Advances in understanding of the molecular processes underlying non-small cell lung cancer (NSCLC) have led to the identification of several specific targets for therapeutic agents. To date, the most beneficial therapies targeting gene rearrangements are those that target the ALK, EGFR and BRAF mutations. However, these alterations are present only in a minority of patients with lung cancer: ALK rearrangements are found in 1.5% of patients with lung adenocarcinoma, the most frequent form of NSCLC,1 EGFR mutations vary by ethnicity, being seen in up to 50% of Asian patients but only 10–15% of other regions,1,2 and BRAF mutations are found in around 7% of patients with lung adenocarcinoma.1 In order to provide individualised treatment for the majority of patients with NSCLC, it is necessary to identify other actionable gene alterations. The 2019 World Conference on Lung Cancer (WCLC), which was held on 7–10 September 2019 in Barcelona, Spain, and hosted by the International Association for the Study of Lung Cancer (IASLC), featured a number of presentations highlighting new therapeutic targets. Here we highlight two important advances in the molecular targeted therapy of NSCLC.
Around 1–2% of NSCLC is associated with fusions of the RET gene.1,3 These are challenging to treat as up to 50% of RET fusion-positive NSCLCs metastasise to the brain.4 Multikinase inhibitors such as cabozantinib and vandetanib have shown limited benefit in patients with NSCLC.5 In addition, programmed cell death 1/ligand 1 (PD-1/PD-L1) inhibitors, have reduced efficacy in NSCLC with driver mutations, including tumours associated with RET fusions.6 However, to date, no RET inhibitors have received regulatory approval. There is a clear need for development of more selective and potent RET inhibitors.
Selpercatinib (Eli Lilly and Company, Indianapolis, Indiana, USA), also known as LOXO-292, has shown potent and selective RET inhibition in preclinical and early stage clinical studies.7 The LIBRETTO-001 phase I/II trial (ClinicalTrials.gov identifier: NCT03157128) is the largest clinical trial to date of patients with RET-altered cancers treated with a RET inhibitor, and has enrolled 531 patients with advanced solid tumours, RET fusion-positive solid tumours, medullary thyroid cancer, and other tumours with RET activation. Of these, 253 patients had RET fusion-positive NSCLC. The trial includes a dose escalation phase (phase I) and a dose expansion phase (phase II).
Primary results from the NSCLC cohort of the LIBRETTO-001 in patients with RET-altered NSCLC were presented at the 2019 WCLC meeting. An analysis of data from 105 patients who had undergone prior platinum-based chemotherapy, found that that selpercatinib showed a 68% objective response rate (ORR) (95% confidence interval [CI]: 58–76%). These patients were heavily pre-treated, with a median of three previous systemic regimens, 55% had previously been treated with an anti-PD-1/PD-L1 antibody and 48% were previously treated with at least one multikinase inhibitor. The ORR was similar regardless of prior therapy. In patients with brain metastases, the central nervous system (CNS) ORR was 91% (95% CI: 59–100%). At the time of data cut-off, the median duration of response was 20.3 months (95% CI: 13.8–24.0) and median progression-free survival (PFS) was 18.4 months (95% CI: 12.9–24.9).8
Selpercatinib was well-tolerated; the most commonly observed treatment-related adverse events (AEs; all grades) were dry mouth (32%), diarrhoea (31%), hypertension (29%), increased aspartate transaminase (28%), increased alanine transaminase (26%), fatigue (24%), constipation (22%), headache (20%), nausea (19%), peripheral oedema (19%), and increased creatinine (18%). The most common AE of grade 3 or higher was hypertension (15%). Treatment-related AEs led to discontinuation in only 9 of the 531 enrolled patients (1.7%).8
An analysis of 34 patients with treatment-naïve RET fusion-positive NSCLC was also presented. In this patient population, selpercatinib treatment resulted in an 85% ORR (95% CI: 69–95%), with the majority of patients remaining in response or progression-free.8
In a press release, lead investigator Alexander Drilon of Memorial Sloan Kettering Cancer Center in New York City, commented: “In this large cohort, selpercatinib’s response rate, durability, robust CNS activity, and safety show promise. Furthermore, this continues to confirm that RET fusions are clinically targetable alterations, placing them in the company of activating EGFR/ALK/ROS1 alterations. We are encouraged by these data as there is currently an unmet need to provide genomically-tailored therapy to patients with RET fusion-positive NSCLCs.”9
On the basis of these findings, the US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to LOXO-292 in patients with pre-treated metastatic RET fusion-positive NSCLC or RET-mutant medullary thyroid cancer. The next step in the clinical development of selpercatinib will be a global phase III trial comparing selpercatinib with or without pembrolizumab (Keytruda®, Merck, Kenilworth, New Jersey, USA) versus platinum-pemetrexed chemotherapy for patients with newly diagnosed RET fusion-positive NSCLC. Eli Lilly are expected to submit a New Drug Application to the FDA for selpercatinib by the end of the year.
Mutations in the KRAS gene are also important oncogenic drivers, but attempts to target them have been hampered by the lack of suitable drug-binding pockets on the KRAS protein.10 The KRAS-G12C mutation, in which cysteine replaces glycine at position 12 in the KRAS protein, is found in around 13% of patients with NSCLC1,11 and is associated with poor outcomes.12 AMG 510 (Amgen, Thousand Oaks, California, USA) is a first-in-class, orally administered small molecule KRAS inhibitor that binds cysteine in the mutated form of the KRAS protein, locking the protein into an inactive state.10,11 Another presentation at the WCLC described an ongoing phase I/II clinical study (ClinicalTrials.gov identifier: NCT03600883) investigating AMG 510 in patients with advanced solid tumours containing the KRAS G12C mutation. The phase I dose-finding portion of the study is investigating four dosage levels of AMG 510. To date, investigators have enrolled 76 patients with pre-treated locally advanced or metastatic solid tumours, including 34 patients with NSCLC. Eligible patients had undergone at least two or more prior lines of treatment. An analysis of 23 patients with NSCLC found that the ORR in patients treated with AMG 510 was 48%, with a disease control rate (DCR) of 96%. In patients with the highest dose (960 mg) of AMG 510, the ORR was 54% (all partial responses), with 46% of patients achieving stable disease, representing a DCR of 100%.13
AMG 510 was well tolerated, with treatment-related grade 1–2 and grade 3 AEs reported in 26.5% and 8.8% of patients, respectively. The grade 3 AEs were anaemia and diarrhoea. No grade 4 treatment-related AEs, dose-limiting toxicities, or AEs leading to treatment discontinuation were reported.13
In a press release, lead investigator Ramaswamy Govindan of Washington University School of Medicine in St Louis, Missouri, said: “These data continue to show encouraging antitumor activity with AMG 510, underscoring the potential to close the treatment gap for non-small cell lung cancer patients with previously treated KRAS G12C-mutation NSCLC.”14 These findings are particularly impressive given that the first person entered the study only 1 year ago.
These presentations have highlighted the changing therapeutic landscape for NSCLC. Further advances in targeting molecular abnormalities should further the aim of individualised treatment based on molecularly defined subtypes.
- Cancer Genome Atlas Research Network; Collisson EA, Campbell JD, Brooks AN, et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.
- Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5:2892–911.
- Kato S, Subbiah V, Marchlik E, et al. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23:1988–97.
- Remon J, Besse B. Brain metastases in oncogene-addicted non-small cell lung cancer patients: incidence and treatment. Front Oncol. 2018;8:88.
- Mendoza L. Clinical development of RET inhibitors in RET-rearranged non-small cell lung cancer: update. Oncol Rev. 2018;12:352.
- Berghoff AS, Bellosillo B, Caux C, et al. Immune checkpoint inhibitor treatment in patients with oncogene- addicted non-small cell lung cancer (NSCLC): summary of a multidisciplinary round-table discussion. ESMO Open. 2019;4:e000498.
- LOXO-292 reins in RET-driven tumors. Cancer Discov. 2018;8:904–5.
- Drilon A, Oxnard GR, Wirth L, et al. A phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. Presented at: IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer, Barcelona Spain, 7-10 September, 2019.
- Lilly announces positive results for selpercatinib (LOXO-292), demonstrating a 68 percent objective response rate and sustained durability in heavily pretreated RET fusion-positive non-small cell lung cancer. Available at: https://investor.lilly.com/news-releases/news-release-details/lilly-announces-positive-results-selpercatinib-loxo-292 (accessed 12 September 2019).
- AMG 510 first to inhibit “undruggable” KRAS. Cancer Discov. 2019;9:988–9.
- Lipford JR. Pre-clinical development of AMG 510: the first inhibitor of KRASG12C in clinical testing. Presented at: AACR 2019, Atlanta GA, 29 March – 3 April, 2019.
- Nadal E, Chen G, Prensner JR, et al. KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma. J Thorac Oncol. 2014;9:1513–22.
- Govindan R, Fakih MG, Price TJ, et al. Phase I study of safety, tolerability, PK and efficacy of AMG 510, a novel KRAS G12C inhibitor, evaluated in NSCLC, phase I study of safety, tolerability, PK and efficacy of AMG 510, a novel KRAS G12C inhibitor, evaluated in NSCLC. J Clin Oncol. 2019;37 (Suppl 15):3003.
- Amgen announces new clinical data evaluating novel investigational KRAS(G12C) inhibitor in larger patient group at WCLC 2019, 2019. Available at: www.amgen.com/media/news-releases/2019/09/amgen-announces-new-clinical-data-evaluating-novel-investigational-krasg12c-inhibitor-in-larger-patient-group-at-wclc-2019/ (accessed 12 September 2019).