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T. Mekhail
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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: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.04 - Activity of Rociletinib in EGFR Mutant NSCLC Patients with a History of CNS Involvement (ID 965)
16:45 - 18:15 | Author(s): T. Mekhail
- 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 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
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MINI31.04 - Intracranial Efficacy of First-Line Crizotinib vs. Chemotherapy in ALK-Positive NSCLC (ID 1238)
18:30 - 20:00 | Author(s): T. Mekhail
- Abstract
- Presentation
Background:
The ongoing multicenter, randomized, open-label phase III study PROFILE 1014 recently demonstrated superior efficacy of crizotinib compared with chemotherapy in patients with previously untreated advanced ALK-positive NSCLC (Solomon et al, N Engl J Med 2014). Intracranial efficacy of crizotinib vs. chemotherapy was compared prospectively in this trial.
Methods:
Patients with previously untreated advanced non-squamous ALK-positive NSCLC (N=343) were randomized 1:1 to receive crizotinib 250 mg orally BID (n=172) or intravenous chemotherapy (pemetrexed 500 mg/m[2 ]+ cisplatin 75 mg/m[2] or carboplatin at AUC 5–6; all q3w for ≤6 cycles; n=171). Patients with treated brain metastases that were stable for ≥2 weeks with no ongoing requirement for corticosteroids were eligible. Treatment was continued until PD. Continuation of, or crossover to, crizotinib after PD (per independent radiology review [IRR]) was allowed for patients randomized to crizotinib or chemotherapy, respectively. Brain scanning was performed every 6 weeks in patients with baseline brain metastases and every 12 weeks in those without baseline brain metastases. Protocol-specified efficacy endpoints included PFS (primary endpoint), ORR, OS, and 12- and 18-month OS, as well as intracranial TTP. Intracranial DCR at 12 and 24 weeks was also evaluated. Efficacy was evaluated in the ITT population and in two subgroups of patients: those with and without baseline brain metastases.
Results:
Of 343 patients in the ITT population, 79 had brain metastases at baseline identified by IRR (23%) and 263 did not (77%; data not reported for one patient). Baseline characteristics of patients randomized to receive crizotinib or chemotherapy were generally well balanced within these two patient subgroups. Among the patients with baseline brain metastases, a significantly higher proportion achieved intracranial disease control with crizotinib than with chemotherapy at 12 weeks (33/39 [85%] vs. 18/40 [45%], respectively; P=0.0003) and at 24 weeks (22/39 [56%] vs. 10/40 [25%]; P=0.006). There was a numerical improvement in prospectively measured intracranial TTP with crizotinib in the ITT population (HR 0.60, P=0.069), as well as in patients either with baseline brain metastases (HR 0.45, P=0.063) or without baseline brain metastases (HR 0.69, P=0.323). The frequency of progression in the brain was low in the ITT population (15%) and in patients with and without baseline brain metastases (27% and 11%, respectively). Overall PFS was significantly longer with crizotinib than with chemotherapy in both subgroups (brain metastases present: HR 0.40, P=0.0007, median 9.0 vs. 4.0 months; brain metastases absent: HR 0.51, P≤0.0001, median 11.1 vs. 7.2 months), as it was in the ITT population (HR 0.45, P<0.0001, median 10.9 vs. 7.0 months). Twenty-five patients in the crizotinib arm of the study experienced intracranial PD; 22 of these patients received crizotinib for ≥3 weeks beyond PD and 19 also received intracranial radiotherapy.
Conclusion:
In this prospective assessment of intracranial efficacy, crizotinib demonstrated significantly greater intracranial disease control and overall efficacy compared with chemotherapy in patients with baseline brain metastases. These findings provide further confirmation of crizotinib as the standard of care for patients with previously untreated advanced ALK-positive NSCLC, including those patients with brain metastases at baseline.
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- 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)
16:45 - 18:15 | Author(s): T. Mekhail
- 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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