Therapeutic advances in lung cancer - 2nd semester 2022

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Therapeutic advances in lung cancer – 2nd semester 2022

Modern thoracic oncology is a highly dynamic field, with the constant introduction of new therapies that successively improve patient survival. The aim of this paper is to summarize recent developments of direct practical interest.

Approval of trastuzumab deruxtecan (T-Dxd) for second-line treatment of metastatic tumours with HER2 gene mutation (ERBB2) in the US.

On 11 August 2022, trastuzumab deruxtecan (T-Dxd) was approved by the US Food and Drug Administration (FDA) for use in patients with metastatic non-small cell lung cancer and HER2 (ERBB2) gene mutation after at least one prior line of therapy. It is a trastuzumab antibody that binds specifically to the HER2 surface oncoprotein of cancer cells and kills them through local release of the conjugated deruxtecan toxin. It is administered every 3 weeks intravenously and resulted in more (approximately 55% of patients) and more prolonged (median duration of approximately 9 months) responses compared to historical chemotherapy data in the phase 2 DESTINY-Lung01 and -Lung02 studies. The main side effect is a usually mild inflammatory reaction of the lungs that can occur in approximately 10% of patients and whose early intervention requires close monitoring of the patient during treatment. T-Dxd is thus the first drug approved for patients with lung cancer and HER2 mutations, which occur in approximately 3% of patients. The European Medicines Agency (EMA) has not yet taken a stand , but the drug is potentially available for patients also in our country as an off-label treatment after an approval of an application that the treating oncologist can submit electronically to the relevant state committee. Further HER2 inhibitors are in the experimental stage, such as poziotinib, tucatinib, BI 1810631 and pyrotinib , while for T-Dxd a randomized phase 3 study against chemoimmunotherapy is also in progress, with the aim of extending the approval of the drug to the first-line treatment (NCT05048797)

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Approval of adagrasib for second-line treatment of metastatic tumors with KRAS G12C mutation in the US

On 12 December 2022, the drug adagrasib was approved by the US Food and Drug Administration (FDA) for use in patients with metastatic non-small cell lung cancer and KRAS G12C mutation after at least one prior line of therapy. It is administered twice daily as a pill and resulted in responses in 43% of patients with a median duration of approximately 9 months in the phase 2 KRYSTAL-1 study, meaning it shows activity comparable to that of previously approved Sotoroasib and clearly superior to historical chemotherapy data. Side effects are generally mild and mainly related to the gastrointestinal system. Thus, adagrasib becomes the second drug approved for lung cancer with the KRAS G12C mutation, which occurs in about 15% of patients and was previously considered untreatable. The European Medicines Agency (EMA) has not yet taken a stand. Based on the encouraging 50% response rate and good tolerance shown by adadrasib together with immunotherapy in the KRYSTAL-7 study, which was presented on 7 December 2022 at the European Society of Medical Oncology Immuno-oncology (ESMO IO 2022) conference in Geneva, phase 3 trials are planned and randomised for newly diagnosed patients with adagrasib alone (for tumours without PD L1 expression) or combined with pembrolizumab, versus chemoimmunotherapy, with the aim of expanding the approval of the drug to first-line.

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Approval of chemoimmunotherapy with cemiplimab for the advanced non-small cell tumours treatment in the USA

On November 8, 2022, the PD-1 inhibitor cemiplimab was approved by the US Food and Drug Administration (FDA) for use along with 4 cycles of platinum chemotherapy in newly diagnosed patients with advanced non-small cell lung cancer without mutation of EGFR, ALK, ROS1 genes, and regardless of PD-L1 expression levels. The drug is administered intravenously every 3 weeks and resulted in an extension of median survival to 22 months versus 13 months for patients receiving chemotherapy alone in the phase 3 EMPOWER-Lung 3 randomized clinical trial. Overall, the efficacy and side effects are comparable to those of alternative chemoimmunotherapy regimens with pembrolizumab or atezolizumab, which are already approved in our country. The decision of the European Medicines Agency (EMA) is pending. Cemimplimab itself is also approved by both the EMA and the FDA as a first-line monotherapy for advanced non-small cell tumours with high PD-L1 expression in at least 50% of cancer cells.

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Approval of durvalumab/tremelimumab chemoimmunotherapy for the treatment of metastatic non-small cell tumors in the US

On 10 November 2022, the durvalumab PD-L1 inhibitor together with the tremelimumab CTLA-4 inhibitor were approved by the US Food and Drug Administration (FDA) for use in newly diagnosed patients with metastatic non-small cell lung cancer without mutation of the EGFR and ALK genes, and regardless of PD-L1 expression levels. The drugs are administered intravenously initially every 3 weeks along with 4 cycles of platinum-based chemotherapy, followed by maintenance with durvalumab every 4 weeks and a single fifth dose of tremelimumab at week 16 until disease progression or severe side effects occur. This quadruple therapy resulted in significantly prolonged survival compared to comparative platinum-based chemotherapy in the phase 3 POSEIDON randomized clinical trial. The main side effects are immunological in origin, most commonly skin, endocrine or hepatic disorders, and require close monitoring of patients throughout treatment. The decision of the European Medicines Agency (EMA) is pending. A similar regimen is the combination of the nivolumab PD-1 inhibitor with the ipilimumab CTLA-4 inhibitor which has already been approved by the EMA and FDA for the same patient group based on the earlier Checkmate-9LA study.

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We would like to thank Dr. Petros Christopoulos for providing this interview to FairLife L.C.C.