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H. Xiong
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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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P2.01-094 - Phase II Trial of Tepotinib/Gefitinib vs Cisplatin/Pemetrexed in T790M-/c-Met+ NSCLC (ID 2105)
09:30 - 17:00 | Author(s): H. Xiong
- Abstract
Background:
The recommended phase II dose of the highly selective c-Met inhibitor tepotinib (MSC2156119J) for use in combination with gefitinib was confirmed as 500 mg/day in the phase Ib part of the current trial, in which patients with gefitinib-resistant locally advanced/metastatic c-Met-positive NSCLC were treated with tepotinib plus gefitinib. This trial demonstrated that the combination regimen is well tolerated and has evidence of antitumor activity that may be associated with c-Met-positive tumor status. These observations suggest that c-Met inhibition may have a role in EGFR tyrosine kinase inhibitor-resistant NSCLC and that a phase II trial is warranted.
Methods:
The design of the phase II part of a phase Ib/II trial (NCT01982955) is described. Asian adults with histologically or cytologically confirmed, gefitinib-resistant locally advanced/metastatic NSCLC other than predominantly squamous histology and ECOG PS 0/1 are eligible. Patients must have tumors with documented activating mutations of EGFR. Tumor tissue obtained between documentation of acquired resistance to gefitinib and enrollment must be available. Tumors must be confirmed as being c-Met positive (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]). EGFR mutation status will be assessed centrally using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). Patients will be enrolled into different parts of the trial based on tumor T790M status. Patients with c-Met-positive, T790M-negative NSCLC (n=136) will be randomized to tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w or cisplatin 75 mg/m[2] + pemetrexed 500 mg/m[2] q3w for up to 6 cycles. Patients with c-Met-positive, T790M-positive NSCLC (n=15) will be treated with tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w. The primary objective is to determine whether progression-free survival (PFS) in patients treated with second-line tepotinib combined with gefitinib is superior to that of pemetrexed + cisplatin in patients with c-Met-positive, T790M-negative advanced NSCLC and acquired resistance to first-line gefitinib. The two T790M subgroups will be analyzed separately. An interim analysis of the randomized part of the study is planned when 50% of PFS events have occurred in both arms. Secondary objectives are to evaluate: the safety and tolerability tepotinib combined with gefitinib; the efficacy of tepotinib combined with gefitinib; the antitumor activity of tepotinib combined with gefitinib in patients with c-Met-positive, T790M-positive tumors; and patient-reported outcomes.
Results:
not applicable
Conclusion:
This randomized phase II trial will provide the first evidence regarding whether tepotinib has a role in the treatment of Asian patients with gefitinib-resistant, c-Met-positive, T790M-negative NSCLC.
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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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P3.01-011 - Antitumor Activity of Tepotinib plus Gefitinib in Asian Patients with Met+ EGFRm+ NSCLC (ID 763)
09:30 - 17:00 | Author(s): H. Xiong
- Abstract
Background:
c-Met abnormalities are key in resistance to EGFR TKIs in EGFRm+ NSCLC patients (pts). The highly selective c-Met inhibitor tepotinib (MSC2156119J) had promising activity in a phase I trial in pts with advanced solid tumors. We report phase Ib data from a trial evaluating tepotinib + gefitinib in pts with Met+ NSCLC (NCT01982955).
Methods:
Asian adults with locally advanced/metastatic NSCLC, Met+ status (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]) and ECOG PS 0/1 were eligible. EGFR mutation status was assessed using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). A 3+3 design was used for the phase Ib part; planned recruitment was 15-18 pts, who received tepotinib 300 or 500 mg p.o. + gefitinib 250 mg/d q3w. Primary objective: determine the RP2D of tepotinib for use in combination; secondary objectives: pharmacokinetics, safety, antitumor activity.
Results:
14 pts have been enrolled (median age 65 years; male 43%; ECOG PS 0/1 2/12; median prior therapy regimens including an EGFR TKI 3.5). 3 pts received tepotinib 300 mg + gefitinib and 11 tepotinib 500 mg + gefitinib. No DLTs were observed; 4 pts had grade 3/4 treatment-related adverse events (amylase increase [n=3], lipase increase [2], decreased neutrophil count [1]). Best overall response by c-Met status (cut-off Jan 20, 2015) for the 12 evaluable pts is shown in the table. EGFR mutation status for these 12 pts was T790M and L858R mutation (n=2), L858R mutation alone (4), exon 19 deletion (4), no mutation detected using the therascreen[®] kit (2).Best overall response (n) n=12 Partial response Stable disease Progression IHC 2+ 0 5 2 3+ 4 0 1 FISH c-Met:CEP7 ratio >2 1 0 0 ≥5 copies in >50% of cells 3 1 1 Negative 0 3 2 Not valid 0 1 0
Conclusion:
The RP2D of tepotinib in combination with gefitinib has been confirmed as 500 mg/d in pts with advanced NSCLC. The data show evidence of antitumor activity and that response may be associated with c-Met status. The phase II trial will randomize ≈136 pts with T790M-/c-Met+ tumors who have failed first-line gefitinib to tepotinib 500 mg/d + gefitinib or cisplatin/pemetrexed.
