The good news
The ESMO annual congress was held in Madrid, Spain from October 23 – 27. Researchers from all over the world attended the conference where the most recent developments in the treatment of cancer were presented. The top research abstracts are chosen to be presented at the Presidential Symposia. These presentations typically spotlight major findings that should be heard by the entire group of attendees. There were presentations from three lung cancer clinical trials, and I have highlighted the results.
DeLLphi-305
Why it’s important
DeLLphi-305 is a study that evaluated the addition of tarlatamab to immunotherapy maintenance in patients treated for extensive stage small cell lung cancer (ES-SCLC). The typical treatment for ES-SCLC is chemotherapy and immunotherapy followed by maintenance immunotherapy. Tarlatamab is a bispecific T-cell engager (BiTE) that connects T-cells (immune cells) to a target (DLL3) on the cancer cell and is approved for second-line treatment. On this study, patients received either durvalumab (immunotherapy) and tarlatamab or durvalumab alone as maintenance therapy after initial treatment with chemotherapy and durvalumab. The tarlatamab–durvalumab patient group had an overall survival (how long patients lived) of 21.1 months compared 12.7 months for the durvalumab patient group.
What it means for patients
There have been many new advances in the treatment of SCLC and patients are living longer. The results of the DeLLphi-305 trial support the use of tarlatamab in the first-line treatment of ES-SCLC as maintenance therapy along with immunotherapy (durvalumab).
What to look for
Despite the positive outcome of this trial, there remain questions to be answered. Many of the patients on the control arm (durvalumab maintenance alone) did not have access to tarlatamab treatment after their cancer grew or spread (progression). The question remains as to whether tarlatamab is most useful as first-line maintenance therapy or whether it should be reserved for second-line treatment at disease progression. Look for more trials that will hopefully clarify the optimal use of tarlatamab. Also look for the development of more novel agents for the treatment of SCLC.
Krascendo 1
Why it’s important
KRAS is a gene that is often mutated and drives cancer growth in several cancers. Over 20% of non-small cell lung cancer (NSCLC) patients have a KRAS mutation. The most common KRAS mutation in lung cancer is KRAS G12C. For many years this mutation was thought to be undruggable but over the last few years, two agents that specifically target KRAS G12C, sotorasib and adagrasib, have been approved.
The Krascendo 1 trial enrolled over 300 patients with previously treated, advanced NSCLC with a KRAS G12C mutation. They received either the study drug, divarasib, or control treatment with sotorasib or adagrasib. The results of the trial show that the disease was controlled for 9.8 months in the patients who received divarasib compared to 5.7 months for the patients who received the standard of care treatment. At one year, 43.9% of the divarasib patients were still living without disease progression while only 24% of the patients who received standard treatment had their disease controlled. There were no new sides effects associated with divarasib treatment.
What it means for patients
The Krascendo 1 trial demonstrates the superiority of the next generation KRAS G12C inhibitor, divarasib. It will likely represent a new standard of care for patients with mutated KRAS G12C NSCLC.
What to look for
Divarasib is being studied in more clinical trials as first-line treatment, in earlier stage disease and in combination with other agents, i.e. immunotherapy. Continue to expect newer, more effective agents to be developed for the treatment of patients with mutated KRAS G12C NSCLC as well as for patients with other KRAS mutations.
SAFFRON
Why it’s important
MET alterations occur in 3-4% of patients with NSCLC, and they are responsible for driving the development of the cancer. MET alterations can be an increase in the protein on the cancer cells (overexpression), an increase in the copy of the MET gene (amplification), and MET mutations. MET changes can also occur when resistance to treatment develops. Savolitinib is a highly selective MET inhibitor. The SAFFRON trial enrolled over 300 patients with advanced EGFR-mutated (EGFRmut+) NSCLC with MET overexpression and/or amplification who progressed (cancer grew or spread) on osimertinib. Patients received either savolitinib and osimertinib or standard chemotherapy. At one year 36%, of the patients who received savolitinib-osimertinib were alive with control of their cancer compared to 10% who received chemotherapy. The overall survival at one year was 70% on the savolitinib-osimertinb study arm versus 53% for those receiving chemotherapy.
What it means for patients
The addition of savolitinib to osimertinib represents a definite option for treatment of EGFRmut+ lung cancer for patients who develop MET overexpression and/or amplification due to resistance to osimertinib. Prior treatments were used primarily for MET exon 14 skipping mutations rather than other MET alterations (like overexpression or amplification).
This trial also illustrates the importance of a new biopsy once the cancer progresses. Determining whether there is an identifiable reason for resistance (i.e. a MET alteration) can help guide the next treatment choice.
What to look for
Having an additional effective treatment option for patients with EGFRmut+ lung cancer who have exhausted other therapies is very important. However, more work needs to be done with the eventual goals of prolonging survival and even curing these patients. Look for more research and clinical trials employing novel agents in the treatment of EGFRmut+ lung cancer, developing more strategies to overcome resistance, and discovering biomarkers that determine which cancers are most likely to respond to treatment.
Although the results of these trials represent significant advancements, there is more work to be done. More research is needed to further improve outcomes for all these patients.