Developments Expanding Frontline NSCLC Treatment

Thomas Eldridge Stinchcombe, MD

Osimertinib (Tagrisso) and alectinib (Alecensa) are 2 new frontline therapies for patients with non—small cell lung cancer (NSCLC) that have demonstrated tremendous advancements for targeted therapy, said Thomas E. Stinchcombe, MD.

In the phase III FLAURA study, osimertinib reduced the risk of progression or death by 54% versus standard tyrosine kinase inhibitor (TKI) therapy of erlotinib (Tarceva) or gefitinib (Iressa) in patients with EGFR-mutant NSCLC. In this trial, 556 treatment-naïve patients with EGFR-positive, locally advanced or metastatic NSCLC were randomly assigned to osimertinib or standard TKI therapy. The median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 12.5-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001). Osimertinib is currently under priority review as a frontline treatment option for this patient population.¹ The objective response rate (ORR) with osimertinib was 80% compared with 76% for erlotinib and gefitinib (OR, 1.28; 95% CI, 0.85- 1.93; P = .2335). The median duration of response with osimertinib was 17.2 months versus 8.5 months in the comparator arm.

Representinng another targeted therapy win, the FDA approved alectinib in November 2017 for the treatment of patients with ALK-positive metastatic NSCLC. The frontline approval of alectinib is based on the phase III ALEX study, findings of which demonstrated a 47% improvement in PFS (HR, 0.53; 95% CI, 0.38- 0.73; P <.0001) compared with crizotinib (Xalkori).²

In this international trial, the median PFS, as determined by an independent review committee, was 25.7 months (95% CI, 19.9-not reached) in the alectinib arm versus 10.4 months (95% CI, 7.7-14.6) in the crizotinib arm. The ORR with alectinib was 79% (95% CI, 72%-85%) versus 72% (95% CI, 64%-79%) with crizotinib (P = .1652). The complete response rates were 13% and 6%, respectively, and the partial response rate was 66% in both arms.

OncLive^®: What are your thoughts on osimertinib and alectinib as first-line treatments for patients with NSCLC?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Stinchcombe, a professor in the Division of Medical Oncology at Duke University and member of Duke Cancer Institute, discussed existing and emerging first-line regimens coming through the pipeline for the treatment of patients with NSCLC.Stinchcombe: There have been tremendous advances with targeted therapy in the last year. A phase III trial compared osimertinib with erlotinib and gefitinib. This revealed an improved PFS with a median of 18.9 months [with osimertinib], which also demonstrated lower grade 3/4 toxicities.

This is a trial that has immediately changed practice. For patients with ALK-rearranged NSCLC, there are 2 trials. Both trials compared alectinib with the previous standard of crizotinib and demonstrated a significant improvement in PFS, with the median being 25 months in the alectinib arm.

In your opinion, are targeted agents surpassing immunotherapy efforts?

What impact would an approval of lorlatinib have on patients with NSCLC?

How are these newer ALK inhibitors being developed to counter resistance?

The FDA granted a priority review designation for osimertinib in patients with EGFR mutations. What led to its use in patients with T790M mutations?

Alectinib was approved for frontline treatment in ALK-positive patients. Is there still a lot of room for drug development in the first-line setting?

Are there any accruing clinical trials that are investigating new targeted therapies or any promising biomarkers that you would like to highlight?

One of the trials prospectively assessed the development of brain metastases. The trial saw a dramatically reduced incidence of brain metastases, which shows that alectinib has more potency and better blood—brain barrier penetration. There are different patient populations in which each strategy will work. For patients with a mutation that is a lower tumor mutational burden or a lower expression of PD-L1, targeted therapies will remain the standard of care. For patients without a mutation, immunotherapy will be the backbone of the therapy either alone or with chemotherapy. Lorlatinib demonstrates significant activity, particularly in patients who progress on first- and second-generation ALK TKIs. This suggests that it was designed to hit the resistance mutation and have good blood—brain barrier penetration. This will become an option for the patients who progress on first-line alectinib. If this is available, it will be the preferred option. There is also activity in the ROS1 space. There is some interest in this rare patient population but when they progress on crizotinib, it is unclear what the next targeted therapy should be. These are valuable data that would provide additional options for our patients.ALK inhibitors are continuing to be developed. We know that with the second-generation ALK inhibitors, the rate of resistance mutations—particularly the G12R resistance mutation—are more common. Therefore, the new ALK inhibitors being developed hit the resistance mutations. Consequently, they are thought to be more effective in terms of targeting those resistance mutations. The brain has been a pharmacokinetic sanctuary, and as a result, greater blood—brain barrier penetration circumvents that issue. Osimertinib was designed to hit the original mutation of T790M, which we often refer to as the acquired resistance mutation, as well as sparing the EGFR wild-type patients. It was approved in a phase III trial of patients who had progressed on EGFR TKIs. This trial demonstrates that [osimertinib] was shown to be better than our platinum doublet. This is proof of principle as we develop molecularly targeted drugs. It also illustrates our investment in translational medicine where we know the mechanism of resistance and we can develop therapies that circumvent or overcome it.Alectinib will remain the preferred agent. A number of agents, such as lorlatinib versus crizotinib or brigatinib (Alunbrig) versus crizotinib, are in phase III trials that have launched. The main questions will be regarding the results of these trials. If they show a PFS greater than 25 months, those could surpass alectinib as the standard of care. There is going to be a renewed focus on the second-line ALK-positive patients as we use a more potent drug in the first-line setting. There was a recent New England Journal of Medicine publication that has captured the attention of many physicians. Patients with TRK fusions in all types of solid tumors were enrolled [in a trial]. Larotrectinib demonstrated activity in those patients and there was a high response rate. This makes us think that we need to expand our molecular testing to include TRK fusion— positive tumors.

Is there anything else you would like to add?

The BRAF V600E inhibitor [dabrafenib] got approved for NSCLC, which provides another targeted therapy at this point. And for RET rearrangements, as well as HER2 mutations, active trials are looking at agents that target those molecular subsets. These should be watched closely over the next year.As we expand the number of targets to incorporate tumor mutational burdens, it is critical that we move toward more next-generation sequencing panels because the days of doing 1 or 3 tests at a time are past us. This is an exciting time in terms of the promise of next-generation sequencing.

References

1. 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 European Society for Medical Oncology Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR.
2. . FDA approves Genentech’s Alecensa (alectinib) as first-line treatment for people with specific type of lung cancer [news release]. South San Francisco, CA: Genentech; November 6, 2017. gene.com/media/press-releases/14689/2017-11-06/fda-approves-genentechs-alecensa-alectin. Accessed April 2, 2018.