing disease progression during two single-arm, open-label, Phase I and II trials of ceritinib (ASCEND-1 [ClinicalTrials.gov Identifier: NCT01283516] and ASCEND-2 [ClinicalTrials.gov Identifier: NCT01685060]) were included in this analysis. For uniformity, all patients analyzed had received crizotinib prior to ceritinib. TTP after the initiation of ceritinib was studied as a predictor for the length of subsequent PPS using Cox proportional hazards models. Adjustments were made for patients’ baseline characteristics, including age, body mass index, gender, race, Eastern Cooperative Oncology Group (ECOG) performance score, number of prior regimens, tumor histology, and presence of brain metastases. A Kaplan-Meier analysis for PPS was performed stratified by shorter (< 6 months) versus longer TTP (≥ 6 months). As a secondary descriptive analysis, associations were quantified between the duration of TTP and the duration of survival (OS) measured as the sum of TTP and PPS.
Results:
Of 181 patients who experienced disease progression during study follow-up, 94% received at least one chemotherapy prior to baseline, 75% had an ECOG performance score greater than zero at screening, and 79 died during subsequent follow-up. In an unadjusted model, each 3 months of longer TTP was associated with a 24% lower hazard of death following progression (hazard ratio [HR]: 0.76, 95% confidence interval [CI]: 0.60-0.96). Results were similar after adjusting for baseline characteristics (HR: 0.77, 95% CI: 0.61-0.97). Patients with TTP ≥ 6 months experienced significantly longer PPS compared to those with TTP < 6 months (median: 9.8 vs. 6.5 months, log-rank p-value < 0.01). This positive relationship between TTP and PPS translated into the duration of OS: each 3 months of longer TTP was associated with a 58% lower hazard of death after adjusting for baseline characteristics (HR: 0.42, 95% CI: 0.32-0.54). Median OS was not reached for patients with TTP ≥ 6 months and was 10.3 months for patients with TTP < 6 months.
Conclusion:
A longer duration of TTP after treatment with ceritinib was significantly associated with both longer duration of PPS and longer OS.
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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): A. Shaw, H. West, M.A. Socinski, I. Ou, L. Gandhi, S. Gadgeel, C.P. Belani, K. Shirai, L. Bazhenova, E. Santos, G.J. Riely, A. Chiappori, J. Cetnar, T. Mekhail, B. Chao, H. Borghaei, K.A. Gold, H. Johannsdottir, T. Ruf, F. Boisserie, V. Henschel, A. Zeaiter, R. Camidge
- 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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ORAL33.04 - Discussant for ORAL33.01, ORAL33.02, ORAL33.03 (ID 3371)
17:18 - 17:28 | Author(s): D.S. Tan
- Abstract
- Presentation
Abstract not provided
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ORAL33.05 - Pooled Analysis of CNS Response to Alectinib in Two Studies of Pre-Treated ALK+ NSCLC (ID 1219)
17:28 - 17:39 | Author(s): S. Gadgeel, A. Shaw, R. Govindan, M.A. Socinski, R. Camidge, L. De Petris, D. Kim, A. Chiappori, D. Moro-Sibilot, M. Duruisseaux, L. Crinò, T. De Pas, E. Dansin, A. Tessmer, J.C. Yang, H. Ji-Youn, W. Bordogna, S. Golding, A. Zeaiter, I. Ou
- Abstract
- Presentation
Background:
The central nervous system (CNS) is a frequent site of progression in ALK+ NSCLC patients treated with crizotinib, thus good CNS efficacy is of crucial importance for new ALK inhibitors. Two recent phase II studies examined the efficacy and safety of alectinib in patients with ALK+ NSCLC who progressed after crizotinib; data from both studies were pooled to further examine the efficacy of alectinib in the CNS.
Methods:
Both phase II, single-arm, multicenter studies enrolled ALK+ NSCLC patients previously treated with crizotinib. One study was conducted in North America only (NP28761; NCT01871805), the other was global (NP28673; NCT01801111). All patients received 600mg oral alectinib twice daily. A primary endpoint of both studies was objective response rate (ORR) by independent review committee (IRC) and key secondary endpoints included CNS ORR by IRC and CNS duration of response (DOR). Response was determined according to RECIST v1.1. All patients underwent imaging at baseline to assess CNS metastases.
Results:
The pooled analysis population comprised 225 patients (n=87 from NP28761 and n=138 from NP28673); baseline characteristics were similar to each study population, with most patients being non-smokers, <65 years old with ECOG performance status 0/1. Median follow-up was 27.7 weeks. Fifty patients had measurable CNS disease at baseline (MD) while a further 85 had non-measurable disease (NMD) at baseline; both groups together (M+NMD) comprised 135 patients, 60% of the overall study population. In the MD group, 34 patients (68%) had received prior radiotherapy, but 24 of them had completed that radiotherapy >6 months prior to starting alectinib. For the M+NMD group, 94 patients (70%) had received prior radiotherapy, with 55 completing this >6 months prior to starting alectinib. In the MD group, 30/50 patients had a CNS response (60.0%; 95% CI 45.2–73.6%), with 7 complete responses (CR; 14.0%) and a CNS DCR of 90.0% (78.2–96.7%). In the M+NMD group, 22 additional patients had a CR (29/135; 21.5%), giving a CNS ORR of 38.5% (30.3–47.3%), with a CNS DCR of 85.2% (78.1–90.7%). Complete responses were seen in patients with and without prior radiotherapy. Median CNS DOR after only 17% of events in both groups was 7.6 months (5.8–7.6) in the MD group (n=30) and 7.6 months (5.8–10.3) in the M+NMD group (n=52), which is similar to the systemic DOR reported in both studies (Ou et al, ASCO 2015; Gandhi et al, ASCO 2015). Tolerability was also similar to the overall study population.
Conclusion:
Alectinib showed promising efficacy in the CNS in ALK+ NSCLC patients previously treated with crizotinib, achieving a complete response rate of 22% and a DCR of 85%, irrespective of prior radiotherapy. The CNS response was sustained for an equivalent duration to the systemic response, suggesting that alectinib could provide an effective treatment for patients with ALK+ NSCLC while actively targeting CNS metastases. The ongoing phase III clinical studies will assess the systemic and CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.
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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): S.N. Gettinger, L. Bazhenova, R. Salgia, C.J. Langer, K.A. Gold, R. Rosell, A. Shaw, G.J. Weiss, D.J. Dorer, V.M. Rivera, M.G. Conlan, D. Kerstein, R. Camidge
- 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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ORAL33.07 - Clinical Activity and Safety of the ALK/ROS1 TK Inhibitor PF-06463922 in Advanced NSCLC (ID 295)
17:50 - 18:01 | Author(s): T. Bauer, B.J. Solomon, B. Besse, A. Navarro, L. James, J. Clancy, G. Mugundu, J. Martini, A. Abbattista, A. Shaw
- Abstract
- Presentation
Background:
Overcoming acquired resistance in ALK+ and ROS1+ non-small-cell lung cancer (NSCLC) patients (pts) is key to optimizing therapy. PF-06463922 is a selective, brain-penetrant tyrosine kinase inhibitor (TKI) with demonstrated clinical activity against de novo fusions as well as resistance mutations, including ALK G1202R, that arise during treatment with other TKIs.
Methods:
In this ongoing phase I study, eligible pts had ALK+ or ROS1+ NSCLC, with or without brain metastases, and were treatment naïve or had disease progression after at least 1 prior TKIs. Pts with central nervous system (CNS) metastases, including untreated asymptomatic metastases, were eligible. Tumor tissue (archival sample or de novo biopsy) was required for enrollment. A modified continual reassessment method was used to estimate the maximum tolerated dose (MTD) and select a recommended phase II dose (RP2D). Once- (QD) or twice-daily (BID) dosing in 21-day cycles was explored. Secondary objectives included efficacy, safety, tolerability, pharmacokinetics (PK), effect on cognitive function, patient-reported outcomes, potential to induce/inhibit CYP3A4, biomarkers of drug response and resistance, and intracranial antitumor activity.
Results:
25 ALK+ pts (20 with CNS metastases, 23 previously treated with at least 1 ALK TKIs) and 5 ROS1+ pts (3 with CNS metastases, 3 previously treated with crizotinib) have been enrolled across 7 QD dose levels and 2 BID dose levels. Of 21 patients evaluable for intracranial response, 16 had stable disease or confirmed complete/partial response. The most common treatment-related adverse events (AEs) were hypercholesterolemia, peripheral neuropathy, and peripheral edema, occurring in 47%, 27% and 23% of pts, respectively. Peripheral neuropathy was reversible following treatment delay or dose reduction. The most common grade 3 and higher treatment-related AE was hypercholesterolemia, occurring in 10% of pts, which was well managed with statins. One DLT was reported for a pt at 200 mg QD, who received less than 16 of the 21 planned doses of study drug due to grade 2 CNS effects. To date, 20 pts remain on treatment. Preliminary PK analyses suggest that exposure increased linearly from 10 to 75 mg QD, with a terminal half-life of 20-28 hrs. At doses beyond 75 mg QD, the increase in exposure appeared to be non-proportional. PF-06463922 is considered a moderate inducer of CYP3A4.
Conclusion:
PF-06463922 is a potent ALK/ROS1 TKI that has demonstrated clinical activity in ALK+ and ROS1+ NSCLC pts, most of whom had CNS metastases and had received at least 1 prior TKI. The RP2D has not yet been established.
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ORAL33.08 - Discussant for ORAL33.05, ORAL33.06, ORAL33.07 (ID 3372)
18:01 - 18:11 | Author(s): M. Ahn
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.10 - Rociletinib in NSCLC Patients with Negative Central Testing for T790M in TIGER-X (ID 951)
17:40 - 17:45 | Author(s): S. Gadgeel
- Abstract
- Presentation
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). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. New insights into mutEGFR NSCLC suggest clonal heterogeneity – activating EGFR mutations are truncal (present in all tumor clones) and T790M is a dominant branch mutation with variable clonal frequency between patients and over time. The extent of this clonal heterogeneity may relate to rociletinib efficacy. Here we present preliminary findings to evaluate this hypothesis from an ongoing Phase 1/2 clinical trial.
Methods:
TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with metastatic or unresectable locally advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). Screening included mandatory tumor biopsy and T790M testing. For Phase 1, patients could be T790M negative, positive or unknown. For Phase 2, T790M negative patients (by validated central testing) could have a contemporaneous local T790M+ result.
Results:
As of March 2015, 36 patients were enrolled in TIGER-X who were T790M central negative by cobas® or Qiagen therascreen® and evaluable for efficacy. Sensitivity analysis indicated that the 2 assay platforms were comparable for T790M detection. 69% (25/36) were T790M negative centrally but positive locally; 4/36 (11%) were negative by both central and local testing; and 7/36 (19%) were centrally negative with no local result. Median number of previous TKIs was 1 and median number of previous therapies was 2; 81% (29/36) were treated with a TKI as their most recent prior therapy. In central negative/local+ patients the ORR was 40% (10/25). In central negative/local negative patients the ORR was 25% (1/4). The most common treatment emergent adverse events in this subset (all grades) were fatigue, diarrhea, nausea and hyperglycemia.
Conclusion:
These preliminary findings suggest that patients who test negative for T790M using a sensitive tissue test may still benefit from treatment with rociletinib. In part, this clinical activity may be driven by T790M tumor heterogeneity, demonstrated by the discordant T790M results described. In addition, inhibition of IGF-1R/IR by the previously reported (Soria 2014) rociletinib metabolite M502 may also be driving some of the activity observed. This possible explanation is important, since the response rates reported herein are higher than described for other T790M inhibitors in T790M-negative patients. Furthermore, TKI re-treatment effect is unlikely to be a major driver of these results, since the majority of patients came on study directly after progression on another EGFR TKI. To further explore these findings, the open-label TIGER-2 (NCT02147990) and the randomized Phase 3 TIGER-3 (NCT02322281) studies include T790M negative patients.
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.03 - Dose Optimization of Rociletinib for EGFR Mutated NSCLC (ID 967)
16:55 - 17:00 | Author(s): S. Gadgeel
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible mutant selective tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. A maximum tolerated dose was not identified in Phase 1 with 1000 mg BID the highest dose studied. Here we assess the efficacy and safety of the three doses of rociletinib (500 mg BID, 625 mg BID and 750 mg BID) selected for Phase 2 study.
Methods:
TIGER-X (NCT01526928) is a Phase 1/2 open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutant NSCLC progressing after ≥1 EGFR tyrosine kinase inhibitor (TKI). Efficacy is assessed using RECIST. Safety is evaluated using standard adverse event (AE) reporting.
Results:
As of April 2015, a total of 231 central T790M positive patients were evaluable for efficacy and 343 for safety (any T790M). All patients were enrolled in the USA (85%), Europe (9%) and Australia (6%). Baseline characteristics were similar in each dose group. The median number of prior therapies was 2. 85% had EGFR TKI as their most recent prior therapy and 10% had a history of diabetes/hyperglycemia. Immature ORRs are 53% (500 mg BID), 52% (625 mg BID) and 43% (750 mg BID), with disease control rates of 89% (500 mg BID), 87% (625 mg BID) and 82% (750 mg BID). The most common ≥grade 3 treatment-related AE was hyperglycemia [16% (500 mg BID), 25% (625 mg BID) and 35% (750 mg BID)] which was managed with oral hypoglycemic agents. Only one patient discontinued the study for hyperglycemia. Grade 3 QTc prolongation was uncommon, occurring in 2% (500 mg BID), 7% (625 mg BID) and 10% (750 mg BID) of patients, and demonstrated a relationship to dose. There were no clinically relevant cutaneous toxicities with 7 cases of grade 1 rash and 4 cases of grade 1 stomatitis (no dose relationship) and no paronychia.
Conclusion:
All 3 Phase 2 doses of rociletinib are active and well tolerated in a Western patient population with advanced NSCLC. The lack of cutaneous toxicities confirms the selectivity of rociletinib for mutant forms of EGFR and is an important contributor to QOL and maintaining dose intensity (Lacouture et al. 2011). Overall, the adverse event frequency appears to be related to dose, but antitumor activity does not, thus the risk/benefit profile may be optimal at the lowest dose studied.
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MINI16.04 - Activity of Rociletinib in EGFR Mutant NSCLC Patients with a History of CNS Involvement (ID 965)
17:00 - 17:05 | Author(s): S. Gadgeel
- Abstract
- Presentation
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) with activity against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). An overall response rate of 67% has previously been reported in this trial for T790M positive patients treated with the 500 and 625 mg BID doses (Soria 2014). Here we provide preliminary data on the activity of rociletinib in the subgroup of patients with a history of CNS disease.
Methods:
Patients with a history of CNS disease were permitted if asymptomatic and stable, as defined by steroid requirements. The primary activity endpoint was RECIST overall response rate. However, patients who developed progressive disease (PD) while on study treatment were allowed to continue therapy with rociletinib if deemed clinically beneficial by the investigator.
Results:
As of 16 March 2015, a total of 401 patients received therapeutic dose levels of rociletinib (500, 625 and 750 mg BID) including 170 (42%) patients with a history of CNS metastases. Based on this interim analysis, the RECIST overall response rate among these patients with a history of CNS disease is 41%. To date, 42 patients with a history of CNS disease have continued therapy with rociletinib post-progression. Of those who continued for at least 14 days the average treatment duration beyond PD was 89 days (range: 14 - 336 days). Twenty-two of the 42 patients with a history of CNS disease with PD also received brain radiation and continued rociletinib treatment for an average of 120 days (range: 22 – 336 days) after PD. Rociletinib is held on radiation days only. Progression-free survival data for these subgroups is not yet mature. The three most common adverse events in the patient population with a history of CNS disease are similar to those found in the general TIGER-X patient population: hyperglycemia, diarrhea and nausea.
Conclusion:
In patients with a history of CNS disease, a factor associated with poor prognosis, rociletinib is active with a RECIST response rate of 41%. Local CNS radiation has been administered safely with rociletinib held on radiation days and continued afterwards. Prolonged use of rociletinib post CNS radiation suggests ongoing systemic benefit is still experienced by these patients. The role of rociletinib in NSCLC patients with CNS involvement is being further explored in the ongoing TIGER clinical development program.
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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:P.A. Bunn, Jr, J. Sage
- Coordinates: 9/09/2015, 16:45 - 18:15, 605+607
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MINI27.08 - NOTCH3 Protein Expression and Outcome in Small Cell Lung Cancer (SCLC) and Therapeutic Targeting with Tarextumab (Anti-Notch 2/3) (ID 2999)
17:25 - 17:30 | Author(s): S. Gadgeel
- Abstract
- Presentation
Background:
NOTCH expression is associated with cancer cell survival via effects on cancer stem/progenitor cells. Targeting NOTCH2 and 3 decreases growth and survival of SCLC patient-derived human tumor xenografts (PDX). Phase1b/2 trials testing Tarextumab (TRXT) anti-NOTCH2/3 therapy are underway (NCT01647828 and NCT01859741) and show promising anti-tumor activity. Here, we studied NOTCH3 protein expression using immunohistochemistry (IHC) in SCLC human tissues and correlated with survival. Also, we studied NOTCH3 gene expression in phase 1b patients (pts) treated with TRXT.
Methods:
For NOTCH IHC staining, murine monoclonal antibodies were generated by immunizing mice with a NOTCH3 extracellular domain (ECD) protein, then creating hybridomas. Clones were screened by FACS and western blots for specificity to NOTCH3.ECD. A lead clone was selected for NOTCH3 protein measurement in 47 SCLC samples represented in a tissue microarray from Yale Pathology Tissue Services (YPTS). NOTCH3 signal was determined in tumors using H-scores generated by Leica Aperio Scanscope IHC membrane image analysis. For survival analysis, NOTCH3 signal was binarized with cutoffs defined by X-tile software. For the phase 1b clinical trial, a standard 3+3 dose escalation design was employed with cohorts of 3 to 6 pts treated at each dose level. TRXT was given IV on Day 1 of each 21 day cycle with etoposide 100 mg/m[2] (Days 1-3) and cisplatin 80 mg/m[2 ]or carboplatin at AUC 5 (Day 1) for 6 cycles, followed by TRXT alone every 21 days until progression of disease or unacceptable toxicities. Then, the MTD TRXT plus etoposide and carboplatin was confirmed in a cohort of 6 subjects. All pts are required to submit tissues for Notch 3 gene expression and IHC staining.
Results:
A single hybridoma clone demonstrating specific reproducible membranous staining with a dynamic range for NOTCH3.ECD in control and PDX tissues was chosen for IHC analysis in SCLC human FFPE tissues (n=47). Forty cases (85.1%) demonstrated NOTCH3 signal, with eighteen (38.3%) having none to very low signal. Of the 31 cases with adequate follow-up, there was a strong trend with worse outcome and high NOTCH3 expression in the extensive stage (p=0.063), but not in limited stage (p=0.857). The level of significance was a function of the experimental cut-point and can only be considered exploratory. Finally, 27 pts were treated with TRXT in the phase 1b trial, with an overall response rate of 84%. The median duration of treatment was 128 days (6 cycles) with mPFS and mOS of 124 and 228 days, respectively. The median follow-up for PFS and OS was 86 and 107 days, respectively. Twenty-five pts have tissues evaluable for NOTCH3 gene expression and the analysis is underway.
Conclusion:
NOTCH3 IHC staining showed expression in most SCLC cases, with high NOTCH3 trending towards worse survival in extensive stage. This supports the rationale of targeting NOTCH3 by TXRT in SCLC pts. Further evaluation of the prognostic and predictive value of TRXT for anti-Notch therapies in SCLC is underway in an ongoing Phase 2 clinical trial.
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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.06 - FP1039/GSK3052230 with Chemotherapy in Patients with Fibroblast Growth Factor (FGF) Pathway Deregulated Squamous NSCLC or MPM (ID 2879)
19:00 - 19:05 | Author(s): S. Gadgeel
- Abstract
- Presentation
Background:
GSK3052230/FP1039 is a soluble fusion protein with the ECD of FGFR1c linked to the hinge and Fc regions of human IgG1 and acts as a ligand trap by sequestering FGFs involved in tumor growth and angiogenesis. In contrast to small molecule FGFR kinase inhibitors, GSK3052230 spares the hormonal FGF ligands, namely FGF19, 21 and 23. GSK3052230 combined with chemotherapy was efficacious in xenograft models of FGFR1-amplified NSCLC and malignant pleural mesothelioma (MPM) with FGF2 mRNA overexpression. A phase I monotherapy study determined 20mg/kg weekly as the maximum feasible dose (MFD) achieving the desired blood concentration, with no maximum tolerated dose (MTD) reached.
Methods:
This study (NCT01868022 funded by GSK) will evaluate the safety and efficacy of GSK3052230 weekly infusion in combination with paclitaxel + carboplatin in previously untreated FGFR1 amplified metastatic sqNSCLC (Arm A), in combination with docetaxel in FGFR1 amplified metastatic sqNSCLC that has progressed after at least 1 line of chemotherapy (Arm B), or in combination with pemetrexed + cisplatin in patients with untreated and unresectable MPM (Arm C). Each arm involves a dose escalation phase utilizing the 3+3 design, followed by an expansion phase up to 30 patients (pts). Key endpoints include the MTD/MFD of GSK3052230 with chemotherapy, safety, response rates and duration.
Results:
Thirty-four pts have been dosed with GSK3052230 at dose levels ranging from 5mg/kg to 20mg/kg in combination with chemotherapy across three Arms, n=15 (A), n=6 (B) and n=13 (C). Baseline characteristics: males/females 29/5; mean age 68.5 years; ECOG PS 0 (n=20), 1 (n=13), 2 (n=1). Most common AEs were: Arm A: asthenia, neutropenia; Arm B: neutropenia, diarrhea, rash; Arm C: decreased appetite, nausea, infusion reaction. Infusion reactions were seen in 8/34 (24%) pts (n=3 Grade (Gr)1, n=3 Gr2, n=2 Gr3). Serious AEs included: Arm A- neutropenia (n=4), fatigue (n=1), asthenia (n=1), fever (n=1), respiratory infection (n=1); Arm B- neutropenia (n=1), abdominal pain (n=1); Arm C-bowel perforation/ischemia (n=1), infusion reaction (n=1), elevated creatinine (n=1). No DLTs have been observed in sqNSCLC pts (Arms A and B). Three DLTs were reported in mesothelioma pts (Arm C 20mg/kg): Gr5 bowel perforation/ischemia, Gr4 elevated creatinine levels and Gr3 infusion reaction. MFD for Arm A is determined at 20mg/kg. Dose escalation is ongoing for Arms B and C. Preliminary PK results revealed no drug-drug interactions. At time of data-cutoff, 10 PR were observed among 23 patients evaluable for efficacy (ORR = 43%) and a clinical benefit rate of 78% with two ongoing subjects on study >300 days. Preliminary efficacy is as follows: Arm A (6 PR, 2 SD, 1 PD, 6= not-yet-evaluable (NE)), Arm B (4 SD, 1 PD, 1 NE), and Arm C (3 PR, 3 SD, 3 PD, 4 NE).
Conclusion:
GSK3052230 is in general well tolerated in combination with chemotherapy. The MFD for GSK3052230 is 20mg/kg in combination with paclitaxel + carboplatin in first line sqNSCLC patients. Toxicities typically associated with small-molecule FGFR inhibitors, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. The initial activity and safety profile of GSK3052230 warrant further study.
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MTE 25 - New Therapies for Squamous Cell Carcinoma (Ticketed Session) (ID 77)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Community Practice
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 07:00 - 08:00, 107
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MTE25.01 - New Therapies for Squamous Cell Carcinoma (ID 2012)
07:00 - 08:00 | Author(s): S. Gadgeel
- Abstract
- Presentation
Abstract:
Management of patients with advanced Non-Small Cell Lung Cancer (NSCLC) in recent years has been approached based on defining the histologic subtype and identifying actionable genetic alterations in the tumor. Many of the recent developments in the management of advanced NSCLC are applicable only to non-squamous NSCLC patients. Cytotoxic chemotherapy has remained the primary systemic therapy for squamous cell lung cancer patients. Despite a decline in the incidence in some parts of the world, squamous cell lung cancer as a single entity remains one of the major causes of cancer related mortality worldwide. Therefore there is a need to advance therapy of squamous cell lung cancer patients beyond chemotherapy. Recently several new agents have been studied in squamous cell lung cancer patients and promising results have been observed, with some of the trial results leading to drug approval for NSCLC patients in general and squamous cell lung cancer patients in particular. The recent advances in drug therapy can be categorized according to drug type into cytotoxic chemotherapy agents, immune checkpoint inhibitors and molecularly targeted agents. Nab paclitaxel, an albumin bound formulation of paclitaxel combined with carboplatin was compared with the standard combination of the carboplatin and paclitaxel in advanced NSCLC patients (1). The nab paclitaxel combination showed a significant improvement in response rate in squamous cell patients (41% vs. 24%), p < 0.001). This improvement in response rate was associated with a modest but statistically non-significant improvement in progression free survival (PFS) and overall survival. These results, have led to the approval of this combination for the management of advanced NSCLC patients and this combination is preferentially considered in squamous cell patients. The immune check point inhibitors have generated most excitement in recent years. In a randomized trial, Checkmate 017, the anti-PD-1 drug nivolumab was compared with docetaxel in patients with progressive squamous cell lung cancer and demonstrated both PFS (HR-0.62) and survival (HR-0.59) improvement (2). Toxicities in general were less in patients who received nivolumab and immune related toxicities were not common. In this trial PD-L1 expression did not correlate with benefit from nivolumab. Ipilimumab, an anti-CTLA4 antibody, has also been evaluated in squamous cell lung cancer patients. In a randomized phase II trial phased in ipilimumab with chemotherapy demonstrated superior outcomes compared to advanced NSCLC patients receiving chemotherapy alone (3). Retrospective analysis suggested greater benefit in squamous cell patients. Based on these results, a randomized study evaluating ipilimumab with chemotherapy in advanced squamous cell patients as front line therapy was initiated and has completed accrual (NCT01285609). Drugs targeting EGFR (Epidermal Growth Factor Receptor) have been studied in squamous cell lung cancer patients. Though EGFR-tyrosine kinase mutations are extremely uncommon in squamous cell lung cancer patients EGFR amplification has been observed in 7-10% of the patients and EGFR is expressed in a high proportion of squamous cell lung cancers. Necitumumab, a recombinant human EGFR antibody combined with chemotherapy cisplatin and gemcitabine demonstrated a modest survival advantage (HR- 0.84, p = 0.01) compared to chemotherapy alone (4). Afatinib, an irreversible EGFR tyrosine kinase inhibitor demonstrated superior survival compared to erlotinib in patients with recurrent squamous cell lung cancer following front line therapy (HR-0.81, p = 0.007) (5). The modest benefit observed suggests that EGFR targeting drugs are useful only in a proportion of squamous cell lung cancer patients and a biomarker to identify patients that benefit from these drugs could be valuable in the future use of these drugs. Another drug that showed clinical benefit in squamous cell lung cancer patients, along with other NSCLC patients is ramucirumab, a VEGFR2 receptor directed monoclonal antibody. In the REVEL study NSCLC patients with progressive disease following front therapy were randomized to docetaxel with or without ramucirumab (6). The combination demonstrated a superior survival compared to single agent docetaxel (HR-0.86, p = 0.023). Benefits were seen across all histologies, including squamous cell lung cancer. Several drugs targeting other signaling pathways, specifically PI3K and FGFR, are currently undergoing evaluation. Results to date in patients with tumors that have these specific molecular alterations have shown only modest benefit or no benefit at all. The reasons for these results are unclear. Ongoing clinical trials will determine the potential benefit for targeting these pathways. A major effort in analyzing targeted drugs based on molecular alteration in the patient’s tumor is ongoing with the LUNG MAP study, led by Southwest Oncology Group (SWOG) with participation from all the US Oncology Cooperative Groups. In conclusion, after a period of no advances for the treatment of squamous cell lung cancer patients, several drugs recently have shown clinical benefit and several others are currently being evaluated. It is clear that therapy of advanced squamous cell lung cancer patients has evolved beyond cytotoxic chemotherapy and will provide greater clinical benefit. References 1. Socinski MA, Bondarenko I, Kasareva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first line therapy in patients with advanced non-small cell lung cancer: final results of a phase III trial. J Clin Oncol 2012;30:2055-62. 2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35. 3. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first line treatment in stage IIIB/IV non-small-cell lung cancer: results of a randomized, double-blind, multicenter phase II study. 4. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015;16:763-74. 5. Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; epub ahead of print. 6. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicenter, double-blind, randomised phase 3 trial. Lancet 2014;384:665-73.
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ORAL 32 - EGFR WT and MT Targeting (ID 144)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K.J. O'Byrne, D.R. Gandara
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL32.01 - Tumor Genomic Analysis from LUX-Lung 8: A Phase III Trial of Afatinib versus Erlotinib in Squamous Cell Carcinoma of the Lung (ID 1401)
16:45 - 16:56 | Author(s): S. Gadgeel
- Abstract
- Presentation
Background:
Overexpression of EGFR and other ErbB receptors, and/or dysregulation of their downstream pathways are implicated in the pathogenesis of squamous cell carcinoma (SCC) of the lung, generating interest in exploring EGFR/ErbB-targeted agents in this setting. Recent analyses from the global LUX-Lung 8 trial (n=795) in patients with SCC of the lung demonstrated that second-line afatinib (an irreversible ErbB family blocker) conferred overall survival (OS; median 7.9 vs 6.8 months; HR [95% CI] 0.81 [0.69‒0.95]; p=0.008) and progression-free survival (PFS; median 2.6 vs 1.9 months; HR [95% CI] 0.81 [0.69‒0.96]; p=0.010) benefit over erlotinib (a reversible EGFR inhibitor). To assess biomarkers for efficacy for these agents in SCC we conducted an exploratory analysis using archival tumor tissue collected at time of study entry.
Methods:
Among all randomized patients, samples were retrospectively enriched for those from patients with PFS >2 months and appropriate controls (PFS ≤2 months; Figure 1) and were selected for analysis using the Foundation Medicine (FM) FoundationOne™ next-generation sequencing (NGS) platform (n=433); 300 cancer-related genes were analyzed for copy number alterations (CNAs), rearrangements and single nucleotide variants (SVs). Preliminary results from the 238 samples analyzable so far (~30% of the randomized patients), focusing on genomic alterations of EGFR and their potential association to survival endpoints PFS and OS, are presented.
Results:
Fourteen EGFR SVs (5.8%) were detected of which 10 were novel with unknown clinical significance (Figure 1). Figure 1 Four had been previously reported; 2 (E114K [afatinib arm], Q1021* [erlotinib arm]) occurred in the non-kinase domains and 2 (L861Q [afatinib arm], L858R [erlotinib arm]) in the kinase domain. The frequency of EGFR CNAs (n=15 [6.3%]; afatinib: 9; erlotinib: 6) was also low. At the time of these ongoing analyses, these low frequencies of EGFR mutations/amplifications were deemed not to be associated with the observed improvements in PFS and OS. Genomic alterations aggregated across two key gene groups (ErbB and FGF families) and their association with survival outcomes will be presented.
Conclusion:
The frequency of EGFR genomic aberrations in the samples tested was low. Based on this analysis of a subgroup of patients, PFS and OS improvements conferred by afatinib in LUX-Lung 8 were not driven by the presence of activating EGFR mutations or amplifications and may be related to afatinib’s ability to inactivate multiple aberrant signaling cascades associated with, and downstream of, ErbB receptors.
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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): S. Gadgeel
- 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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ORAL33.05 - Pooled Analysis of CNS Response to Alectinib in Two Studies of Pre-Treated ALK+ NSCLC (ID 1219)
17:28 - 17:39 | Author(s): S. Gadgeel
- Abstract
- Presentation
Background:
The central nervous system (CNS) is a frequent site of progression in ALK+ NSCLC patients treated with crizotinib, thus good CNS efficacy is of crucial importance for new ALK inhibitors. Two recent phase II studies examined the efficacy and safety of alectinib in patients with ALK+ NSCLC who progressed after crizotinib; data from both studies were pooled to further examine the efficacy of alectinib in the CNS.
Methods:
Both phase II, single-arm, multicenter studies enrolled ALK+ NSCLC patients previously treated with crizotinib. One study was conducted in North America only (NP28761; NCT01871805), the other was global (NP28673; NCT01801111). All patients received 600mg oral alectinib twice daily. A primary endpoint of both studies was objective response rate (ORR) by independent review committee (IRC) and key secondary endpoints included CNS ORR by IRC and CNS duration of response (DOR). Response was determined according to RECIST v1.1. All patients underwent imaging at baseline to assess CNS metastases.
Results:
The pooled analysis population comprised 225 patients (n=87 from NP28761 and n=138 from NP28673); baseline characteristics were similar to each study population, with most patients being non-smokers, <65 years old with ECOG performance status 0/1. Median follow-up was 27.7 weeks. Fifty patients had measurable CNS disease at baseline (MD) while a further 85 had non-measurable disease (NMD) at baseline; both groups together (M+NMD) comprised 135 patients, 60% of the overall study population. In the MD group, 34 patients (68%) had received prior radiotherapy, but 24 of them had completed that radiotherapy >6 months prior to starting alectinib. For the M+NMD group, 94 patients (70%) had received prior radiotherapy, with 55 completing this >6 months prior to starting alectinib. In the MD group, 30/50 patients had a CNS response (60.0%; 95% CI 45.2–73.6%), with 7 complete responses (CR; 14.0%) and a CNS DCR of 90.0% (78.2–96.7%). In the M+NMD group, 22 additional patients had a CR (29/135; 21.5%), giving a CNS ORR of 38.5% (30.3–47.3%), with a CNS DCR of 85.2% (78.1–90.7%). Complete responses were seen in patients with and without prior radiotherapy. Median CNS DOR after only 17% of events in both groups was 7.6 months (5.8–7.6) in the MD group (n=30) and 7.6 months (5.8–10.3) in the M+NMD group (n=52), which is similar to the systemic DOR reported in both studies (Ou et al, ASCO 2015; Gandhi et al, ASCO 2015). Tolerability was also similar to the overall study population.
Conclusion:
Alectinib showed promising efficacy in the CNS in ALK+ NSCLC patients previously treated with crizotinib, achieving a complete response rate of 22% and a DCR of 85%, irrespective of prior radiotherapy. The CNS response was sustained for an equivalent duration to the systemic response, suggesting that alectinib could provide an effective treatment for patients with ALK+ NSCLC while actively targeting CNS metastases. The ongoing phase III clinical studies will assess the systemic and CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.
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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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P1.01-079 - Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone as First-Line Therapy for NSCLC (ID 2993)
09:30 - 09:30 | Author(s): S. Gadgeel
- Abstract
Background:
Platinum doublet chemotherapy with or without bevacizumab is the standard first-line therapy for patients with advanced NSCLC without EGFR sensitizing mutations or ALK rearrangement. Pembrolizumab (MK-3475), a humanized monoclonal antibody against PD-1 designed to block the interaction of PD-1 with its ligands PD-L1 and PD-L2, has shown efficacy and a manageable toxicity profile in patients with NSCLC treated at doses ranging from 2 mg/kg every 3 weeks to 10 mg/kg every 2 weeks. In 45 patients with treatment-naive advanced NSCLC treated in KEYNOTE-001, single-agent pembrolizumab has demonstrated a response rate of 26%.
Methods:
KEYNOTE-021 (ClinicalTrials.gov, NCT02039674) is an international, open-label, multi-arm, phase 1/2 trial of pembrolizumab for advanced NSCLC. After establishing the safety and tolerability of pembrolizumab plus carboplatin and pemetrexed in phase 1, a randomized phase 2 cohort comparing the efficacy of pembrolizumab plus carboplatin and pemetrexed with that of carboplatin and pemetrexed has been initiated. Key eligibility criteria for this cohort are previously untreated stage IIIB/IV nonsquamous NSCLC, no sensitizing EGFR mutation or ALK rearrangement, and ECOG PS 0-1. Patients will be randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg Q3W plus carboplatin and pemetrexed at standard doses or carboplatin and pemetrexed alone. Randomization will be stratified by PD-L1 expression determined by immunohistochemistry at a central laboratory (positive [membranous expression in ≥1% of tumor cells] vs negative). Pembrolizumab will be given for 24 months or until progression, intolerable toxicity, or investigator decision. Pembrolizumab may be continued beyond radiographic progression in eligible patients. Carboplatin and pemetrexed will be given for 4 cycles followed by maintenance pemetrexed, alone or with pembrolizumab. Patients allocated to the chemotherapy-alone arm who experience progression may cross over to the pembrolizumab arm of the study. AEs will be monitored throughout treatment and for 30 days thereafter. Response will be assessed every 6 weeks for the first 18 weeks, then every 9 weeks in year 1 and every 12 weeks in year 2. Survival follow-up will occur every 3 months after discontinuation of study treatment. Primary end point is progression-free survival (RECIST v1.1, central review); secondary end points include overall survival, objective response rate, and correlation of PD-L1 expression with antitumor activity. This cohort is currently enrolling patients.
Results:
Not applicable.
Conclusion:
Not applicable.
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P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.03-034 - Utility of Surveillance Imaging in Detection of Recurrence in Treated Stage III NSCLC Patients (ID 2766)
09:30 - 09:30 | Author(s): S. Gadgeel
- Abstract
Background:
About a third of newly diagnosed NSCLC patients have stage III disease at diagnosis, of whom, a quarter achieve long term survival. The current recommendation of National Comprehensive Cancer Network (NCCN) for surveillance following completion of therapy is to perform CT scan of the chest every 6-12 months for 2 years. However, it is unclear if strategy of surveillance scans is superior in detecting recurrences as compared to the strategy of scans done for symptoms suggestive of disease progression. We conducted a retrospective analysis of stage III NSCLC at our institution to estimate the rate of detection of recurrence in scans performed for symptomatic worsening, in patients on surveillance scans.
Methods:
This study is a single institutional, retrospective, review utilizing the Karmanos Cancer Institute lung cancer database established in 2010. Inclusion criteria: stage III lung cancer patients who had completed therapy and who were treated between 2011 and 2013. Exclusion criteria: inadequate documentation and those who were not eligible for treatment based on clinician or patient preference. Patients were followed until progression or last assessment. The primary objective was to estimate the percentage of patients who had documented tumor recurrence on a surveillance scan.
Results:
Fifty four patients met the eligibility criteria. Mean age was 61 years (40-80), 34% were males; 44% were Caucasians and 39% were African-Americans; 85% were current or former smokers. Histology at diagnosis was adenocarcinoma in 67% and squamous cell in 31%, the remaining were large cell and poorly differentiated. Thirty-seven (69%) patients received chemotherapy and radiation, 12 (22%) received surgery with chemotherapy and radiation, and 5 (9%) received surgery and chemotherapy. The median follow up following completion of treatment was 18 months. Eighteen (33%) patients have had disease recurrence, with 11 (20%) recurrences within 1 year following completion of therapy. Of all 18 patients with recurrences, 17 (98%) were detected on surveillance scans. Only 1 (2%; 95% CI: 0-10%) recurrence was detected on scans obtained for worsening symptoms.
Conclusion:
In this retrospective analysis in stage III NSCLC patients who had completed therapy, except one case, all of the recurrences were detected on surveillance scans, strongly suggesting that routine surveillance scans provide clinical utility.
