Updates in Oncogene-Driven NSCLC from ESMO Congress

With advances in molecular diagnostic technology uncovering numerous actionable targets, and with the rapid pace of development of new targeted treatment options, the management of biomarker-driven lung cancer is becoming increasingly complex. Despite being held only 1 month after the World Conference on Lung Cancer, plenty of new research data on the management of biomarker-driven non-small cell lung cancer (NSCLC) were presented at the 2022 European Society for Medical Oncology (ESMO) Congress, held in Paris during 9 – 13 September. These included updates on targeted therapy in early-stage EGFR-mutant (EGFRm) NSCLC, emerging data on the mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs), details on MET amplification (METamp)-dependent resistance, and targeted strategies to overcome this. Furthermore, data relevant to clinical practice were presented on targeting rare molecular drivers, such as MET exon 14 skipping mutations, HER2 mutations, and RET fusion-positive NSCLC, as well as first phase III data with targeted therapy for KRAS G12C-mutated NSCLC. Highlights from some of these studies are summarized below.

Sustained disease-free survival benefit with adjuvant osimertinib in early-stage EGFRm NSCLC  

The success of the third-generation EGFR TKI, osimertinib, in terms of improved outcomes and a more favorable safety profile compared with first-generation EGFR TKIs (gefitinib/erlotinib) in advanced EGFRm NSCLC,1 led to the investigation of this agent as adjuvant therapy in patients with early-stage EGFRm NSCLC. ADAURA was a phase III, double-blind, placebo-controlled trial in which 682 patients with sensitizing EGFR mutations after complete resection with/without adjuvant chemotherapy were randomized to receive adjuvant osimertinib or placebo for up to 3 years. The primary analysis in 20202 showed an impressive disease-free survival (DFS) benefit in patients with EGFRm NSCLC stage II/IIIA (hazard ratio [HR], 0.17; P < 0.001) and in the overall population, including stages IB/II/IIIA (HR, 0.20; P < 0.001). Additionally, osimertinib reduced the risk of central nervous system (CNS) recurrence, and quality of life was maintained.  

Updated analysis from the ADAURA trial, presented by Masahiro Tsuboi, MD (National Cancer Center Hospital East, Kashiwa, Japan; LBA47)3 reinforced the DFS benefit shown in the primary analysis. After 2 years of additional follow-up, in which all patients had the opportunity to receive the full 3 years of adjuvant treatment, the median DFS was 65.8 months in patients with stage II/IIIA disease treated with osimertinib vs. 21.9 months with placebo (HR, 0.23). In patients with stage IB/II/IIIA disease, DFS was 65.8 months with osimertinib vs. 28.1 months with placebo (HR, 0.27); the benefit was seen across all predefined subgroups, including patients who had or had not received adjuvant chemotherapy. The rate of disease recurrence with osimertinib was less than half that seen with placebo (27% vs. 60%, respectively). In addition, a clinically meaningful improvement in CNS DFS was seen with osimertinib in stage II – IIIA NSCLC (HR, 0.24). In terms of toxicity, no new safety concerns were reported. The investigators concluded that the updated data support adjuvant osimertinib as standard of care for patients with EGFRm stage IB/II/IIIA NSCLC after complete resection, with or without adjuvant chemotherapy. Although these data provide hope for higher cure rates in EGFRm early-stage disease, they also indicate that the benefit of osimertinib may wane after treatment discontinuation as the risk of recurrence of both extracranial and CNS relapses starts increasing after 3 years. 

Obtaining tissue biopsies to define molecular mechanisms of resistance to targeted therapy is challenging 

For EGFRm advanced NSCLC, osimertinib is the preferred first-line treatment choice;4 however, the development of treatment resistance is inevitable. The phase II ELIOS study aims to characterize prospectively the resistance mechanisms to first-line osimertinib, with a primary objective of comparing next-generation sequencing (NGS) results of paired tumor tissue biopsies (TBx) obtained pre-treatment and after progression on osimertinib (LBA53).5 Zofia Piotrowska, MD (Massachusetts General Hospital, Boston, Massachusetts, US), who presented the results, highlighted that paired biopsies with valid NGS results were obtained in only 46/119 (39%) of patients. Results showed that the high-frequency mutations at baseline (EFGR, TP53, and EGFR amplification, and CDKN2A loss) did not differ significantly at the time of disease progression. Similarly, as previously reported,6,7 the most prevalent acquired resistance mechanisms to first-line osimertinib were MET amplification (METamp; 8/46; 17%) and over-expression (3/6; 50%), as well as EGFR C797S mutation (7/46; 15%). In addition, NKX2-1 amplification was identified as a potentially new resistance mechanism, but this requires further exploration. Furthermore, MET and AXL upregulation was found in a subset of tumors post-progression, indicating that they play a role in acquired resistance to EGFR TKIs. The collection of molecular data for the remaining patients included in the ELIOS study is ongoing, as well as retrospective analyses of histologic data. The challenge of obtaining TBx post-progression indicates a need for more comprehensive non-invasive testing methods. 

Tepotinib plus osimertinib highly active for EGFRm NSCLC with METamp after progression on first-line osimertinib 

METamp is one of the most common acquired resistance mechanisms to EGFR TKIs in EGFRm NSCLC and occurs in approximately 15% – 30% of patients progressing on first-line osimertinib. Fluorescence in situ hybridization (FISH) is the gold standard for detecting METamp, which is defined as MET gene copy number (GCN) ≥ 5 or MET/CEP7 ≥ 2.0. Although METamp could be detected by NGS TBx and liquid biopsy (LBx) panels, the sensitivity of current assays may be an issue. Treatment options for these patients are limited and remain a high unmet need. Concurrent inhibition of both MET and EGFR may potentially overcome acquired METamp, and promising results from phase I/II trials support this approach.8,9  

At the ESMO congress, Dr. Julien Mazières (University Hospital, Toulouse, France) presented the initial results from the open-label, two-arm, international, phase II INSIGHT 2 study evaluating the combination of tepotinib plus osimertinib (n = 88) and tepotinib monotherapy (n = 12) in patients with EGFRm NSCLC with METamp after progression on first-line osimertinib (LBA52).10 Among 425 pre-screened patients, METamp was detected by FISH TBx in 33% of patients and by NGS LBx in 11% of patients. The confirmed overall response rate (ORR) was 54.5% in patients with METamp detected by TBx FISH with a median of ≥ 9 months follow-up (N = 22) and 45.8% in those with a ≥ 3 months follow-up (n = 48). Half of the responders at ≥ 9 months follow-up remain on treatment. Median duration of response (mDOR) was not reached. In patients treated with tepotinib monotherapy (n = 12), the ORR was only 8.3% (METamp detected by FISH); seven patients switched to the combination therapy at the time of disease progression. The safety profile of the combination was consistent with the known safety profiles of tepotinib and osimertinib; diarrhea (41%) and peripheral edema (24%) were the most common any-grade adverse events (AEs). These initial results are promising and signal that tepotinib plus osimertinib may be a potential chemotherapy-sparing all-oral targeted therapy for patients with EGFRm NSCLC with MET amplification after progression on first-line osimertinib.  

Tepotinib effective in patients with MET exon 14 skipping NSCLC regardless of prior therapies  

Although the latest evidence and guidelines4,11,12 support the first-line use of selective MET inhibitors for patients with MET exon 14 skipping (METex14) NSCLC, in Europe and some other countries, MET inhibitors, including tepotinib, are approved for patients previously treated with immunotherapy and/or platinum-based chemotherapy. Thus, analysis of tepotinib efficacy in patients included in the phase II VISION trial (Cohort A and C) according to prior therapies is particularly clinically relevant (985P).13 Of 313 patients enrolled, about half were previously treated (over 80% had received platinum-based chemotherapy, over 50% had prior immunotherapy, and about 15% had prior immunotherapy plus chemotherapy in any line). Among previously treated patients, 62% received tepotinib as second-line treatment and 38% as third-line and beyond. Results from these analyses showed a robust and clinically meaningful efficacy (ORR; DOR; progression-free survival [PFS], and overall survival [OS]) of tepotinib regardless of treatment lines and prior therapies. In treatment-naïve patients, ORR was 56.1%, mDOR was 46.4 months, mPFS was 12.6 months, and mOS was 19.1 months; in previously treated patients, ORR was 45.0%, mDOR was 12.4 months, mPFS was 11.0 months, and mOS was 19.6 months. Similar efficacy was seen regardless of prior therapy with chemotherapy and/or immunotherapy. Importantly, the safety profile was manageable irrespective of line of treatment and prior immunotherapy. In general, AEs were mostly mild-to-moderate, with peripheral edema being the most common. About 15% of patients discontinued treatment due to AEs.  

Baseline MET expression in patients with METex14 skipping NSCLC associated with response to capmatinib 

An exploratory whole-transcriptome analysis in patients with METex14 skipping NSCLC treated with capmatinib was performed in the phase II GEOMETRY Mono-1 study (986P).14 Patients’ baseline tumor biopsies were successfully profiled by RNA sequencing: 41 patients received capmatinib as first-line therapy and 70 patients as second- or third-line treatment. Baseline MET and PD-L1 expression was similar in all patients, regardless of line of treatment. High baseline MET expression (above median) was significantly associated with overall response in treatment-naive patients; a similar trend was seen in previously treated patients. In addition, high MET gene expression was significantly associated with longer PFS and OS in patients receiving capmatinib as first-line therapy, but not in those patients receiving second- or third-line treatment. Notably, PD-L1 expression showed no correlation with response to capmatinib in any line of treatment.  

Selected patients with RET-positive NSCLC benefit from selpercatinib beyond progression 

Selpercatinib is a highly selective RET kinase inhibitor that showed high and durable efficacy (including in CNS) in patients with RET fusion-positive NSCLC in the phase I/II LIBRETTO-001 trial. Based on this, it was granted approval in various regions for patients with RET fusion-positive NSCLC. In the LIBRETTO-001 trial, patients were permitted to continue selpercatinib beyond progression if they derived ongoing benefit (980P).15 Among 169 patients who progressed on selpercatinib, 120 continued treatment beyond progression. Exploratory post-hoc analyses of safety and efficacy data were undertaken in this subset of patients. These patients had a higher rate of baseline CNS metastases (43% vs. 30%). The median duration of treatment prior to progressive disease was 10.9 months; after disease progression, the median duration of treatment was 5.0 months. Of the 120 patients who continued treatment after progression, 40 patients (33%) received localized treatment for progressing lesions, including radiotherapy (36 patients, of whom 12 received brain radiotherapy). Median time on treatment for these patients was 5.4 months, while for those patients who did not receive radiotherapy, it was 3.56 months. The safety profile in patients receiving selpercatinib post-progression was generally consistent with the overall safety profile. These results support continuing selpercatinib beyond progression in selected patients with RET fusion-positive NSCLC. 

Lower dose of trastuzumab deruxtecan effective in HER2-mutated NSCLC 

In the recently reported DESTINY-Lung01 trial,16 trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate, given at a dose of 6.4 mg/kg showed strong and durable clinical activity in HER2-mutated NSCLC patients refractory to standard therapy. However, 26% of patients experienced adjudicated drug-related interstitial lung disease (ILD). The majority of patients (75%) had grade 1 or 2 ILD, but four patients had grade 3 ILD, and two patients died. Thus, the phase II DESTINY-Lung02 trial was conducted to assess the benefit-risk profile of two doses of T-DXd (5.4 mg/kg and 6.4 mg/kg). Results from an interim analysis of a prespecified early cohort that included patients randomized at least 4.5 months before the interim analysis data cutoff, were presented by Koichi Goto, MD, PhD (National Cancer Center Hospital East, Kashiwa, Japan; LBA55).17 At a median follow-up of 5.4 months, the ORR by blinded independent central review was 53.8% at a dose of 5.4 mg/kg, and 42.9% at a dose of 6.4 mg/kg. The mDOR was not reached with the lower dose and was 5.9 months with the higher dose. Additional 90-day follow-up response analysis was conducted for the lower dose cohort and showed ORR 57.7% and mDOR 8.7 months. In terms of safety, a more favorable toxicity profile was seen with the 5.4 mg/kg dose: treatment-emergent AEs were lower, as were drug reduction, and treatment interruption or discontinuation. Importantly, the incidence of ILD was 5.9% vs. 14.0% with the higher dose. Nevertheless, investigators highlighted that ILD remains an important risk factor and requires early detection and management. They concluded that these positive benefit-risk results support the approval of T-DXd at the 5.4 mg/kg dose as a new standard of care for patients with previously treated HER2-mutated NSCLC.  

Oral sotorasib superior to standard chemotherapy in KRAS G12C-mutated NSCLC 

Until recently, KRAS mutations in NSCLC were considered undruggable, but now targeted therapies have been developed that target KRAS G12C, the most common KRAS mutation in NSCLC. Sotorasib is the first specific and irreversible KRAS G12C inhibitor approved for patients with previously treated KRAS G12C-mutated advanced NSCLC, based on promising results from the phase I/II CodeBreaK100 trial.18 Eagerly awaited results from the confirmatory phase III CodeBreaK 200 clinical trial comparing sotorasib with docetaxel were presented during the last Presidential Symposium of the ESMO congress 2022 by Melissa Johnson, MD (Sarah Cannon Research Institute at Tennessee Oncology, Nashville, Tennessee, US; LBA10).19 In this trial, patients with KRAS G12C-mutated NSCLC who progressed after prior treatment, including platinum-based chemotherapy and immunotherapy, were randomized to receive either oral sotorasib (960 mg daily) or intravenous docetaxel (75 mg/m2 every 3 weeks). At a median follow-up of 17.7 months, the primary endpoint was met, with a statistically significant improvement in mPFS with sotorasib vs. docetaxel (5.6 vs. 4.5 months; HR, 0.66; P = 0.002). The 1-year PFS was 24.8% for sotorasib vs. 10.1% for docetaxel, and PFS benefit was consistent across subgroups. ORR was significantly improved for sotorasib vs. docetaxel (28.1% vs. 13.2%, respectively; P < 0.001). Sotorasib was associated with a faster median time to response (1.4 vs. 2.8 months) and a longer mDOR (8.6 vs. 6.8 months). OS was not significantly different between treatment arms; however, the study was not powered for OS. In addition, there was a 34% crossover to sotorasib following disease progression on docetaxel. Sotorasib was well tolerated, with fewer grade ≥3 treatment-related AEs than docetaxel, and clinically meaningful patient-reported outcomes were superior for sotorasib compared with docetaxel. Dr. Johnson concluded that the results endorse sotorasib as an important treatment option for patients with KRAS G12C-mutated NSCLC and reinforce the importance of NGS testing in advanced NSCLC. 

References:

  1. Soria JC, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. 
  2. Wu YL, et al. Osimertinib in resected EGFR-mutated non-small-cell-lung cancer. N Engl J Med. 2020;383(18):1711-1723. 
  3. Tsuboi M, et al. Osimertinib as adjuvant therapy in patients with resected EGFRm stage IB-IIIA NSCLC: Updated results from ADAURA. ESMO 2022; Abstract LBA47. 
  4. NCCN Guidelines. NSCLC (Version 4.2022). Updated: 2 September 2022.  
  5. Piotrowska Z, et al. ELIOS: A multicentre, molecular profiling study of patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC treated with first-line (1L) osimertinib. ESMO 2022; Abstract LBA53. 
  6. Ramalingam SS, et al. Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study. ESMO 2018; Abstract 5005. 
  7. Ramalingam SS, et al. Real-world landscape of EGFR C797X mutation as a resistance mechanism to osimertinib in non-small cell lung cancer. WCLC 2022; Abstract MA07.03. 
  8. Wu YL, et al. Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): An open-label, phase 1b/2, multicentre, randomised trial. Lancet Respir Med. 2020; 8(11):1132-1143. 
  9. Sequist LV, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: Interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 2020;21(3):373-386. 
  10. Mazieres J, et al. Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study. ESMO 2022; Abstract LBA52. 
  11. Thomas M, et al. Tepotinib in patients with MET exon 14 (METex14) skipping NSCLC: Primary analysis of the confirmatory VISION Cohort C. WCLC 2022; Abstract OA03.05. 
  12. Wolf J, et al. Capmatinib in MET exon14-mutated or MET-amplified non-small cell lung cancer. N Engl J Med. 2020;383(10):944-957. 
  13. Smit EF, et al. Tepotinib outcomes according to prior therapies in patients with MET exon 14 (METex14) skipping NSCLC. ESMO 2022; Abstract 985P. 
  14. Wolf, J, et al. Response to capmatinib in patients (pts) with advanced non-small cell lung cancer (NSCLC) and MET exon 14 skipping (METex14) mutation: Whole transcriptome analysis from Phase 2 GEOMETRY Mono-1 study. ESMO 2022; Abstract 986P. 
  15. Drilon AE, et al. Continuation of selpercatinib beyond progression in RET fusion-positive NSCLC: Data from LIBRETTO-001 study. ESMO 2022; Abstract 980P. 
  16. Li BT, et al. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. 2022;386:241-251. 
  17. Goto, K et al. Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutant metastatic non–small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial. ESMO 2022; Abstract LBA55. 
  18. Dy GK, Govindan R, Velcheti V, et al. Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100. AACR 2022; Abstract CT008. 
  19. Johnson M, et al. Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. ESMO 2022; Abstract LBA10.