Precision Medicine in NSCLC The Power of Molecular Testing

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Evolution of Personalized Therapy via Biomarker Testing

Personalized therapy for non–small cell lung cancer (NSCLC) has evolved significantly with the advent of comprehensive molecular testing.¹ Biomarker testing, specifically via next-generation sequencing (NGS), has become crucial for identifying driver mutations. These testing strategies facilitate timely and precise delivery of targeted therapy, which has shown meaningful improvements in overall survival (OS) in NSCLC.²

Biomarker testing allows the identification of actionable mutations to guide treatment decisions, avoid unnecessary chemotherapy, and implement individualized treatment plans based on molecular profiling.³ Therapies targeted to biomarkers identified have significantly extended progression-free survival (PFS) and overall response rates (ORRs).³ Therapy selection relies on accurate molecular profiling to determine the most effective targeted therapy.³

Managing NSCLC With MET Mutations

MET alterations, including MET exon 14 skipping mutations and amplifications, are significant therapeutic targets in NSCLC.3 Approximately 3% to 4% of patients with NSCLC will harbor MET exon 14 skipping mutations.⁴ The MET tyrosine kinase inhibitors crizotinib, capmatinib, and tepotinib have demonstrated efficacy in patients with these mutations.^5-7

In the PROFILE 1001 (NCT00585195) trial, crizotinib use was studied in patients with MET exon 14 skipping mutations.⁵ Results showed an ORR of 32% with a median duration of response (mDOR) of 9.1 months and a median PFS (mPFS) of 7.3 months. Common treatment-related adverse events (TRAEs) included edema (51%), vision disorder (45%), nausea (41%), diarrhea (39%), and vomiting (29%).

Capmatinib demonstrated efficacy in the GEOMETRY Mono-1 trial (NCT02414139) in the first-line setting (ORR, 67%; mDOR, 12.6 months; PFS, 12.3 months; OS, 20.8 months) and the second-line setting (ORR, 44%; mDOR, 9.7 months; and PFS, 5.5 months).⁶ Grade 3/4 TRAEs occurred in 68.5% of patients.

Tepotinib showed substantial activity in MET exon 14 skipping mutation–positive NSCLC in the VISION trial (NCT02864992).⁷ The trial reported an ORR of 54% in treatment-naive patients and of 44% in previously treated patients (second line or more) with an mDOR of 11.1 months. The mPFS was 10.4 and 11.0 months in the first line and second line and beyond, respectively. Peripheral edema was the most common TRAE of at least grade 3, occurring in 7% of patients.

Approximately one quarter of patients with EGFR wild-type NSCLC have c-Met protein overexpression.8 Telisotuzumab vedotin, a c-Met–directed antibody-drug conjugate, resulted in ORRs of 34.6% and 22.95% in patients with high and intermediate expression, respectively, in patients who had received 2 or fewer prior lines of therapy. The ORR was 28.6%. Grade 5 interstitial lung disease and respiratory failure occurred in 2 patients.

RET Fusion–Targeted Therapy

RET fusions represent key therapeutic targets in NSCLC, with 1% to 2% of all patients with NSCLC harboring RET fusions.⁹ In general, RET fusions do not occur concurrently with alterations in EGFR, ALK, ROS1, BRAF, or KRAS.10 Use of the selective RET inhibitors selpercatinib and pralsetinib demonstrated significant efficacy in clinical trials.

Outcomes of theLIBRETTO-001 trial (NCT03157128) showed that use of selpercatinib resulted in an ORR of 84% in treatment-naive patients and of 61% in those previously treated with platinum-based chemotherapy.¹¹ The mPFS when the drug was used in the first or second lines was 22.0 vs
24.9 months, respectively.

When compared with chemotherapy plus pembrolizumab, first-line selpercatinib resulted in improved PFS (24.8 vs 11.2 months; HR, 0.46; P < .001), ORR (84% vs 65%), and DOR (24.2 vs 11.5 months) in a phase 3 LIBRETTO-431 trial (NCT04194944).¹²

In the ARROW trial (NCT03037385), pralsetinib demonstrated an ORR of 72% in treatment-naive patients and 59% in patients previously treated with platinum-based chemotherapy.^13,14 The mDOR was not reached in treatment-naive patients and was 22.3 months in previously treated patients.

The ongoing, phase 3 AcceleRET Lung trial (NCT04222972) is assessing pralsetinib vs standard-of-care therapy for RET fusion–positive NSCLC in the first-line setting.¹⁵ PFS is the primary end point, and the estimated completion date is June 2025.

In perioperative trials, such as the LIBRETTO-432 (NCT04819100) and NAUTIKA1 (NCT04302025) studies, the role of selpercatinib and other targeted therapy in stage II to III NSCLC is being explored.^16,17

Targeting KRAS Mutations

KRAS mutations, particularly KRAS G12C, represent a common and challenging target in NSCLC. The development of the selective KRAS G12C inhibitors sotorasib and adagrasib has marked a significant advancement in the management of these mutations.

Sotorasib resulted in an ORR of 37.1% (including a 3.2% complete response rate) with a median PFS and OS of 6.8 and 12.5 months, respectively, in the phase 2 CodeBreaK 100 trial (NCT03600883) in patients previously treated with platinum-based chemotherapy and PD-L1 inhibitors.¹⁸

In the phase 3 CodeBreaK 200 trial (NCT04303780), sotorasib was compared with docetaxel in previously treated patients with KRAS G12C–mutated NSCLC.¹⁹ Sotorasib demonstrated a superior ORR of 28% compared with 13% with use of docetaxel. The mPFS was longer with sotorasib (5.6 vs 4.5 months, respectively; HR, 0.66; P = .0017). Patients treated with sotorasib experienced fewer grade TRAEs of at least grade 3 (18% vs 34%).

In the phase 1/2 KRYSTAL-1 trial (NCT03785249), adagrasib was evaluated in previously treated patients with KRAS G12C–mutated NSCLC.²⁰ Adagrasib demonstrated an ORR of 42.9% with an mPFS of 6.5 months. Additionally, the mDOR was 8.2 months. Follow-up data revealed an OS of 12.6 months. Notably, the intracranial ORR was 33.3%. TRAEs of at least grade 3 occurred in 44.8% of patients, with 6.9% of patients discontinuing treatment based on AEs.

Further expanding on the results of KRYSTAL-1, adagrasib was compared with docetaxel in patients with KRAS G12C–mutated NSCLC in the KRYSTAL-12 trial (NCT04685135).²¹ Primary results showed a significantly longer PFS (5.49 vs 3.84 months; HR, 0.58; P < .0001) and higher ORR (32% vs 9%; OR 4.68; P < .0001) with adagrasib than with docetaxel. The mDOR was also longer in the adagrasib group (8.3 vs 5.4 months, respectively). Rates of TRAEs of grade 3 or more were similar in both groups (47.0% vs 45.7%). AEs led to treatment discontinuation in 7.7% and 14.3% of patients treated with adagrasib and docetaxel, respectively.

References

1. Mitchell CL, Zhang AL, Bruno DS, Almeida FA. NSCLC in the era of targeted and immunotherapy: what every pulmonologist must know. Diagnostics (Basel). 2023;13(6):1117. doi:10.3390/diagnostics13061117
2. Aggarwal C, Marmarelis ME, Hwang WT, et al. Association between availability of molecular genotyping results and overall survival in patients with advanced nonsquamous non-small-cell lung cancer. JCO Precis Oncol. 2023;7:e2300191. doi:10.1200/PO.23.00191
3. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 10.2024. Accessed October 1, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
4. Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944-957. doi:10.1056/NEJMoa2002787
5. Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020;26(1):47-51. doi:10.1038/s41591-019-0716-8
6. Wolf J, Garon EB, Groen HJM, et al. Capmatinib in MET exon 14-mutated, advanced NSCLC: updated results from the GEOMETRY mono-1 study. J Clin Oncol. 2021;39(suppl 15):9020. doi:10.1200/JCO.2021.39.15_suppl.9020
7. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931-943. doi:10.1056/NEJMoa2004407
8. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC: primary analysis of the LUMINOSITY trial. J Clin Oncol. 2024;42(suppl 16):103. doi:10.1200/JCO.2024.42.16_suppl.103
9. Gautschi O, Milia J, Filleron T, et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol. 2017;35(13):1403-1410. doi:10.1200/JCO.2016.70.9352
10. Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23(8):1988-1997. doi:10.1158/1078-0432.CCR-16-1679
11. Drilon A, Subbiah V, Gautschi O, Tomasini P, Braud Fd, Solomon BJ. Selpercatinib in patients with RET fusion–positive non–small-cell lung cancer: updated safety and efficacy from the registrational LIBRETTO-001 phase I/II trial J Clin Oncol. 2022;385-394. doi:10.1200/JCO.22.00393
12. Zhou C, Solomon B, Loong HH, et al; LIBRETTO-431 Trial Investigators. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC. N Engl J Med. 2023;389(20):1839-1850. doi:10.1056/NEJMoa2309457
13. Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22(7):959-969. doi:10.1016/S1470-2045(21)00247-3
14. Griesinger F, Curigliano G, Thomas M, et al. Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial. Ann Oncol. 2022;33(11):1168-1178. doi: 10.1016/j.annonc.2022.08.002
15. Popat S, Felip E, Kim ES, et al. AcceleRET lung: a phase 3 study of first-line pralsetinib in patients with RET fusion–positive advanced/metastatic NSCLC. J Clin Oncol. 2022;40(suppl 16):TPS9159. doi:10.1200/JCO.2022.40.16_suppl.TPS9159
16. A study of selpercatinib after surgery or radiation in participants with non-small cell lung cancer (LIBRETTO-432). ClinicalTrials.gov. Updated June 16, 2024. Accessed October 1, 2024. https://clinicaltrials.gov/study/NCT04819100
17. A study of multiple therapies in biomarker-selected patients with resectable stages IB-III non-small cell lung cancer. ClinicalTrials.gov. Updated May 1, 2024. Accessed October 1, 2024. https://clinicaltrials.gov/study/NCT04302025
18. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381. doi:10.1056/NEJMoa2103695
19. de Langen AJ, Johnson ML, Mazieres J, et al; CodeBreak 200 Investigators. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401(10378):733-746. doi:10.1016/S0140-6736(23)00221-0
20. Janne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation. N Engl J Med. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619
21. Mok TSK, Yao W, Duruisseaux M, et al. KRYSTAL-12: phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. J Clin Oncol. 2024;42(suppl 17):LBA8509. doi:10.1200/JCO.2024.42.17_suppl.LBA8509

RELEASE DATE: November 1, 2024
EXPIRATION DATE: November 1, 2025

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better
prepared to:

•Apply molecular testing strategies effectively to identify targetable mutations in clinical practice

•Apply results of molecular profiling of NSCLC to individualized treatment plans for patients

•Implement practices to facilitate real-time updates and adjustments to treatment plans based on evolving biomarker status.

Acknowledgment of commercial support

This activity is supported by educational grants from Novartis Pharmaceuticals Corporation and Rigel Pharmaceuticals, Inc.

Off-label disclosure/disclaimer

This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.

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