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Phase1 study of cisplatin plus pemetrexed with erlotinib and bevacizumab for chemotherapy-naïve advanced non-squamous non-small cell lung cancer with EGFR mutations

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Summary

Background Cisplatin and pemetrexed are very effective against advanced non-squamous non-small cell lung cancer (NSCLC) without EGFR mutations. Erlotinib plus bevacizumab are highly effective against advanced NSCLCs with activating EGFR mutations. We performed this phase I ‘Quartet Trial’ to determine the safety and efficacy of all 4 agents as a first-line treatment for non-squamous NSCLC patients harboring activating EGFR mutations. Patients and Methods Patients received escalating quartet-agent doses every 3 weeks for 4 cycles. We examined the dose-limiting toxicity (DLT) to determine the maximum tolerated dose (MTD) and recommended dose (RD). Results Ten patients (3 men and 7 women) with a median age of 69 years were enrolled. Four and 6 patients had exon 19 and 21 mutations, respectively; 8 received maintenance therapy without unexpected or cumulative toxicities. One of 6 patients experienced grade 3 vagal reflex at 60 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab, which was designated the RD. Four patients experienced no DLT with 75 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab (designated the MTD); however, 3 underwent dose reduction due to severe toxicities (grade 3 gastrointestinal hemorrhage, skin rash, nausea, and febrile neutropenia) during induction chemotherapy. The most frequent DLT-phase adverse events were nausea, anorexia, and fatigue. The overall response rate was 100%. Furthermore, the progression-free and overall survival rates were 17.9 and 32.0 months, respectively. Conclusions This quartet chemotherapy regimen was tolerable and effective in our patient population (UMIN000012536).

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Acknowledgments

We thank the patients, their families, and all the investigators who participated in this study.

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Authors and Affiliations

  1. Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemachi Chuo-ku, Osaka, 541-8567, Japan

    Motohiro Tamiya

  2. Department of Internal Medicine, Kinki-chuo Chest Medical Center, Sakai, Japan

    Akihiro Tamiya, Yujiro Naito, Naoki Omachi, Yohei Kimura & Tomonori Hirashima

  3. Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino, Japan

    Takayuki Shiroyama, Sawa Takeoka, Naoko Morishita, Hidekazu Suzuki & Norio Okamoto

  4. Department of Clinical Research Center, Kinki-chuo Chest Medical Center, Sakai, Japan

    Kyoichi Okishio & Shinji Atagi

  5. Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Tomoya Kawaguchi

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  1. Motohiro Tamiya
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Correspondence to Motohiro Tamiya.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Tamiya, M., Tamiya, A., Shiroyama, T. et al. Phase1 study of cisplatin plus pemetrexed with erlotinib and bevacizumab for chemotherapy-naïve advanced non-squamous non-small cell lung cancer with EGFR mutations. Invest New Drugs 36, 608–614 (2018). https://doi.org/10.1007/s10637-017-0527-z

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