Therapeutic advances in Lung Cancer – 1st Quarter 2022
Modern thoracic oncology is a highly dynamic field with continuous introduction of new therapies that improve patient survival. Aim of this series is to summarize recent developments of immediate practical interest.
- Approval of Sotorasib (AMG-510) as second-line treatment for metastatic non-small-cell lung cancer with the KRASG12C mutation
On January 6, 2022 the first-in-class KRAS G12C inhibitor Sotorasib (developed by AMGEN) was approved by the European Medicines Agency (EMA) for use in patients with metastatic non-small-cell lung cancer and this specific mutation after at least one previous line of treatment. The drug is administered once daily as a pill and lead to responses in approximately 40% of patients with a median duration of almost 1 year in the CodeBreaK 100 phase 1/2 study, whose results are clearly superior to historical data under chemotherapy. Side effects are generally mild and mainly affect the gastrointestinal system. This is the first approval of a KRAS inhibitor in Medicine and represents a major landmark, because KRAS G12C is relatively common in lung cancer, affecting almost 15% of patients, and because targeting of KRAS mutations had been considered impossible up until a few years ago. Further KRAS inhibitors are under development, such as Adagrasib, which has shown results comparable to those of Sotorasib in the Krystal-1 trial and is also available in Greece through participation in clinical studies.
Ref: https://www.nejm.org/doi/full/10.1056/NEJMoa1917239
https://ascopubs.org/doi/full/10.1200/JCO.21.02752
- Approval of Lorlatinib as initial treatment for advanced non-small-cell lung cancer with ALK fusion
On February 3, 2022, the European Medicines Agency (EMA) approved the third-generation ALK inhibitor Lorlatinib (developed by Pfizer) as initial treatment for the approximately 5% of non-small-cell lung cancers harbouring an ALK fusion. These tumors are characterized by the lowest mutational burden and the longest survival in the entire thoracic oncology, currently exceeding 5 years in median. Compared to other ALK inhibitors, Lorlatinib is more potent and achieves stronger suppression of the oncogenic ALK signalling, better prevention of acquired ALK resistance mutations, and better protection against cancer spread to the brain compared to earlier, first- and second-generation drugs. All patients receiving Lorlatinib as first-line therapy showed tumour shrinkage with a median progression-free survival over 2 years, but the exact duration could not be estimated due to the relatively short follow-up of the phase 3 CROWN study so far. Updated data are expected on April 12, 2022 at this year’s American Association for Cancer Research (AACR) conference. It is worth noting that most tumors resistant to second-generation ALK inhibitors, e.g. Alectinib, Ceritinib, and Brigatinib, remain sensitive to Loratinib, with a response rate of approximately 50% and median progression-free survival over 6 months. One issue with Lorlatinib are some special side effects, most frequently lipid abnormalities or weight gain, which require special handling, but can usually be managed with dose modifications, without the need to stop treatment.
Ref: https://www.nejm.org/doi/full/10.1056/NEJMoa2027187
https://linkinghub.elsevier.com/retrieve/pii/S0923-7534(21)00129-0
- Approval of Tepotinib as a second-line treatment for metastatic non-small-cell lung cancer with MET exon 14 skipping
On February 16, 2022, Tepotinib (developed by Merck) was approved by the European Medicines Agency (EMA) for use in patients with metastatic non-small-cell lung cancer with MET exon14 skipping (METΔex14) mutations after at least one prior line of therapy. Administered once daily as a pill, it caused tumour shrinkage in most patients with a median duration of response approaching one year, as shown in the phase 1/2 VISION study. The drug is generally well tolerated with peripheral edema as the main side effect. Tepotinib is the first targeted therapy approved for METΔex14, which occurs in approximately 3-4% of lung cancer patients and is associated with older age and poor medical condition, rendering chemotherapy problematic. Further MET inhibitors are under development, such as Capmatinib, which has data comparable to these of Tepotinib and is expected to also receive approval in the next few months.
Ref: https://www.nejm.org/doi/full/10.1056/NEJMoa2004407
https://www.nejm.org/doi/full/10.1056/NEJMoa2002787
We thank Dr. Petros Christopoulos for granting this interview to FairLife LCC.