Focus in Oncogene-Driven NSCLC Turns to Sequencing Strategies, Overcoming Resistance

Kartik Konduri, MD

The ability to target driver mutations among patients with non—small cell lung cancer (NSCLC) continues to grow with combination therapies and newer agents, and research is now focusing on sequential treatment for other key targets, explained Kartik Konduri, MD.

Pending the full data set from the phase III RELAY trial, the combination of ramucirumab (Cyramza) and erlotinib (Tarceva) may offer another frontline option to patients with metastatic EGFR-mutant NSCLC. However, it is unclear whether the combination will replace osimertinib (Tagrisso) as the frontline standard of care, especially in light of early data from the expansion cohort of the AURA trial,¹ which boasted a joint objective response rate (ORR) of 77% with osimertinib at 80 mg and 160 mg.

Additionally, the TRK inhibitor larotrectinib (Vitrakvi) and the multikinase inhibitor entrectinib continue to show sustained activity among patients with NTRK gene fusions and ROS1-fusion—positive NSCLC, respectively. According to data from the 2019 European Lung Cancer Congress, both agents showed ORRs in the range of 70% to 80%. Moreover, the median duration of response (DOR) had yet to be reached at the time of analysis for larotrectinib.² The median DOR was 25 months for patients treated with entrectinib.³

“All of these agents fill a niche in the paradigm,” said Konduri. “If we can find these alterations and build on our knowledge of them, we may be able to reproduce an ALK-like story, in which patients have sequential treatments available to them.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Konduri, medical director, Chest Cancer Research and Treatment Center, Baylor Charles A. Sammons Cancer Center, Baylor Scott & White Health, discussed the use of these agents in patients with targetable driver mutations.

OncLive: Could you shed light on the optimal use of TKIs in EGFR-positive NSCLC?

Konduri: We are waiting on data from the RELAY trial regarding the combination of erlotinib and the antiangiogenic agent ramucirumab. The trial was reported to be positive, but we want to know by [what degree]. We want to know what the progression-free survival (PFS) is and what the adverse events are [with this regimen].

Data from the early-phase AURA trial presented at the 2019 European Lung Cancer Congress show similar signals of benefit with osimertinib, both at the 80-mg dose and the 160-mg dose. This is in the frontline setting, in which the PFS is nearly 20 to 22 months.

What we are trying to unravel right now is how to treat patients who develop resistance to osimertinib. There are many trials that are in progress that are looking at particular combinations or using biomarkers to find a particular drug that can be combined with an EGFR TKI. There are also chemotherapy options; we may consider the combination of chemotherapy and immunotherapy.

Is there still a role for the older-generation TKIs?

The role is still there. The question is how to sequence them appropriately; that debate continues to be ongoing. The data from the frontline trial with osimertinib show a significant improvement in PFS. Many people have used or are continuing to talk about using osimertinib. For drugs like dacomitinib (Vizimpro) or erlotinib, we know that some of these drugs are somewhat better than first-generation TKIs. The question is, “In which patient will we utilize these drugs?” How will we predict the patient who may develop a possible T790M secondary mutation for which we could use osimertinib later on? That's another question that we do not know the answer to. Another [unknown question is], “How will we sequence the combination of erlotinib and ramucirumab for a patient down the line [if the RELAY trial is positive]?”

Could oncogene-driven NSCLC be considered a chronic disease?

That would be wonderful to say, but we still have a lot more work to do. Many of our patients are surviving years, but there are many patients who have disease progression in a matter of months. We would like to be able to sequence medications to improve their survival.

You also discussed other biomarkers in your presentation. Have any advances been made for patients with NTRK mutations?

There are many drugs that are being looked at in this space. We have the ability to try to test for these kinds of fusions and mutations. A small proportion of patients with NSCLC will have these alterations, and we have a few drugs that are showing excellent promise, such as larotrectinib, which is already approved, and entrectinib. We have many patients who continue on treatment and have good responses both inside the brain as well as extracranially.

Are there drugs on the horizon for patients with alterations in RET, MET, or HER2?

Many promising drugs are coming out. Each “sliver of the pie” seems to have a promising drug [under investigation]. There are RET inhibitors in progress, which have shown significant benefit in terms of improvement in response rates and a prolongation of activity over a period of many months. There are also similar evaluations going on for patients with c-MET mutations and exon 14 skipping mutations. There are a couple of drugs that are looking at exon 20 insertions, which have been hard to treat.

How can tumor mutational burden (TMB) be applied to practice?

It's mostly used in research-based studies. We know that there are data that suggest TMB is a biomarker. Although we get that information through the next-generation sequencing panels, it is hard to apply to practice because we don't have any particular approved thought processes [to sort through the data]. The trials are still working through the information. Hopefully, we will have more information [that will allow us to] not just use TMB, but to correlate it with other biomarkers that will help us determine which patients could significantly benefit from immunotherapy.

As chair of the meeting, what is the importance of hosting these State of the Science Summits™?

Information can get lost in a large crowd, and we’ve received a lot of data in the past few years. Smaller presentations allow for better interactions. You can catch up, talk to your colleagues and peers, and have personalized discussions on all the progress that has been made. Smaller meetings are always better in that sense.

References

1. Yang J, Ramalingam S, Lee C, et al. Osimertinib as first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC): Final efficacy and safety results from two phase I expansion cohorts. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract 122P.
2. Drilon A, Kummar S, Moreno V, et al. Activity of larotrectinib in TRK fusion lung cancer. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract 111O.
3. Barlesi F, Drilon A, De Braud F, et al. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract 109O.