Optimal Sequencing and Patient Selection Investigated in NSCLC

Frank E. Mott, MD

As novel agents, such as checkpoint inhibitors and targeted therapies, continue to emerge for the treatment of patients with non—small cell lung cancer (NSCLC), the sequencing of these agents is a new challenge for physicians.

This is particularly relevant for patients with EGFR mutations, as recent pivotal trial findings are likely to affect frontline therapy. For example, the phase III FLAURA study demonstrated an improved progression-free survival (PFS) when osimertinib (Tagrisso) was moved to the first-line setting for patients with EGFR-mutant NSCLC.

In the double-blind study, the median PFS was 10.2 months (95% CI, 9.6-11.1) for standard therapy, which was a first-generation EGFR inhibitor (erlotinib [Tarceva] or gefitinib [Iressa], and 18.9 months (95% CI, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).

“This is traditionally used for patients with T790M acquired-resistant EGFR-positive disease. However, there are some data demonstrating that using it earlier in the first-line setting may have benefit,” explained Frank E. Mott, MD.

OncLive: Can you discuss molecular profiling for patients with adenocarcinoma of the lung?

What immunotherapy and targeted therapies are showing excitement right now?

In an interview during the 2017 OncLive State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Mott, an associate professor in the Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed optimal treatment selection strategies for patients with NSCLC.Mott: Adenocarcinoma of the lung has come a long way in the last decade in terms of new treatment options based on molecular targets. It is now standard of care to analyze the tumor for the presence of targets such as EGFR, ALK/ROS1, and PD-L1. There are some newer targets that have approved therapies; these include the MET exon 14 skipping mutation and BRAF mutations. In ALK-positive tumors, which only represent 2% to 4% of patients with NSCLC, we have new data suggesting that targeted therapies demonstrate a better response than chemotherapy. Also, some newer agents, such as alectinib (Alecensa), are demonstrating good penetration for patients with central nervous system metastases. Those patients are responding well with good durable responses in PFS. We are seeing changing patterns of care with some of these drugs.

What ongoing trials are showing promise in the pipeline?

The immunotherapy area is also very exciting. There are many ongoing studies, but we have had at lease 3 immunotherapy drugs to prove the benefit for patients with advanced adenocarcinoma or squamous cell carcinoma of the lung. This has been an exciting era and there is a lot of work still ongoing. I highlighted a study that we are doing at The University of Texas MD Anderson Cancer Center investigating EGFR mutations with the exon 20 insertion mutations. This is a rare mutation seen in about 1% to 2% of patients. Up until now, these patients did not have a good response to the standard first-line tyrosine kinase inhibitors (TKIs). We are looking at a drug called poziotinib; early data have shown a response rate of 74% to 75% in a disease that previously did not have good [available] treatment. Hopefully, this is something exciting.

How do you determine the sequencing of these agents and when to give 1 regimen over another?

We have the data for immunotherapy used in the first- and second-line settings in advanced disease. We are now starting to look at these agents earlier on, even in the neoadjuvant setting. There are several trials investigating this, as well. We think that is the next era of use for these agents. That is a difficult decision. There are many factors that go into that, such as the histology and the profile of the tumor—as well as the patient, their comorbidities, and so forth. For example, immunotherapy indications are based on PD-L1 levels, which influences the choice of giving PD-1/PD-L1 inhibitors early on.

[For patients with driver mutations], the decision of which TKI to use first is somewhat similar. The ALEX study suggests using alectinib for patients with ALK-positive tumors as it has supplanted crizotinib (Xalkori) as the first-line therapy.

There was another study presented at the 2017 ESMO Congress, which looked at osimertinib in the first-line setting. There is a movement focused on moving osimertinib further up the ladder.

What is the status of osimertinib?

What additional information would you like to add about this evolving paradigm?

Those are factors that we are considering, but a lot of times it comes down to the patient. Some of these drugs have different side effects than others, which needs to be considered in terms of their comorbidities.Osimertinib is approved if you have an acquired T790M mutation, which is resistance acquired following first-line TKIs with the EGFR-mutated population. The FLAURA study that was just presented at the 2017 ESMO Congress showed that using frontline osimertinib may have some prolonged PFS benefit. We may see that move up, but it is not currently approved in the first-line setting. It is not even approved in the second-line setting if you do not have the T790M demonstrated.In addition to the treatments that I have mentioned and advanced disease, I presented some data on oligometastatic disease, which is a population of patients who we encounter frequently in advanced lung cancer. These are patients who usually have fewer than 5 metastatic lesions. We have data from a study published in The Lancet Oncology in December 2016 by our group that looked at chemotherapy followed by localized treatment for the oligometastatic sites. Those patients have a better survival than those who were kept on maintenance therapy alone.

We are now looking at incorporating immunotherapy into that in a trial. The point to keep in mind is that there are patients with oligometastatic disease for which surgery or radiation, as part of their treatment after systemic therapy, might still be worth considering. It is not for everyone, but it is something that the right patient might benefit from.

The newer movement with the targeted agents, such as alectinib versus crizotinib and the osimertinib advances, are exciting areas. There are some changes on the horizon coming soon. There are new drugs being tested, as well. We have changed NSCLC into a more chronic illness and, although it is not curable, we have a lot more treatment options compared with 10 or 15 years ago.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. In: Proceedings from the 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR.