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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.I. Ou
- 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.I. Ou
- 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 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.09 - Clinical Response to Entrectinib in a Patient with NTRK1-Rearranged Non-Small Cell Lung Cancer (NSCLC) (ID 2913)
19:15 - 19:20 | Author(s): S.I. Ou
- Abstract
- Presentation
Background:
Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in less than 1% of NSCLCs. Cell-based assays have demonstrated that NTRK1 rearrangement leads to expression of an oncogenic TrkA fusion protein. While inhibition of TrkA in preclinical models reduces TrkA auto-phosphorylation and cell proliferation, the clinical activity of TrkA inhibitors in NSCLCs harboring an NTRK1 fusion is not known. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor of TrkA, TrkB, TrkC, ROS1, and ALK, with IC50 values for kinase inhibition ≤ 2 nM.
Methods:
We used an anchored multiplex polymerase chain reaction (AMP) assay to screen for NTRK1 rearrangements (Zheng et al., Nature Medicine 2014). Among over 663 NSCLC cases screened, we identified one positive case in which the 3’ end of SQSTM1 exon 6 was fused to the 5’ end of NTRK1 exon 10, leading to an SQSTM1-NTRK1 fusion transcript. We enrolled the patient onto the Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). The dose of entrectinib was 400 mg/m[2] (750 mg) once daily. We assessed safety of entrectinib and response to treatment using RECIST 1.1.
Results:
The patient is a 46 yo male with a 30 pack year smoking history who was first diagnosed with metastatic NSCLC in November 2013. Prior therapies included carboplatin/pemetrexed, pembrolizumab, docetaxel, and vinorelbine. At the time of study enrollment, the patient had an ECOG performance status of 2 and required supplemental oxygen at a rate of 3 liters per minute by nasal cannula. He reported significant pain and dyspnea due to widely metastatic disease, including a large left hilar mass narrowing the left upper lobe bronchus and obstructing the left lower lobe bronchus, extensive and palpable neck and chest lymphadenopathy, and a palpable expansile left chest wall mass. Staging head CT also revealed numerous (15 to 20) asymptomatic brain metastases measuring up to 1.7 cm that had not been previously treated. The patient was started on entrectinib and tolerated the study medication well, with one adverse event of grade 1 dysgeusia, which resolved after two weeks. Within three weeks of starting treatment, the patient reported resolution of dyspnea and pain, and improvement in energy and appetite. He no longer required supplemental oxygen and all sites of palpable disease had improved or resolved. At four weeks of treatment, restaging CT scans demonstrated a partial response by RECIST of -47%, with significant regression or resolution of lymphadenopathy, reduction in size of the chest wall mass, and marked reexpansion of the left lung. Restaging of the CNS by head CT demonstrated near complete resolution of previously visualized brain metastases.
Conclusion:
In a heavily pre-treated patient with NSCLC harboring an NTRK1 gene fusion, entrectinib therapy resulted in rapid clinical improvement and a radiologic partial response at 4 weeks with minimal toxicity. This preliminary report suggests that entrectinib may be an effective therapy for patients with NTRK1-rearranged NSCLC.
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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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MINI31.10 - Discussant for MINI31.06, MINI31.07, MINI31.08, MINI31.09 (ID 3390)
19:20 - 19:30 | Author(s): S.I. Ou
- Abstract
- Presentation
Abstract not provided
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