Enriching Responses With Targeted Therapy in NSCLC

Stephen Liu, MD

EGFR, ALK, and ROS1 abnormalities are no longer the only oncogenic drivers worthy of discussion in non–small cell lung cancer (NSCLC), explained Stephen Liu, MD, who added that the field has seen an abundance of highly selective RET, MET, HER2, and KRAS inhibitors that have the potential to deliver durable responses.

“One of the most exciting areas of lung cancer is our ability to increasingly subdivide the disease into different molecular types. Although we are comfortable with treating patients with EGFR- and ALK-, and ROS1-positive lung cancers differently, we’re learning that, in NSCLC, there many other subtypes that represent different biologies, and we now have the tools to really treat those differently,” said Liu.

In an interview with OncLive^® during the 2020 Institutional Perspectives on Cancer webinar on lung cancer, Liu, associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center, discussed some pivotal data that support the expanding reach of targeted therapy in NSCLC.

OncLive^®: How has precision medicine affected the field of lung cancer?

Liu: Joining the ranks of EGFR, ALK, ROS, and BRAF [inhibitors], we had approvals this year of inhibitors targeting RET and MET exon 14 skipping mutations. Hopefully soon, we’ll have new agents for [patients with] HER2 and KRAS [mutations]. I’m excited to see our ability to recognize the different biology underlying lung cancers, and to treat those cancers as we should, which is as different cancers altogether.

Targeted therapy continues to extend its reach in lung cancer. Could you highlight some of the pivotal trials that were presented in 2020?

Some of the key results that came out of the big meetings this year were results from several of the targeted therapy trials. These are single-arm studies, but what we’re seeing are high levels of efficacy and pretty consistent trends. Earlier this year, we saw data with capmatinib (Tabrecta) in patients with MET exon 14 skipping mutations, and while overall, the response rate was a respectable 47%; in the frontline setting, those response rates were higher.

Response rates around 60% in the frontline setting are what we’re seeing with RET inhibitors as well. Selpercatinib had a response rate approaching 70% overall. In the first-line setting, this rate was even higher at almost 90%. [These are] highly selective inhibitors with a likelihood of response and durable responses out past 1.5 years.

At the 2020 ASCO Virtual Scientific Program, we saw the results from the ARROW trial led by Justin Gainor, MD, of Massachusetts General Hospital. Pralsetinib is another selective RET inhibitor. In the ARROW study, we saw very high response rates higher in the frontline setting.

We can see durable, fast, rapid, reliable responses [with these agents]. We also see very favorable toxicity profiles giving us that big, wide therapeutic window to select a drug that’s going to work with little toxicity.

One of the best examples of that are some of the newer drugs that are targeting KRAS. We’ve seen some data in that regard with direct KRAS G12C inhibitors. G12C shouldn’t really exist in the normal body, so there shouldn’t be much toxicity at all. However, because of the structure of the drugs, there is some risk for mechanical toxicity, as they can act almost like a detergent in some ways. G12C inhibitors have a very favorable toxicity profile.

We’ve been very impressed by response rates. Although initial response rates between the 2 lead compounds are in the 30% to 40% range, the disease control rate for both [agents are] in the 90% range.

KRAS has been a target; it’s very common. [In the past,] we just didn’t have a way to really exploit that context of vulnerability, but that is finally changing. We’re going to see newer combinations providing more durable responses to patients with KRAS mutations in the months to come.

We’re also seeing targeted therapy make its way into the adjuvant setting. Are there any concerns in bringing these drugs to this setting?

One of the big stories from the 2020 ASCO Virtual Scientific Program came from the ADAURA trial with the use of adjuvant osimertinib [Tagrisso]. The results showed a significant improvement in disease-free survival [DFS], which wasn’t unexpected. However, we don’t know if that’s going to translate into an overall survival benefit.

The bigger philosophical question is: Is a DFS benefit enough to warrant use here, particularly with such a well-tolerated drug? We’re relying more on patient-shared decision-making, and really discussing the potential risks and benefits even in the absence of a survival benefit. Without those long-term data, its use in the clinic is still somewhat controversial.

What are some of the new areas of development that you’re excited about?

With regard to immunotherapy, we have many different options to choose from. We have monotherapy with PD-1 and PD-L1 inhibitors, as well as combinations of chemotherapy and immunotherapy. We now have dual checkpoint blockade targeting PD-1 and CTLA-4 alone or in combination with chemotherapy. However, we don’t know which [regimen] is superior and we won’t for quite some time.

Some of the newer immunomodulatory agents are also very exciting, particularly one targeting TIGIT. We saw results from the phase 2 CITYSCAPE trial at the ASCO meeting. That trial is evaluating the combination of tiragolumab, an anti-TIGIT antibody, with atezolizumab [Tecentriq] in PD-L1–positive NSCLC. In the PD-L1–high group, the addition of tiragolumab to atezolizumab more than doubled the response rate, and significantly improved progression-free survival [PFS] with a hazard ratio of .30. This is a subset that has good options. However, good options can always be better and building upon that activity in small cell lung cancer and other tumor types is particularly exciting. Seeing how new immunomodulatory agents can expand the reach for durable immune-mediated antitumor responses, will be particularly exciting.

I’m also excited to see newer targets developed. We saw some data with [fam-]trastuzumab deruxtecan[-nxki (Enhertu)]. These were early results, but we saw very impressive PFS in HER2-mutant NSCLC. We want to see how durable responses are and how good the PFS is with more follow-up and a more robust data set. We also want to see if that translates to patients with HER2 overexpression.

Is this a drug that we should really be implementing and would expect to introduce in our arsenal?

HER2 exon 20 mutations are relatively common compared with some of the other rare mutations like ROS1, but we don’t have an approved drug in that setting yet. There are also some newer targets that are rapidly evolving. NRG1 fusions, for example, clearly represent an actionable target. They have a low incidence. About 0.2% of cancers will harbor an NRG1 fusion. They’re hard to find. We really need to use RNA sequencing to discover those. But when present, they represent a new target. There are now 4 clinical trials available in the United States that are targeting NRG1 and more to come. This is a new target where we don’t have an approved drug yet, but we will have one soon.

What other research efforts would you like to spotlight?

At our institution, we’re really focused on overcoming acquired resistance. Although achieving initial responses is important, we know those responses are often very transient. So, we’re looking at ways to try to maintain the durability of those responses. We have a protocol through the ETCTN [Experimental Therapeutics Clinical Trials Network] through the NCI [National Cancer Institute], combining atezolizumab with a MEK inhibitor. That has shown some very promising durable responses in the resistance setting.

We’re also looking at chemotherapy-free immunotherapy combinations in NSCLC that has not responded to immunotherapy or EGFR-positive NSCLC, which is a common subgroup. We know that the IMpower150 regimen of carboplatin, paclitaxel, and bevacizumab [Avastin] plus atezolizumab has shown efficacy in an EGFR-mutant population. We’re now developing a chemotherapy-free, immunotherapy-based approach for EGFR-mutant lung cancer after TKI that has the chance to change some of what we know about immunotherapy in that space.

Newer targets are critical. We’ve been fortunate to lead a lot of the studies looking at NRG1 fusions across tumor types. When we look more frequently, we find things. We’ve been able to find a lot of these fusion events and have been participating in several of the NRG1 trials with very encouraging results thus far.

Editor's Note: This interview was conducted prior to the December 18, 2020 FDA approval of osimertinib for use as an adjuvant treatment following tumor resection in patients with NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.