Sequencing and Resistance Mechanism Challenges Arise in Biomarker-Driven NSCLC

Resistance mechanisms and sequencing challenges remain roadblocks that need to be addressed in order to further drug development in the settings of ALK-, ROS1-, and RET-positive non–small cell lung cancer (NSCLC), said Kartik Konduri, MD, adding that identifying causes of resistance should also be a focus in the next phase of research.

“Look for a sequencing evaluation and try to use a potent drug,” advised Konduri, medical director of the Chest Cancer Research and Treatment Center, site research leader, and chair of the Chest Site Tumor Committee at Texas Oncology-Baylor Charles A. Sammons Cancer Center. “When [a patient experiences] progression, look for resistance, and try to sequence therapies accordingly.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Konduri, who is also the associate chair of the Lung Cancer Research Committee, US Oncology Research, and chair of the Lung Cancer Pathways Committee, The US Oncology Network, discussed current treatment options that are available for patients with ALK, ROS1, and RET–positive NSCLC, as well as promising agents in the pipeline.

OncLive^®: What is your current approach to sequencing for patients with ALK-positive NSCLC?

Konduri: The usual treatments are second-generation ALK inhibitors. Multiple [ALK inhibitors are] now approved, including alectinib (Alecensa), brigatinib (Alunbrig), and ceritinib (Zykadia). Of course, the consideration at this time is how to use them up front.

Alectinib and brigatinib are, of course, the agents that are the most talked about. I typically use alectinib because the survival data, which were updated at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, was based on a longer period of follow-up [than we have with brigatinib]. However, either [alectinib or brigatinib] are effective agents that can be used [in the first-line setting].

We have also seen data from the ALKA-372-001 and STARTRK trials. Could you elaborate on the findings from those studies?

Those [trials showcased data on] entrectinib (Rozlytrek). [Entrectinib] is approved for [patients with ROS1-positive metastatic NSCLC] at this time. However, the most important thing about entrectinib is that it has intracranial efficacy, which makes it more beneficial for a lot of those patients who have intracranial metastases. It is certainly a drug that will be used significantly in this patient population.

We also saw findings from the TRIDENT trial of repotrectinib (TPX-0005) in the ROS1-positive space. What are your thoughts on these data?

These are interesting data on treatment-naive patients, as well as pretreated patients. The data show significant benefit especially in mutations, such as G232R, that [develop in] pretreated patients with ROS1-positive disease. Additionally, it [showed] efficacy, at least in a small proportion of patients in the updated presentation.

We look forward to seeing further analysis and data on this drug. It looks promising, but we will have to wait and see.

In the RET-positive space, the FDA approved selpercatinib (Retevmo; formerly LOXO-292) and pralsetinib (Gavreto). What are your thoughts on how this setting has evolved?

We are still awaiting further analysis of the pralsetinib data, but [at the 2020 ASCO Virtual Scientific Program] Justin F. Gainor, MD, of Massachusetts General Hospital, presented an updated analysis that looked very promising for pralsetinib. The question is, How do pralsetinib and selpercatinib compare head-to-head? We don’t have that data, but both drugs look promising for RET-positive patients with NSCLC. We are fortunate that we have the choice of several drugs for these patients.

Where does that leave research in terms of understanding resistance mechanisms?

An important question is, How do we define and easily [identify] the circumstances that cause resistance for these patients? When patients progress, could that be a bypass track, or can we add another medication to accentuate the potency of therapeutics like vaccines? Can we put a different type of mechanism in to reduce effects of drugs that might reduce their efficacy inside the tumor? These are questions that will [be answered] in our next phase of [research]. As we learn more and have the ability to interact with testing, where we can pick up specific indications of trying to add or change treatments in real time, we will hopefully be able to increase overall survival for these patients.

Is there any translational work that you would like to spotlight in that regard?

Evaluation of adding chemotherapy [to some of these agents] is ongoing. Trials are looking at combinations with other targeted therapies, as well as looking at MET inhibitors in the space of secondary resistance. There are also studies looking at combinations with immunotherapy or vaccines. We just have to wait and see which [approaches] will be beneficial for our patients.

It is recommended that patients undergo sequencing to identify these driver mutations. However, upon resistance, is it commonplace to perform repeat biopsies to understand acquired mutations?

I don’t know that it is common, but we strongly recommend it to see whether there is a different mutation that can be targeted. This is especially important in the ALK-positive space where multiple drugs are available, but even in the ROS1-positive space, we can potentially add a patient to a clinical trial list or find a mutation that cannot be treated with standard therapies.

In the ALK-positive space particularly, we know of many circumstances where certain mutations can be treated with different drugs that will overcome the resistance of these mutations. It is very important to sequence these evaluations and test patients again. There is always the possibility that we end up with another medication that can be easily used to treat patients.

What is your outlook for the future of targeted therapy in NSCLC?

We are waiting to see what the results of the CROWN trial will show. A progression-free survival advantage was [claimed] in a press release, but we will wait to see. As we mentioned, [we are also awaiting the results of] the TRIDENT trial.

There are also earlier-phase trials that are looking at different drugs in combinations. [Data with] ensartinib was recently presented during the 2020 World Conference on Lung Cancer and also showed efficacy. That is another drug to be looking out for in consideration [with other agents].

My recommendation is to look for clinical trials where there is potential for exploring other efficacious treatments that could prolong outcomes for patients.