Osimertinib Combos Are Under Evaluation in EGFR+ NSCLC

Osimertinib (Tagrisso) HAS BECOME a standard of care in the first-line and adjuvant settings; however, EGFR/VEGF-targeting combinations and other approaches are being studied to further improve outcomes and overcome resistance mechanisms in patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to Jyoti D. Patel, MD.

“Although osimertinib is a standard first-line therapy, many efforts are trying to make [outcomes] better, some of which include VEGF inhibition,” Patel, associate vice chair for clinical research in the Department of Medicine and a professor of medicine in the Division of Hematology and Oncology at Northwestern University, said. “We know that EGFR-mutant tumors are particularly susceptible to VEGF inhibition. Two large, ongoing trials in the United States are evaluating osimertinib and ramucirumab [Cyramza] or osimertinib and bevacizumab [Avastin]. Both of those trials are looking at survival end points.”

For patients who have developed resistance to osimertinib and who have MET amplifications or an off-target mutation, several other tyrosine kinase inhibitors (TKIs), such as crizotinib (Xalkori), capmatinib (Tabrecta), and tepotinib (Tepmetko), have shown potential and are now approved by the FDA. Larger ongoing efforts are under way to determine how these agents can best be used and potentially combined in clinical practice.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on lung cancer, Patel, who is also medical director of thoracic oncology and assistant director for clinical research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, discussed how the FDA approval of adjuvant osimertinib has affected the treatment of patients with EGFR-positive NSCLC, efforts being made to overcome resistance to the third-generation EGFR TKI, and other approaches that may further improve outcomes in this population.

OncLive^®: Could you speak to the significance of the phase 3 ADAURA trial (NCT02511106)?

Patel: ADAURA examined osimertinib in patients with resected disease. We know that primary surgery is the best local therapy for [this population]. For the past 15 years, chemotherapy [has been] shown to improve outcomes in patients with large stage I tumors up to [stage] IIIA tumors, but [giving] osimertinib after surgery changes the entire landscape.

We are using genomically driven therapy to allocate the best treatment for our patients. Osimertinib showed an improvement in disease-free survival [DFS], which is an earlier end point than overall survival [OS] but one that is especially important for our patients and for all practitioners—it changes the landscape. We know that [giving] osimertinib 3 years after surgery correlates with a significant reduction in relapse from fatal cancer. In patients with [stage] IIIA disease, [we saw about a] 90% reduction [in risk of relapse]. Even in patients with [earlier]-stage disease [such as] stage I, we see that survival advantage.

This study was really focused on patients with stage II and IIIA [disease, although] patients with stage I [disease] were included. Across the board, all patients benefited [from treatment]. Moreover, the therapy was well tolerated; 3 years of a TKI is feasible. [We saw] very low rates of discontinuation.

This [study resulted in] a couple of [changes]. All patients who have resected tumors need to undergo evaluation to see if they [can] have an EGFR TKI. Patients who are resected and have an EGFR mutation need to be advised about their potential improvement in OS and clear improvement in DFS with 3 years of adjuvant osimertinib.

How has the FDA approval of adjuvant osimertinib affected the treatment paradigm thus far?

[The use of] a targeted therapy in the adjuvant setting revolutionizes lung cancer treatment. It means that we are able to deliver precision medicine to our patients. We know surgery is the primary treatment for patients with early- stage disease. Chemotherapy also improves outcomes, but such a dramatic [improvement] in DFS with 3 years of a well-tolerated oral therapy changes the landscape. If we reduce [a patient’s] risk of recurrence by over 80%, that [equates to] significantly more [individuals] who are alive, free from disease, and doing well.

What are some of the efforts being made to overcome acquired resistance to osimertinib?

Osimertinib is a targeted drug that offers deep response to patients, as well as good PFS and OS benefits. Unfortunately, however, resistance [to the agent] always develops. We are trying to understand whether that resistance is on target within the EGFR gene or [whether it is] related to different growth mechanisms, off-target [mechanisms], or even some unknown mechanisms.

Right now, patients with EGFR-mutant disease [who are] on osimertinib should absolutely undergo a biopsy to understand their mechanism of resistance. If resistance is [found to] only [be] in 1 area, if it’s local, or if it’s oligoprogressive, we usually favor continuation of the TKI with some local therapy, such as radiation. If patients have multifocal resistance, then biopsy can help us understand whether other mechanisms, such as MET amplification or on-target mutations, may change how osimertinib binds. Moreover, some patients are at risk for histologic transformation and may develop small cell lung cancer [SCLC]. For those patients, chemotherapy with carboplatin/ etoposide provides the best opportunity to control disease.

What combination regimens are being studied to improve outcomes?

Several preclinical, as well as clinical, studies have demonstrated how inhibition with erlotinib [Tarceva] and bevacizumab or erlotinib and ramucirumab can be effective. Osimertinib combinations [are also under exploration]. Some other strategies [that may] improve outcomes include [the addition of] chemotherapy up front, particularly [for] those with co-occurring RB or TP53 mutations. [The idea is to] treat [these patients] with a SCLC regimen with a TKI or, in the absence of those, [the addition of] carboplatin and pemetrexed up front to treat any resistor cells.

If resistance develops and there is an off-target mutation or MET amplification, several TKIs are now commercially available. Crizotinib, capmatinib, and tepotinib are all FDA approved; they have been studied in some small trials and demonstrated response rates of around 30% following osimertinib resistance. Certainly, larger trials are ongoing and will provide better clarity on how to better layer these agents.

Is there anything else that you would like to add?

Since EGFR TKIs were tested in patients in the early 2000s, we have come a long way in this 20-year journey. We now have a third-generation EGFR TKI that improves survival over first- and second-generation drugs. [Osimertinib can] overcome common resistance mechanisms. We have learned to use these drugs in early-stage disease to prevent recurrence. We also now have ideas on how to manage resistance [to osimertinib] with [the addition of] multiple targeted therapies. When we were [seeing] OS and PFS [improvements] 10 years ago, it was certainly exciting but not a home run. Seeing multiple randomized clinical trials with OS approaching 5 years in this huge group of patients has certainly been rewarding. However, we still have a lot of work to do.