Refining Biomarker Testing and Targeted Treatment of NSCLC With Common and Uncommon EGFR Mutations
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Chair, Natasha B. Leighl, MD, MMSc, FRCPC, FASCO, Zofia Piotrowska, MD, and Catherine Shu, MD, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “Refining Biomarker Testing and Targeted Treatment of NSCLC With Common and Uncommon EGFR Mutations.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3OAddvR. CME/MOC credit will be available until October 24, 2023.
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Refining Biomarker Testing and Targeted Treatment of NSCLC With Common and Uncommon EGFR Mutations
- 1. NSCLC Treatment Algorithm1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/RJV40 NSCLC treatment algorithm Stage and workup based on stage • cT1abc, N0: PFT, bronch, mediastinal staging, PET • cT2a-4, N0-3, M0-1: PFT, bronch, mediastinal staging, PET, brain MRI, and biomarker/mutation testing Stage IA Surgical candidate? Lobectomy (preferred) or Segmentectomy/wedge resection (in select cases) SBRT or conventionally fractionated RT Surgical resection Consider mutation and PD-L1 testing results EGFR ex19del/ex21 L858R present? Surgical resection T1 N0 M0 Operable disease Yes Yes Yes No (PD-L1 1%) No No Multidisciplinary discussion for neoadjuvant candidacy Stage IB-IIIA (resectable) Mutation (minimum EGFR; broad NGS if possible) and PD-L1 testing T1–2, N1–2, M0 T3–4, N0–1, M0 Neoadjuvant chemoimmunotherapy Nivolumab + platinum-based chemotherapy x 3 cycles CheckMate -816: Nivo + chemo vs chemo mEFS: 31.6 vs 20.8 mo (HR, 0.63) Adjuvant chemotherapy Platinum-based chemotherapy LACE Meta-analysis: 5-y OS improvement of 5.4% vs no chemo Adjuvant chemotherapy (Stage II-IIIA) Atezolizumab x 16 cycles IMpower010: Atezo vs BSC mDFS: NR vs 35.3 mo (HR, 0.66) Adjuvant targeted therapy Osimertinib x 3 y ADAURA: Osimertinib vs placebo 2-y DFS (stage II-IIIA): 90% vs 44% (HR, 0.17)
- 2. NSCLC Treatment Algorithm1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/RJV40 Stage IIIA (unresectable) or IIIB/C Definitive chemoradiation → durvalumab Concurrent platinum-based chemotherapy and radiation with consolidation durvalumab PACIFIC: Durvalumab vs placebo mPFS: 16.8 vs 5.6 mo (HR, 0.52) BRAF V600E Dabrafenib + Trametiniba BRF113928: Dabrafenib + trametinib single arm ORR: 64% (95% CI, 46–79) 2nd line: KRAS G12C Sotorasib CodeBreaK100: Sotorasib single arm ORR: 37.1% (95% CI, 29-46); mPFS: 6.8 mo ALK Alectiniba ALEX: Alectinib vs crizotinib 1-y PFS: 68.4% vs 48.7% (HR, 0.47) Brigatiniba ALTA-1L: Brigatinib vs crizotinib mPFS: 24 vs 11.1 mo (HR, 0.48) Lorlatiniba CROWN: Lorlatinib vs crizotinib mPFS: NR vs 9.3 mo (HR, 0.28); 1-y PFS: 78% vs 39% Ceritinib ASCEND-4: Ceritinib vs chemo mPFS: 16.6 vs 8.1 mo (HR, 0.55) Crizotinib PROFILE 1007: Crizotinib vs chemo mPFS: 7.7 vs 3 mo (HR, 0.49) NTRK Larotrecteniba Entrectiniba ALKA/STARTRK: Entrectinib single arm ORR: 70% (NSCLC) RET Selpercatiniba LIBRETTO-001: Selpercatinib single arm ORR: 64%; mDOR: 17.5 mo Pralsetiniba ARROW: Pralsetinib single arm ORR: 61% (95% CI, 50–71) 2nd line: EGFR (ex20) Amivantamab CHRYSALIS: Amivantamab single arm CBR: 74% (95% CI, 63-83); mPFS: 8.3 mo Mobocertinib AP32788-15-101: Mobocertinib single arm DCR: 78% (95% CI, 69-85); mPFS: 7.3 mo HER2 Trastuzumab deruxtecan DESTINY-Lung02: Trastuzumab deruxtecan dose optimization study ORR: 58% (95% CI, 43-71); mDOR: 8.7 mo (efficacy results of the approved recommended dose of 5.4 mg/kg) ROS1 Crizotiniba PROFILE 1001: Crizotinib single arm ORR: 72% (95% CI, 58–84) Entrectiniba ALKA STARTRK: Entrectinib single arm ORR: 67.1%; mPFS: 19 mo Ceritinib YONSEI: Ceritinib single arm ORR: 67% (95% CI, 48–81) EGFR (ex19 del or L858R) Osimertiniba FLAURA: Osimertinib vs erlotinib/gefitinib mPFS: 18.9 vs 10.2 mo (HR, 0.46) Erlotinib EURTAC: Erlotinib vs chemo mPFS: 9.7 vs 5.2 mo (HR, 0.37) Afatinib LUX-Lung 3: Afatinib vs cis/pemetrexed mPFS: 13.6 vs 6.9 mo (HR, 0.47) Gefitinib IFUM: Gefitinib single arm mPFS: 9.7 mo Dacomitinib ARCHER 1050: Dacomitinib vs geftinib mOS: 34.1 vs 27 mo (HR, 0.75) Erlotinib + ramucirumab RELAY: Erlotinib + ramucirumab vs elotinib mPFS: 19.4 vs 12.4 mo (HR, 0.59) Erlotinib + bevacizumab ARTEMIS-CTONG1509: Erlotinib + bevacizumab vs erlotinib mPFS: 17.9 vs 11.2 mo (HR, 0.55) MET (ex14) Capmatiniba GEOMETRY mono-1: Capmatinib single arm mPFS: 12.4 mo Tepotiniba VISION: Tepotinib single arm mPFS: 8.5–11 mo T1-2, N2–3, M0 T3, N1–3, M0 T4, N0–3, M0 Stage IV Tx Nx M1 Actionable mutation detected NSCLC treatment algorithm Stage and workup based on stage • cT1abc, N0: PFT, bronch, mediastinal staging, PET • cT2a-4, N0-3, M0-1: PFT, bronch, mediastinal staging, PET, brain MRI, and biomarker/mutation testing Please see the next page for recommendations if no actionable mutation is detected • EGFR (ex19, ex20ins) • ALK • ROS1 • BRAF V600E • RET • MET (ex14) • NTRK1/2/3 • KRAS G12C • HER2 Mutation (minimum EGFR; broad NGS if possible) and PD-L1 testing
- 3. NSCLC Treatment Algorithm1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/RJV40 a Denotes NCCN-preferred regimens. 1. Created by Aakash Desai, MBBS, MPH, and Matthew Ho, MD, PhD. Used with permission from the authors. PD-L1 1% IMMUNOTHERAPY + CHEMOTHERAPY SQUAMOUS: • Pembrolizumab + chemotherapya (carboplatin + paclitaxel/nab-paclitaxel) KEYNOTE-407: Pembro + chemo vs chemo mPFS: 6.4 vs 4.8 mo (HR, 0.56); mOS: 15.9 vs 11.3 mo (HR, 0.64) NONSQUAMOUS: • Pembrolizumab + chemotherapy (carboplatin + pemetrexed)a KEYNOTE-189: Pembro + chemo vs chemo mPFS: 8.8 vs 4.9 mo (HR, 0.52), 12-mo; OS: 69% vs 49% (HR, 0.49) • Atezolizumab + chemotherapy (carboplatin + paclitaxel + bevacizumab) IMpower150: Atezo + chemo vs chemo mPFS: 8.3 vs 6.8 mo (HR, 0.62) DUAL IMMUNOTHERAPY + CHEMOTHERAPY Nivolumab + ipilimumab + chemo (2 cycles) CheckMate -9LA: Nivo/ipi + chemo vs chemo mOS: 14.1 vs 10.7 mo DUAL IMMUNOTHERAPY Nivolumab + ipilimumab CheckMate -227: Nivo/ipi vs chemo mOS: 17.1 vs 14.9 mo DUAL IMMUNOTHERAPY + CHEMOTHERAPY Nivolumab + ipilimumab + chemo (2 cycles) CheckMate -9LA: Nivo/ipi + chemo vs chemo mOS: 14.1 vs 10.7 mo IMMUNOTHERAPY MONOTHERAPY Pembrolizumab KEYNOTE-042: Pembro vs plat-based chemo mOS: 16.7 vs 12.1 mo (HR, 0.81) PD-L1 1%-49% IMMUNOTHERAPY + CHEMOTHERAPY SQUAMOUS: • Pembrolizumab + chemotherapya (carboplatin + paclitaxel/nab-paclitaxel) KEYNOTE-407: Pembro + chemo vs chemo mPFS: 6.4 vs 4.8 mo (HR, 0.56); mOS: 15.9 vs 11.3 mo (HR, 0.64) NONSQUAMOUS: • Pembrolizumab + chemotherapy (carboplatin + pemetrexed)a KEYNOTE-189: Pembro + chemo vs chemo mPFS: 8.8 vs 4.9 mo (HR, 0.52); 12-mo OS: 69% vs 49% (HR, 0.49) • Atezolizumab + chemotherapy (carboplatin + paclitaxel + bevacizumab) IMpower150 : Atezo + chemo vs chemo mPFS: 8.3 vs 6.8 mo (HR, 0.62) DUAL IMMUNOTHERAPY Nivolumab + ipilimumab CheckMate -227: Nivo/ipi vs chemo mOS: 17.1 vs 14.9 mo DUAL IMMUNOTHERAPY + CHEMOTHERAPY Nivolumab + ipilimumab + chemo (2 cycles) CheckMate -9LA: Nivo/ipi + chemo vs chemo OS: 14.1 vs 10.7 mo PD-L1 50% IMMUNOTHERAPY MONOTHERAPY Pembrolizumaba KEYNOTE-024: Pembro vs platinum-based chemo mPFS: 10.3 vs 6 mo (HR, 0.50) Atezolizumaba IMpower110: Atezo vs platinum-based chemo mOS: 20.1 vs 13.1 mo (HR, 0.59) Cemiplimaba EMPOWER-Lung1: Cemi vs platinum-based chemo mPFS: 8.2 vs 5.7 mo; mOS: NR vs 14.2 mo (HR, 0.57) IMMUNOTHERAPY + CHEMOTHERAPY SQUAMOUS: • Pembrolizumab + chemotherapya (carboplatin + paclitaxel/nab-paclitaxel) KEYNOTE-407: Pembro + chemo vs chemo mPFS: 6.4 vs 4.8 mo (HR, 0.56); mOS: 15.9 vs 11.3 mo (HR, 0.64) NONSQUAMOUS: • Pembrolizumab + chemotherapya (carboplatin + pemetrexed) KEYNOTE-189: Pembro + chemo vs chemo mPFS: 8.8 vs 4.9 mo (HR, 0.52); 12-mo OS: 69% vs 49% (HR, 0.49) • Atezolizumab + chemotherapy (carboplatin + paclitaxel + bevacizumab) IMpower150: Atezo + chemo vs chemo mPFS: 8.3 vs 6.8 mo (HR, 0.62) No actionable mutation detected (stratify based on PD-L1 staining %)
- 4. Therapies for EGFR-Mutated NSCLC Current Approvals and Indications1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/RJV40 1. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. Third-Generation Irreversible EGFR TKI Osimertinib Metastatic Early Stage Third-Generation Irreversible EGFR TKI Osimertinib • 1L for EGFR exon 19 deletions or L858R mutations • Treatment of T790M-positive NSCLC with progression on or after EGFR TKI therapy EGFR/MET Bispecific Antibody Amivantamab • 2L for EGFR exon 20 insertion mutations in patients whose disease has progressed on or after platinum-based chemotherapy Irreversible EGFR/HER2 (Exon 20 Insertion) TKI Mobocertinib • 2L for EGFR exon 20 insertion mutations in patients whose disease has progressed on or after platinum-based chemotherapy EGFR TKI + VEGFR2 Antagonist Erlotinib + Ramucirumab • 1L for EGFR exon 19 deletions or L858R mutations • Adjuvant therapy after tumor resection in patients with stage IB-IIIA NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations First-Generation Reversible EGFR TKIs Gefitinib Erlotinib • 1L for EGFR exon 19 deletions or L858R mutations • 1L for EGFR exon 19 deletions or L858R mutations Second-Generation Irreversible EGFR TKIs Afatinib Dacomitinib • 1L for EGFR exon 19 deletions or L858R, S768I, L861Q, and/or G719X mutations • 1L for EGFR exon 19 deletions or L858R mutations
- 5. The New Role of EGFR Exon 20 Insertions in NSCLC Full abbreviations, accreditation, and disclosure information available at PeerView.com/RJV40 Impact of Deletions and Insertions on EGFR Activation1,2 Incidence of EGFR Exon 20 Insertions in NSCLC1-3 • EGFR exon 20 insertion mutations represent the third most common EGFR mutation in NSCLC1 • First- and second-generation EGFR TKIs have limited efficacy in patients with NSCLC harboring EGFR exon 20 insertions1 • Advances with EGFR TKIs and bispecific antibodies have established a new standard of care in NSCLC for patients with EGFR exon 20 insertions1 WT EGFR WT EGFR Exon 19 Deletion Exon 20 Insertion Deletions Insertions “C-helix in” “C-helix out” Inactive Active Active Active β3 β3 β3 β4 β4 β4 β3 β4 • Insertions: 6% • S768I: 1% • T790M (de novo): 5% EGFR 1.7% D761-E762 insX “Classical” EGFR mutations Exon 19 deletions L858R Extracellular domain Trans- membrane domain Tyrosine kinase domain I/II III/IV Exon 18 Exon 19 Exon 20 Exon 21 Exon 22 Exon 23 Exon 20 insertions C-helix Loop following C-helix 762 E 763 A 764 Y 765 V 766 M 767 A 768 S 769 V 770 D 771 N 772 P 773 H 774 V 775 C A763-Y764 insX Y764-V765 insX V765-M766 insX A767-S768 insX S768-V769 insX V769-D770 insX D770 N771 insX N771-P772 insX P772-H773 insX H773-V774 insX V774-C775 insX 4.6% 0.3% 0.3% 1.4% 0.9% 5.4% 8.3% 22.6% 4.3% Percentage of Total Exon 20 EGFR Insertions (n = 349) 761 D 24.6% 25.5% • 4%-10% of all EGFR-mutant NSCLC - This could be limited by testing type • First/second-generation EGFR TKIs have limited activity - Erlotinib/gefitinib: mPFS, 1.5-2 mo - Afatinib: mPFS, 2.9 mo • Worse prognosis than other types of EGFR-mutant NSCLC Exon 18 3% Exon 19 45% Exon 21 42% Exon 20 10%
- 6. The New Role of EGFR Exon 20 Insertions in NSCLC Full abbreviations, accreditation, and disclosure information available at PeerView.com/RJV40 Current and Emerging Treatment Strategies for NSCLC With EGFR Exon 20 Insertions1 Amivantamab Osimertinib Mobocertinib Tarloxotinib Poziotinib CLN-081a EGFR/MET bispecific antibody FDA approved Third-generation EGFR TKI EGFR/HER2 exon 20ins TKI EGFR/HER2/HER4 TKI Pan-EGFR-mutation TKI Hypoxia-activated EGFR TKI C-lobe Exon 20 insertions Exon 19 deletions Gly719 A-loop Leu858 Leu861 N-lobe EGFR FDA approved a Other name: TAS6417. 1. Remon J et al. Cancer Treat Rev. 2020;90:102105. 2. Vyse S, Huang PH. Signal Transduct Target Ther. 2019;4:5. 3. Le X et al. 2020 American Association for Cancer Research Annual Meeting (AACR 2020). Abstract CT081.