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Helena Yu
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.03 - TATTON Ph Ib Expansion Cohort: Osimertinib plus Savolitinib for Pts with EGFR-Mutant MET-Amplified NSCLC after Progression on Prior EGFR-TKI (ID 8985)
11:00 - 12:30 | Author(s): Helena Yu
- Abstract
- Presentation
Background:
MET amplification is a well described mechanism of acquired resistance to EGFR inhibition in EGFR-mutant NSCLC, making combined MET/EGFR inhibition a compelling therapeutic approach. We previously reported tolerability of the oral, CNS active, third-generation EGFR-TKI osimertinib, which is selective for both EGFR-TKI sensitizing and EGFR T790M resistance mutations, combined with the highly selective MET-TKI savolitinib (volitinib, HMPL-504, AZD6094). Here we assess safety and preliminary activity of this combination in a cohort of patients (pts) with EGFR-mutant NSCLC and MET-positive acquired resistance in the multi-arm, Phase Ib TATTON study (NCT02143466).
Method:
Eligible pts were aged ≥18 years (WHO performance status 0/1) with locally advanced or metastatic EGFR-mutant NSCLC who progressed on at least one prior EGFR-TKI with centrally confirmed MET-amplification (fluorescence in-situ hybridisation, MET gene copy ≥5 or MET/CEP7 ratio ≥2). Pts received osimertinib 80 mg QD plus savolitinib 600 mg QD. Primary objective was safety and tolerability; secondary objectives included preliminary assessment of anti-tumour activity and pharmacokinetics.
Result:
As of data-cut off (15 April 2017), 45 pts with centrally confirmed MET-amplification (FISH) were enrolled and received treatment, including 25 pts previously treated with a third-generation EGFR-TKI and 20 without prior third-generation EGFR-TKI treatment (T790M negative n=13; T790M positive n=7). At baseline, median age was 58 years (range 38–76), 24 (53%) were female, 36 (80%) were Asian. The most frequent adverse events (AEs) were nausea (n=21, 47%), decreased appetite (n=15, 33%), fatigue (n=13, 29%) vomiting (n=13, 29%), rash (n=11, 24%), myalgia (n=8, 18%), pyrexia (n=7, 16%), ALT/AST increased (n=6, 13%), and WBC decreased (n=6, 13%), consistent with the known safety profiles. Serious AEs were reported in 15 (33%) pts; events reported in >1 patient were pneumonia, dyspnoea, acute kidney injury and pyrexia (all n=2). Four pts died due to AEs, none were considered related to study drugs. At data cut-off, confirmed partial responses were reported in 5/25 (20%) pts previously treated with a third-generation EGFR-TKI; 5/12 (42%) T790M negative pts without prior third-generation EGFR-TKI and 3/7 (43%) T790M positive pts without prior third-generation EGFR‑TKI. Twenty-eight (62%) pts are ongoing treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and osimertinib were consistent with historical data.
Conclusion:
These findings demonstrate promising safety, tolerability, and preliminary activity of osimertinib plus savolitinib and support further investigation of this combination for the treatment of pts with locally advanced or metastatic EGFR-mutant NSCLC and MET-amplification. Updated data will be presented.
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-001 - Osimertinib with Ramucirumab or Necitumumab in Advanced T790M-positive EGFR-Mutant NSCLC: Preliminary Ph1 Study Results (ID 7940)
09:30 - 16:00 | Presenting Author(s): Helena Yu
- Abstract
Background:
Combination studies of a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) and either a VEGF or EGFR-targeting monoclonal antibody have recently shown promising clinical results in EGFR-mutant non-small cell lung cancer (NSCLC) patients. The preliminary safety results from the phase 1 study JVDL (NCT02789345), combining third-generation EGFR TKI osimertinib (Osi) with human IgG1 monoclonal antibodies ramucirumab (Ram) or necitumumab (Neci), are reported.
Method:
Eligible pts naïve to third-generation EGFR TKI therapy with advanced EGFR T790M-positive NSCLC who progressed after initial EGFR TKI therapy were enrolled. In the dose-finding portion, following a dose de-escalation 3+3 design, patients received daily oral Osi (80 mg) and either 10 mg/kg intravenous (IV) Ram on day 1 (D1) every two weeks (Q2W), or 800 mg (IV) Neci on D1 and D8 Q3W. Primary objective of the study is to assess the safety and tolerability of Ram or Neci combined with Osi, and secondary objectives include preliminary evaluation of efficacy.
Result:
As of data cutoff on 09-May-2017, 7 pts were treated in the completed dose-finding portion: 3 pts with Ram+Osi (Arm A) and 4 pts (1 non-evaluable and replaced) with Neci+Osi (Arm B). No DLTs were observed in either arm, and the initial dose level became the recommended dose for expansion cohort. After the DLT observation period was complete, the only Grade ≥3 (Gr≥3) treatment-related adverse event (TRAE) was dermatitis acneiform (Arm B), with one unrelated Gr≥3 treatment-emergent AE (TEAE) of increased lipase (Arm B) and one serious AE of Gr2 diverticulitis (unrelated to study treatment) (Arm A). Expansion cohort A of Ram+Osi is fully enrolled with 22 pts. Safety data were available for 18 out of 22 cohort A patients. Gr≥3 TEAEs were reported in 4 patients, including dyspnea (unrelated [n=1]), decreased appetite (unrelated [n=1]), and hypertension (related [n=2]). Three patients reported serious adverse events (none related to study treatment): Gr3 dyspnea and Gr2 pyrexia, Gr2 dyspnea, and Gr2 urinary tract infection. No death was reported in patients in the dose-finding portion, and one death unrelated to study treatment was reported in the expansion cohort.
Conclusion:
No DLTs were observed and no unexpected safety signals were seen to date. The recommended dose for expansion cohort was the initial dose level of 10 mg/kg ramucirumab IV Q2W with oral 80 mg osimertinib. Additional safety and efficacy observation for the combination of Ram+Osi is ongoing, and will be presented at the meeting.
