Clinical Trials Needed to Determine the Utility of Targeted Therapies in Oncogene-Driven Locally Advanced NSCLC

Although adjuvant treatment with durvalumab (Imfinzi) after chemoradiation has transformed the management of patients with unresectable stage III non–small cell lung cancer (NSCLC), the lack of benefit observed in patients with EGFR mutations underscores the need to develop clinical trials to determine whether patients with oncogene-driven locally advanced disease should receive immunotherapy or targeted therapy, said Julie Renee Brahmer, MD, MSc.

Moreover, the uncertainty regarding this treatment decision underscores the importance of genetic testing prior to initiation with immunotherapy in this patient population.

“We need at least phase 2 studies to show us that it is safe to give TKIs after chemoradiation therapy,” said Brahmer in an interview with OncLive® during the 16th Annual New York Lung Cancers Symposium®, a program hosted by Physicians’ Education Resource® (PER®), LLC.

“We need to collect and run next-generation sequencing on larger studies to be able to drill down [on the utility of targeted therapy in locally advanced NSCLC], particularly for the rare subsets. Being able to look at a group of RET-positive patients [to determine] how well they do with durvalumab after chemoradiation would be important,” Brahmer added.

In the interview, Brahmer, a professor of medicine, director of the Thoracic Oncology Program at the Sidney Kimmel Comprehensive Cancer Center, and co-director of the Upper Aerodigestive Department within the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine, discussed remaining questions regarding immunotherapy and targeted therapy in locally advanced NSCLC, data from the phase 3 PACIFIC (NCT02125461) and ADAURA (NCT02511106) trials, and her hopes for future clinical trials in the paradigm.

OncLive^®: How do the results of the PACIFIC trial inform the decision of whether to use immunotherapy or targeted therapy as consolidative treatment for patients with NSCLC?

Brahmer: For oncogene-driven locally advanced NSCLC, the big question in this patient group is: Should we be using immunotherapy or targeted therapy as consolidation? [During the 2021 New York Lung Cancers Symposium], I highlighted the data from the PACIFIC trial, particularly looking at EGFR-mutant disease. [I explored] how we can extrapolate what we know about immunotherapy in oncogene-driven stage IV disease and how to best use the data we have with adjuvant osimertinib [Tagrisso] and atezolizumab [Tecentriq].

In the PACIFIC study, durvalumab improved overall survival [OS] in general for patients with NSCLC after concurrent chemoradiation. Although there wasn’t a huge number of patients with EGFR mutations, [the data] clearly showed that [durvalumab] did not seem to improve progression-free survival [PFS] or OS in that small patient group.

How are you interpreting these results for clinical decisions?

Many of us will not automatically give [patients with EGFR mutations] durvalumab in the consolidative setting because we know these patients have a high likelihood of progression. If we start TKIs shortly after immunotherapy, we may run into issues with toxicity, much more so than if we started with TKIs alone in the stage IV setting.

We are trying to extrapolate from advanced disease where we know that single-agent immunotherapy does not work at all for patients with EGFR, ALK, ROS1, HER2, or RET [mutations]. The jury is out for patients with KRAS or BRAF mutations where single-agent immunotherapy in advanced disease works quite well. Data support the use of single-agent immunotherapy in BRAF V600E–mutated disease in the metastatic setting; however, the jury is out for patients after concurrent chemoradiation. We don’t have that information, but we need it if we are truly going to deliver precision oncology.

Adjuvant osimertinib is being used after chemotherapy, but what is known about the agent’s utility after concurrent chemoradiation?

With the data from the ADAURA trial showing a significant improvement in disease-free survival [(DFS) with osimertinib] after adjuvant chemotherapy, we need to go back and look at osimertinib after chemoradiation. We saw data that turned us off initially to using concurrent chemoradiation followed by docetaxel and gefitinib [Iressa]. Patients who received gefitinib did poorly, but this was in a general patient population. We need to drill down to patients with specific mutations to try TKIs after definitive therapy.

A study out of Japan [UMIN000008366] was recently presented looking at gefitinib with concurrent thoracic radiation therapy in locally advanced, EGFR-mutated NSCLC. The response rate was quite high at 81.5% with the combination. The median OS was 61.1 months. [The results didn’t show] a significant problem with pneumonitis or other toxicities, but it was a relatively small study.

We have some retrospective studies from different institutions looking at EGFR-mutant stage III disease. It seems that the survival is much better in those patients who received EGFR TKIs after concurrent chemoradiation compared with that same population receiving durvalumab vs a TKI.

What studies need to be developed to address whether to select immunotherapy vs targeted therapy in these patients?

Regarding immunotherapy in unresectable stage III disease, consolidation durvalumab does not seem to benefit patients with EGFR mutations. However, there are limited data in this setting [to determine] what the best [treatment] to give these patients is. Plus, if we extrapolate from stage IV disease, single-agent immunotherapy does not seem active, and it certainly adds toxicity when we start TKIs.

In patients with EGFR-mutant disease, adjuvant osimertinib does improve DFS. We need a study to look at this in the locally advanced setting after definitive therapy. We have mixed results, but if we look at a specific group of oncogene-driven disease, we could do a study on this.

There is a black hole with no data in patients with other oncogene-driven NSCLC. This is an area where we need to bring precision oncology to the locally advanced setting.

What barriers need to be overcome to ensure patients who are eligible for targeted therapy receive it vs immunotherapy?

In patients with nonsquamous histology or patients who are never smokers that come in with other histologies, trying to get testing performed can be a barrier all the way from making sure we have enough tissue. If tissue is the issue, being able to get on top of things right away with a liquid biopsy in patients with advanced disease [is important]. However, trying to figure out how to time [liquid biopsies is challenging].

For patients, insurance issues [can arise when companies are] billed for a liquid and tissue biopsy. This can become burdensome and complicated for patients as some insurance companies only cover 1 [test]. Making sure that patients’ insurance covers the mutation testing from a particular company adds another layer of complexity to the situation.

Certainly, in the academic environment, [navigating these challenges] is a bit easier given the fact that we have in-house testing. For the most part, patients have not noticed a huge problem with getting [in-house genetic testing] covered by insurance, but that continues to be an issue for patients depending on their insurance.

Additionally, we don’t have the time that mutation testing takes. Certainly, if [the patients fall into] the 70% of patients where we can detect tumor DNA in their blood, blood-based testing significantly shortens the time [required for genetic testing]. However, sometimes we don’t even have time for that.

Those are the biggest barriers right now. We need to get these tests, preferably before starting therapy, to [deliver] the best treatment for patients with metastatic disease.

What are some future research efforts you hope to see in this space?

We always worry whether we will repeat the same issue we saw with gefitinib after concurrent chemoradiation. However, we need more studies like that. I would take real-world data and have a better idea to guide my treatment selection for after definitive therapy.

For most patients who don’t have oncogene-driven [NSCLC], other combination therapies [are needed] to certainly raise the tail of the curve even further, which is important.