afatinib + crizotinib

The combination of afatinib and crizotinib represents a targeted therapy approach that has shown promise in treating various cancers, particularly non-small cell lung cancer (NSCLC) with specific genetic alterations.\n\n## Combination Overview\n\nAfatinib + crizotinib is a combination therapy that pairs two distinct targeted agents:\n\n1. **Afatinib** is an irreversible inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases. It's marketed under the brand names Gilotrif and Giotrif, and was FDA-approved in July 2013 for NSCLC[4].\n\n2. **Crizotinib** is a tyrosine kinase inhibitor targeting MET, ALK, and ROS1 kinases. It was FDA-approved in August 2011 for ALK-positive NSCLC and is marketed under the brand name Zalkori[1][10].\n\n## Mechanism of Action\n\nThe combination works through complementary mechanisms:\n\n- Afatinib irreversibly inhibits EGFR and HER2 tyrosine kinases, blocking signaling pathways involved in cancer cell proliferation and survival[4].\n- Crizotinib inhibits MET, ALK, and ROS1 kinases, targeting different oncogenic drivers[1][3].\n\nThis dual inhibition strategy has shown particular efficacy in overcoming resistance mechanisms that develop with single-agent therapy, especially in cases where MET amplification emerges as a resistance mechanism to EGFR inhibitors[6][8].\n\n## Clinical Evidence\n\nSeveral case reports and studies demonstrate the efficacy of this combination:\n\n- In one case, a patient with advanced lung adenocarcinoma harboring EGFR L861Q mutation achieved tumor control with afatinib for 16 months, and when resistance developed due to MET amplification, the addition of crizotinib overcame this resistance[6].\n\n- Another case showed a durable response of more than two years when afatinib was added to crizotinib in a rare case of lung cancer[2].\n\n- The combination has shown stronger inhibition of cell proliferation in malignant pleural mesothelioma cells than either drug alone in both in vitro and in vivo studies[1].\n\n## Safety Profile\n\nThe combination therapy has shown manageable toxicity profiles:\n\n- Common adverse events include rash, hand-foot syndrome, liver dysfunction, and diarrhea[6].\n- In some cases, dose adjustments were necessary, with crizotinib reduced to 200 mg every other day and afatinib to 20 mg at 2 out of 3 days due to toxicities like edema and skin reactions[2].\n- Despite these side effects, the combination did not significantly increase the incidence and severity of adverse events compared to monotherapy in reported cases[6].\n\n## Current Applications\n\nThe combination has been used in several clinical contexts:\n\n- Treatment of EGFR-mutant NSCLC with acquired resistance to EGFR inhibitors due to MET amplification[8]\n- Management of malignant pleural mesothelioma with overexpression of MET and EGFR[1]\n- Treatment of brain metastases in NSCLC patients, though crizotinib appears numerically inferior to other MET inhibitors for brain metastases[8]\n\nThis combination represents an important strategy in the evolving landscape of precision oncology, particularly for addressing resistance mechanisms in targeted therapy.

Brand names

Zalkori