Patrizia Froesch1, Michael Mark2, Sacha I Rothschild3, Qiyu Li4, Gilles Godar5, Corinne Rusterholz6, Elisabeth Oppliger Leibundgut7, Sabine Schmid8, Ilaria Colombo9, Yannis Metaxas10, David König11, Cristiana Sessa12, Oliver Gautschi13, Martin Früh14. 1. Oncology Institute of Southern Switzerland, Via Ospedale, 6500 Bellinzona, Switzerland. Electronic address: patrizia.froesch@eoc.ch. 2. Department of Medical Oncology/Hematology, Cantonal Hospital Graubünden, Loëstrasse 170, 7000 Chur, Switzerland. Electronic address: Michael.Mark@ksgr.ch. 3. Department of Medical Oncology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. Electronic address: Sacha.Rothschild@usb.ch. 4. SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland. Electronic address: Qiyu.Li@sakk.ch. 5. SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland. Electronic address: Gilles.Godar@sakk.ch. 6. SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland. Electronic address: Corinne.Rusterholz@sakk.ch. 7. Department of Hematology, University Hospital Bern, and Department for BioMedical Research (DBMR), Bern University, 3010 Bern, Switzerland. Electronic address: elisabeth.oppligerleibundgut@insel.ch. 8. Department of Oncology/Hematology, Cantonal Hospital St.Gallen, Rorschacher Strasse 95, 9007 St.Gallen, Switzerland. Electronic address: sabine.schmid@uhn.ca. 9. Oncology Institute of Southern Switzerland, Via Ospedale, 6500 Bellinzona, Switzerland. Electronic address: Ilaria.Colombo@eoc.ch. 10. Department of Medical Oncology/Hematology, Cantonal Hospital Graubünden, Loëstrasse 170, 7000 Chur, Switzerland. Electronic address: ioannis.metaxas@ksgr.ch. 11. Department of Medical Oncology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. Electronic address: david.koenig@usb.ch. 12. Oncology Institute of Southern Switzerland, Via Ospedale, 6500 Bellinzona, Switzerland. Electronic address: Cristiana.Sessa@eoc.ch. 13. Medical Oncology, Cantonal Hospital Lucerne, Spitalstrasse, 6004 Lucerne, Switzerland; University of Berne, Hochschulstrasse 6, 3012 Bern, Switzerland. Electronic address: oliver.gautschi@luks.ch. 14. University of Berne, Hochschulstrasse 6, 3012 Bern, Switzerland; Department of Oncology/Hematology, Cantonal Hospital St.Gallen, Rorschacher Strasse 95, 9007 St.Gallen, Switzerland. Electronic address: Martin.Frueh@kssg.ch.
Abstract
BACKGROUND: KRAS mutations are found in 20-25 % of non-squamous non-small cell lung cancer (NSCLC) and therapies targeting the RAS/MEK/ERK pathway are in development. We performed a multicenter open-label phase 1B trial to determine the recommended phase 2 dose and early antitumor activity of the MEK-inhibitor binimetinib combined with cisplatin and pemetrexed. METHODS: Eligible patients (pts) had stage III-IV NSCLC unsuitable for curative treatment, KRAS exon 2 or 3 (codon 12, 13 or 61) mutations, no prior systemic therapy. Pts were enrolled into part 1: 3 + 3 design with dose escalation in 2 dose levels (DL) of binimetinib and part 2: expansion cohort at the maximum tolerated dose (MTD). Pts received 4 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2and binimetinib 30 (DL1)/45 mg (DL2) orally twice a day (bid) d1-14 q3w followed by pemetrexed and binimetinib until progressive disease (PD) or unacceptable toxicity. RESULTS: From May 2017 to Dec 2019, 18 pts (13 dose escalation, 5 expansion cohort) were enrolled. Median age was 60 (48-73, range). KRAS mutations were 87.5 % at codon 12. No DLT occurred in the dose escalation cohort. Median number of cycles was 2 (1-17, range). Treatment discontinuation was mainly due to PD (33 %) or pts/physicians' decision (27 %). Together with the expansion cohort, 16 pts were evaluable for safety. Most frequent treatment-related grade 3 AEs were lung infection (25 %), fatigue (19 %), anemia (19 %). Overall response rate among 9 evaluable pts receiving binimetinib at MTD (45 mg bid) was 33 % (7-70 %, 95 % CI). Median progression-free survival was 5.7 months (1.1-14.0, 95 % CI) and overall survival 6.5 months (1.8-NR, 95 % CI). CONCLUSIONS: Pts treated with combination of cisplatin, pemetrexed and binimetinib presented no unexpected toxicity. No early signal of increased antitumor activity of binimetinib added to chemotherapy was observed in our pts population.
BACKGROUND:KRAS mutations are found in 20-25 % of non-squamous non-small cell lung cancer (NSCLC) and therapies targeting the RAS/MEK/ERK pathway are in development. We performed a multicenter open-label phase 1B trial to determine the recommended phase 2 dose and early antitumor activity of the MEK-inhibitor binimetinib combined with cisplatin and pemetrexed. METHODS: Eligible patients (pts) had stage III-IV NSCLC unsuitable for curative treatment, KRAS exon 2 or 3 (codon 12, 13 or 61) mutations, no prior systemic therapy. Pts were enrolled into part 1: 3 + 3 design with dose escalation in 2 dose levels (DL) of binimetinib and part 2: expansion cohort at the maximum tolerated dose (MTD). Pts received 4 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2and binimetinib 30 (DL1)/45 mg (DL2) orally twice a day (bid) d1-14 q3w followed by pemetrexed and binimetinib until progressive disease (PD) or unacceptable toxicity. RESULTS: From May 2017 to Dec 2019, 18 pts (13 dose escalation, 5 expansion cohort) were enrolled. Median age was 60 (48-73, range). KRAS mutations were 87.5 % at codon 12. No DLT occurred in the dose escalation cohort. Median number of cycles was 2 (1-17, range). Treatment discontinuation was mainly due to PD (33 %) or pts/physicians' decision (27 %). Together with the expansion cohort, 16 pts were evaluable for safety. Most frequent treatment-related grade 3 AEs were lung infection (25 %), fatigue (19 %), anemia (19 %). Overall response rate among 9 evaluable pts receiving binimetinib at MTD (45 mg bid) was 33 % (7-70 %, 95 % CI). Median progression-free survival was 5.7 months (1.1-14.0, 95 % CI) and overall survival 6.5 months (1.8-NR, 95 % CI). CONCLUSIONS:Pts treated with combination of cisplatin, pemetrexed and binimetinib presented no unexpected toxicity. No early signal of increased antitumor activity of binimetinib added to chemotherapy was observed in our pts population.