5 Key Targeted Therapy Advances for Lung Cancer

H. Jack West, MD; Charu Aggarwal, MD, MPH


March 26, 2020

Lung cancer treatment has been transformed over the past decade. As we entered 2010, thoracic medical oncologists were moving away from a histology-agnostic approach and increasingly testing for activating mutations in EGFR. That same year, the first report to show that a subgroup of non-small cell lung cancers (NSCLCs) responded to targeted therapy was published.

This was only the beginning. We also saw new and improved treatment options for EGFR- and ALK-positive disease and a growing array of new driver mutations with paired targeted therapies. These promised not only dramatic responses but also better tolerability, allowing for longer-term treatment in patients fortunate enough to benefit from them. Thanks to these advances, lung cancer mortality consistently declined over the past decade.

We recently surveyed the foremost developments in lung cancer immunotherapy that contributed to this transformation. Now we offer the top 5 developments in targeted therapy.

1. Novel drugs for old and new targets are available. In the past decade, applicability of targeted therapy expanded from EGFR and ALK to now include six other actionable mutations—RET, BRAF, ROS1, MET exon 14, NTRK, and KRAS—with strong enough data to be included in National Comprehensive Cancer Network guidelines.

Even though several agents had been tested for RET fusions, including vandetanib, cabozantinib, and sunitinib, their use was often hampered by associated toxicities and a relatively modest improvement in progression-free survival (range, 2.5-3 months). We now have two highly potent and selective RET inhibitors: pralsetinib and selpercatinib. These drugs have proven to be safe and well tolerated, and also are associated with significant responses, including in heavily pretreated patients and in those with brain metastases. We believe that they should soon become a new therapeutic option for patients with RET-rearranged tumors.

Crizotinib remains an option for patients with ROS1 fusion. Entrectinib is a novel tyrosine kinase inhibitor (TKI) with activity against ROS1 and NTRK fusions that has been approved by the US Food and Drug Administration. The efficacy of combination therapy targeting MEK and BRAF has established BRAF testing in all newly diagnosed patients and BRAF targeted therapy as a valid first-line approach. At least two agents (tepotinib and capmatinib) have demonstrated efficacy and tolerability in clinical trials for the subset of patients with MET exon 14, and deserve consideration as a potential first-line therapy when commercially available. Larotrectinib and entrectinib are also highly active drugs for patients with NTRK fusions.

With emerging targets, such as EGFR exon 20 and HER2, we are hopeful this trend of newly recognized driver mutations and therapies will continue in the current decade.

2. Sensitive and reliable plasma testing can be done when tissue is scant. Recent studies have demonstrated that integrating plasma-based multiplex gene sequencing into routine clinical care can help more patients with NSCLC receive effective molecularly guided therapies. Molecular testing is of paramount importance in NSCLC, given the increased number of actionable mutations and the knowledge that immunotherapy may be less effective in oncogene-addicted tumors.

Considering the challenges around tissue testing, plasma-based approaches are a novel, noninvasive option with a relatively quick turnaround time. We now know from both retrospective and prospective reports that although liquid biopsy can't entirely replace tissue testing at this time, it should be considered a viable alternative when there are barriers to tissue-based testing.

3. Activity in KRAS-mutant NSCLC is being achieved. As the most common mutation in NSCLC, KRAS accounts for 25%-30% of all such cancers. This is why it has long been seen as the Holy Grail of targeted therapies in NSCLC.

At the 2019 annual meeting of the American Society of Clinical Oncology, we saw exciting data on AMG 510 (a new KRAS G12C-specific TKI), which showed an encouraging 50% response rate in a small group of pretreated patients. We subsequently saw updated data reported at the World Conference of Lung Cancer. Among these 34 patients, 96% achieved disease control, with a 48% overall response rate. This trial generated swift interest, with rapid accrual to the dose-expansion portion of the study. It remains to be seen whether these early reports translate into long-term responses. Nevertheless, at the dawn of a new decade, we have more reason than ever before to be optimistic about finally targeting KRAS-mutant NSCLC.

4. EGFR and ALK inhibitors have efficacy after acquired resistance. Not long after the first report that ALK translocations were a targetable mutation, the use of first-generation EGFR TKIs (erlotinib, afatinib, and later gefitinib) and ALK-specific TKIs (crizotinib) became standard of care for patients with these alterations. Although this was a paradigm shift in our management of patients with NSCLC, we were soon grappling with what to do in the post-TKI progression setting.

A better understanding of these resistance mechanisms led to the development of effective third-generation TKIs. The AURA trial evaluated AZD2991 (now osimertinib) in patients with EGFR T790M mutation, the most common resistance mechanism after therapy with a first-generation TKI. The response rate in a second or greater line of therapy was 62%, and the disease control rate was 90%. These results quickly led to the approval of osimertinib in the second-line setting for patients with T790M mutant NSCLC.

Similarly, we expanded upon our knowledge of molecular mechanisms of resistance to first- and second-generation ALK TKIs, leading to the development of several drugs, including ceritinib, alectinib, and brigatinib.

5. Third-generation TKIs are associated with improved central nervous system efficacy. The rewards of delivering targeted therapy became even sweeter with the development of agents that had better penetration into the blood-brain barrier. The FLAURA, ALEX, and ALTA-1L trials showed superiority over first-generation TKIs with the use of osimertinib, alectinib, and brigatinib, respectively, for patient subgroups with driver mutations. The improvements in the treatment-naive setting, coupled with a superior toxicity profile and favorable tolerability, made them a clear choice as first-line therapy. The significant intracranial activity of these agents served as the icing on the cake, providing an important benefit to the challenging problem of central nervous system progression on earlier-generation targeted therapies against EGFR and ALK.

What Lies Ahead

With so much progress in targeted therapy over the past 10 years, we should expect that trials with newer agents, either alone or in combination with other therapies, will continue to advance the field. Of note, as the list of compelling therapies for driver mutations grows well beyond what can feasibly be checked with individual tests, NSCLC has become the disease in which broad molecular testing has emerged as most valuable. The more widespread incorporation of next-generation sequencing of lung and other cancers will catalyze a new era of molecular oncology over this next decade.

H. Jack West, MD, associate clinical professor and executive director of employer services at City of Hope Comprehensive Cancer Center in Duarte, California, regularly comments on lung cancer for Medscape.

Charu Aggarwal, MD, MPH, is an assistant professor in the Department of Medicine at the University of Pennsylvania and a contributor to Medscape Oncology Decision Point.

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