Marina Chiara Garassino, MD, reflects on the first-line approval of osimertinib, recent data with durvalumab, and the promise for combination chemoimmunotherapy in patients with non–small cell lung cancer.
Marina Chiara Garassino, MD
In the wake of recent data presented at the 2018 ASCO Annual Meeting, the landscape of non—small cell lung cancer (NSCLC) continues to rapidly shift. Immunotherapy has consistently shown promise, but the future of treatment for many patients may be with combination chemoimmunotherapy, said Marina Chiara Garassino, MD.
During the meeting, Garassino presented updated data from the phase II ATLANTIC study, which investigated the PD-L1 inhibitor durvalumab (Imfinzi) as a treatment for heavily pretreated patients with advanced NSCLC in the third- or later-line setting.1 The median overall survival (OS) was 13.3 months in patients with EGFR- or ALK-positive NSCLC and PD-L1 expression ≥25%. Among EGFR+/ALK+ patients with PD-L1 expression <25%, the median OS was 9.9 months. The 1-year OS rates were 53.3% and 40.4% in these 2 cohorts, respectively.
In EGFR/ALK wild-type patients with PD-L1 expression ≥25%, the median OS was 10.9 months compared with 9.3 months in EGFR/ALK wild-type patients with PD-L1 expression <25%. The 1-year OS rates were 47.8% versus 34.5%, respectively. The median OS was 13.2 months among EGFR/ALK wild-type patients with PD-L1 expression >90%, and the 1-year OS rate was 51.8% in these patients.
These interim findings were durable and suggest durvalumab is a promising therapy for this patient population. Durvalumab is currently approved by the FDA for the treatment of patients with locally advanced, unresectable stage III NSCLC who have not progressed following chemoradiotherapy.
The EGFR-mutant NSCLC space has also undergone recent transformations. Prior to the 2018 ASCO Annual Meeting, the FDA approved osimertinib (Tagrisso) as a frontline treatment for patients with NSCLC whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations). This approval was based on data from the phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus standard tyrosine kinase inhibitor (TKI) therapy with either erlotinib (Tarceva) or gefitinib (Iressa).2
Although osimertinib is now a go-to regimen in the first-line setting, Garassino said that more work needs to be done to address resistance to the third-generation TKI.
In an interview with OncLive, Garassino, chief of the Thoracic Oncology Unit at the National Cancer Institute of Milan, Italy, reflected on the first-line approval of osimertinib, recent data with durvalumab, and the promise for combination chemoimmunotherapy in patients with NSCLC.Garassino: Osimertinib remains the cornerstone [of treatment]—we have 19.2 months of progression-free survival (PFS) with a very low toxicity. However, the scientific community should not think that there are no other strategies to consider. A good option could be a strategy of erlotinib plus bevacizumab (Avastin) followed by osimertinib. There is just a 3-month increase in PFS.
For dacomitinib, the results are very interesting because we have never seen such [an improvement in] survival, but the toxicities could be an issue for patients doing the drug for such a long time. We have few data on Western countries, but no data on those with brain metastases.
There was also a very interesting Japanese trial adding chemotherapy to gefitinib. This trial had the best OS ever. It is a Japanese trial though, and those patients are different than Western patients. However, it is something that we have to consider because we have never seen a 50-month OS. This part of research should be considered for the future.The big problem with osimertinib is that we do not have any drug to overcome resistance, as the fourth-generation TKIs are far away [in development]. This is the most important problem of osimertinib because, currently, we have to move onto chemotherapy. Personally, we must find the right balance between the quality of life and the PFS for these patients. The combination with chemotherapy could be a nice option because of the 5 years of survival that were not seen before. One could consider to combine chemotherapy with an EGFR TKI is quite heavy for this population of patients who have been on therapy for several years.
We have to work more on sequencing new drugs and overcoming resistance to osimertinib. We also must work on the balance of quality of life and duration of life. This was a trial with 3 cohorts—the first was dedicated to EGFR- and ALK-positive patients. What we observed in this cohort was that patients with PD-L1 expression of more than 25% can benefit from treatment with durvalumab. The second cohort was for EGFR and ALK wild-type patients with PD-L1 expression more than 25%, and [there was improved] survival data in these very highly pretreated patients. In [the third cohort of EGFR/ALK wild-type] patients with more than 90% PD-L1 expression, the survival rates were again, very high. The long-term follow up data are very interesting.
It is clear that durvalumab is another PD-L1 inhibitor that is very active with a proven efficacy in advanced lines of treatment. Combinations with chemotherapy in EGFR-mutated patients are interesting. Although there were a small number of these patients in the IMpower150 trial, there are interesting results in patients who are treated with immunotherapy and chemotherapy together. The combination of chemotherapy and bevacizumab plus immunotherapy can be a nice way to introduce immunotherapy in these patients. Many things. Mainly, there are several strategies being researched combining chemotherapy and radiotherapy. However, there are some strategies combining new agents with immunotherapy, such as agonists and IDO inhibitors. [Agonists and IDO inhibitors] are not dead after the results seen in melanoma. The right place for immunotherapy might be in the neoadjuvant setting in combination with chemotherapy. We are working on combinations of chemotherapy and immunotherapy in stage III disease at my institute.
In the future, we may also want to work on innate immunity. In the last few years, trials have been focused on adaptive immunity, so maybe the crosstalk between the innate and the adaptive immune system should be studied. We will also have to work on biomarkers.