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About This Activity

Activity Description and Learning Objectives

In this activity, experts in NSCLC discuss the latest developments in NSCLC with MET exon 14 skipping alterations.  This activity was recorded at the European Society for Medical Oncology (ESMO) Annual Meeting in Barcelona 27 September–1 October 2019.

This activity has been jointly provided by Oakstone and touchIME ONCOLOGY.  Oakstone Publishing is accredited by the ACCME to provide continuing medical education to physicians.

After watching this activity, participants should be able to:

Target Audience

This activity has been designed to meet the educational needs of oncologists, nurse specialists, pathologists and other allied healthcare professionals involved in the management of NSCLC.

Disclosures

Oakstone Publishing has assessed conflict of interest with its faculty, authors, editors, and any individuals who were in a position to control the content of this CME activity. Any identified relevant conflicts of interest were resolved for fair balance and scientific objectivity of studies utilized in this activity. Oakstone Publishing’s planners, content reviewers, and editorial staff disclose no relevant commercial interests.

Prof. David Planchard discloses Consultant/Advisory Board positions with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eli Lilly, MedImmune, Merck, Novartis, Peer CME, Pfizer, prIME Oncology and Roche.

Prof. Enriqueta Felip has disclosures from the following companies AbbVie, AstraZeneca, BerGenBio, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, priME Oncology, Roche, Samsung, Takeda and touchIME. She has been an independent Board member of Grifols and has received research funding from Fundación Merck Salud, Grant for Oncology Innovation EMD Serono.

Prof. Frank Griesinger has disclosures from the following companies: Abbvie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Lilly, Medac, Merck, MSD, Novartis, Pfizer, Roche and Takeda.

Content Reviewer

Walter Murray Yarbrough, MD has no financial interests/relationships or affiliations in relation to this activity.

Touch Medical Director

Martin Quinn has no financial interests/relationships or affiliations in relation to this activity.

Requirements for Successful Completion

Oakstone Publishing designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™️. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In order to receive credit for this activity, participants must review and complete the post-test and evaluation form. A score of 70% or higher is needed to obtain CME credit. Statements of credit are awarded upon successful completion of the post-test and evaluation form.

Date of original release: October 22, 2019. Date credits expire: October 22, 2020.

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Q1. Which of the following mutations should be routinely assessed in NSCLC?

  1. MET, T790M, ALK and ROS1 only
  2. EGFR, ALK and ROS1 only
  3. EGFR, ALK, ROS1 and BRAF V600
  4. EGFR, T790M, ALK, ROS1, BRAF V600 and MET
  5. None of the above

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According to current ESMO guidelines, testing for EGFR mutations and rearrangements involving the ALK and ROS1 genes are now considered mandatory in most European countries. BRAF V600E mutations are rapidly approaching this status as first-line BRAF/MEK inhibitors are more widely approved, while HER2 and MET exon 14 mutations and fusion genes involving RET and NTRK1 (neurotropic tropomyosin receptor kinase 1) are evolving targets/biomarkers. T790M should routinely be assessed on relapse.

Reference
Planchard D, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv192–iv237.

Q2. You request a liquid biopsy for a plasma sample for a patient with EGFR+ NSCLC who has experienced disease progression. The laboratory results identify a MET amplification. What should you do next?

  1. Prescribe therapy based on the liquid biopsy result
  2. Repeat the liquid biopsy for confirmation and then prescribe therapy
  3. Discuss with your pathologist and confirm via tissue biopsy if possible, before deciding on the next step
  4. The liquid biopsy result should not influence disease management and is for research purposes only

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Liquid biopsy is approved for initial EGFR T790M detection, so other uses should be confirmed where possible. Current ESMO guidelines recommend that patients with MET amplification are entered into appropriate clinical trials.

Reference
Planchard D, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv192–iv237.

Q3. IRC-verified ORRs for MET inhibitors in patients with advanced MET exon 14+ NSCLC from the VISION, GEOMETRY and PROFILE 1001 studies reveal response rates of up to 45% in pre-treated patients and up to 68% in first-line patients (reported up to August 2019). What duration of response would you expect for these MET inhibitors in this context?

  1. <1 month
  2. 3–6 months
  3. 9–15 months
  4. >24 months

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VISION1: ORR was 50.0% (patients identified by liquid biopsy; 95% CI: 35.2, 64.8) and 45.1% (patients identified by tissue biopsy; 95% CI: 31.1, 59.7) by IRC in patients with MET exon 14+ NSCLC. Median duration of response was 12.4 months (liquid biopsy; 95% CI: 5.8, not evaluable) and 15.7 months (tissue biopsy; 95% CI: 9.0, not evaluable).

GEOMETRY2: ORR by IRC was 40.6% (95% CI: 28.9, 53.1) in pre-treated patients and 67.9% (95% CI: 47.6, 84.1) in first-line; median DOR by IRC was 9.72 months (95% CI: 5.55, 12.98) in pre-treated patients and 11.14 months (95% CI: 5.55, not evaluable) in first-line patients.

PROFILE 10013<: Confirmed ORR was 32% (95% CI: 21, 45); median DOR was 9.1 months (95% CI: 6.4, 12.7).

References
1. Paik PK, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations. Presentation at 2019 ASCO Annual Meeting; abstract 9005.
2. Wolf J, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. Presentation at 2019 ASCO Annual Meeting; abstract 9004.
3. Drilon A, et al. Updated antitumor activity of crizotinib in patients with MET exon 14-altered advanced non-small cell lung cancer. J Thoracic Oncol. 2018;13(S348):abstract OA.12.02.

BIRC, blinded independent review committee; ctDNA, circulating tumour DNA; DOR; duration of response; IRC, independent review committee; ILBx, liquid biopsy; NSCLC, non-small cell lung cancer; ORR, overall response; PFS, progression-free survival; TBx, tissue biopsy.

Q4. What are the most common adverse events with tepotinb and capmatinib when given for MET exon 14-skipping-positive NSCLC in the VISION and GEOMETRY trials reported to date (August 2019)?

  1. Peripheral oedema + gastrointestinal events
  2. Gastrointestinal events + asthenia
  3. Neutropenia + fatigue
  4. Alopecia + skin rash
  5. Neutropenia + lymphopenia

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VISION1: Any grade TRAEs reported by ≥10% of 87 patients evaluable for safety were peripheral oedema (48.3%), nausea (23.0%), diarrhoea (20.7%) and increased blood creatinine (12.6%).

GEOMETRY2: Most common AEs (≥10% all grades) across all cohorts (n = 334), were peripheral oedema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), vomiting (18.9%), fatigue (13.8%), decreased appetite (12.6%) and diarrhoea (11.4%); the majority of AEs were Grade 1 or 2.

References
1. Paik PK, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations. Presentation at 2019 ASCO Annual Meeting; abstract 9005.
2. Wolf J, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer. (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. Presentation at 2019 ASCO Annual Meeting; abstract 9004.

AE, adverse events; TRAEs, treatment-related adverse events.

Q5. A 56-year-old male patient with EGFR+ L858R+ Stage IV lung adenocarcinoma, experiences a partial response with EGFR inhibitor therapy. After 2 years, the patient presents with recurrent EGFR+ L858R+ disease and tests negative for T790M, but positive for a MET exon 14-skipping mutation. How would you treat this patient?

  1. Monotherapy with a MET inhibitor
  2. Entry into an appropriate clinical trial
  3. Doublet chemotherapy
  4. Combination therapy with an EGFR inhibitor and a MET inhibitor
  5. Palliative care

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Two major MET variants may play a key role as NSCLC oncogenic drivers: MET exon 14 variants (METex14) and MET amplification. Current ESMO guidelines recommend that these patients are entered into clinical trials.

Reference
1. Planchard D, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv192–iv237.

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touchPANEL DISCUSSION

How is our understanding of treating MET exon 14 skipping mutations in NSCLC evolving?