Finding a Treatment Option for Patients with Non-small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations

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Sponsored by The Janssen Pharmaceutical Companies of Johnson & Johnson

Therapeutic Needs for Non-small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations

Each year, approximately 236,000 people in the US are newly diagnosed with lung cancer, which is responsible for 25 percent of cancer deaths in this country each year.1,2 Of the two main types of lung cancer—small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), 80 percent–85 percent of patients have NSCLC.3 Despite advances in treatment, particularly the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), the 5-year survival rate for NSCLC is about 26 percent.4,5

As with many other types of cancer, there are different mutation types for patients with NSCLC.6 EGFR is a receptor tyrosine kinase that, when activated, triggers multiple signaling pathways promoting cell survival, proliferation and migration.7 These three biological activities are each important for the development and proliferation of cancer cells.7

Exon 20 insertion mutations of the EGFR gene are the third most common EGFR mutation and occur in 9 percent–12 percent of all EGFR mutations.8,9 Patients newly diagnosed with advanced NSCLC with EGFR exon 20 insertion mutations are more likely to have a worse prognosis and shorter survival (16.2 months versus 25.5 months) according to real world data, compared with NSCLC driven by more common mutations, such as L858R point mutations in exon 21 or exon 19 deletions.10 The five-year survival rate for all EGFR-mutated metastatic NSCLC treated with EGFR TKIs is less than 20 percent.11

NSCLC with EGFR exon 20 insertion mutations are seen more frequently in people who do not smoke, women, and individuals of Asian descent.12 Although occurring in a minority of NSCLC patients, EGFR exon 20 insertion mutations represent a particular treatment challenge because these cancers respond poorly to most EGFR TKIs and are generally insensitive in treating NSCLC driven by EGFR exon 20 insertion mutations.13,14 There is a pressing need not only for treatments against EGFR exon 20 insertion mutated NSCLC, but also better strategies to identify patients who need these treatments.

EGFR exon 20 insertion mutations are a diverse group of mutations that are more reliably detected with next-generation sequencing (NGS).15 These mutations typically cause constitutive activity without exposing a drug-binding pocket; most EGFR TKIs cannot bind to the mutation and therefore have limited benefit in NSCLC with EGFR exon 20 insertion mutations.9,16,17,18,19,20

What is RYBREVANT® (amivantamab-vmjw)?

RYBREVANT® (amivantamab-vmjw), approved by the FDA in May 2021, is the first bispecific antibody approved for the treatment of adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.21 RYBREVANT® is a bispecific antibody that binds to the extracellular domains of EGFR and MET and disrupts EGFR and MET signaling functions through blocking ligand binding, and degradation of EGFR and MET and antibody-dependent cellular cytotoxicity and trogocytosis.21

RYBREVANT® is FDA-approved for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations based on positive results from the Phase 1 CHRYSALIS study (NCT02609776), a multicenter, open-label, clinical study evaluating RYBREVANT® as a monotherapy in patients who had progressed on or after platinum-based chemotherapy.21 In that study, the overall response rate to RYBREVANT® in patients with NSCLC with EGFR exon 20 insertion mutations was 40 percent (95 percent confidence interval (CI), 29 – 51), with 3.7 percent having complete responses and 36 percent achieving partial responses and a median duration of response of 11.1 months (95 percent CI, 6.9, NE).21

Identifying Patients for RYBREVANT®

Identifying the minority of NSCLC patients with EGFR exon 20 insertion mutations is important for providing them with the appropriate treatment.22 It is important to use the approved diagnostic test when screening patients for EGFR exon 20 insertion mutations. PCR test methods are projected to miss 50 percent of the EGFR exon 20 insertion mutations as compared with NGS test methods, therefore, PCR tests will not detect most EGFR exon 20 insertion mutations.15

Through the use of testing techniques that detect a broader range of mutations—either liquid or tissue NGS—and careful examination of biomarker test results, patients can better understand the full picture of treatment options for EGFR-positive NSCLC.8,23,24 Black and Asian individuals are at higher risk for lung cancer, but early diagnosis, biomarker testing and advanced treatment statistics are substantially lower compared to patients who are non-Hispanic Whites—leading to poorer outcomes.25,26 Black, Asian American, Latinx, and Native American populations are all less likely than White Americans to be diagnosed early and more likely to not receive any treatment.25

“Genetic testing of lung cancer, using either a tissue or liquid biopsy, is an incredibly important step in the diagnostic work-up for someone living with non-small cell lung cancer and may result in identifying a specific mutation that is amenable to treatment with a targeted therapy,” said Denise D’Andrea, MD, FACP, Therapeutic Area Lead, Solid Tumor Targeted Therapies at The Janssen Pharmaceutical Companies of Johnson & Johnson. “For example, patients with EGFR exon 20 insertion mutation-driven non-small cell lung cancer are seeing poorer outcomes than those with more common EGFR mutations. Next-Generation Sequencing could help these patients more precisely identify their specific mutation. Once testing rates go up, it dramatically increases our ability as researchers to push further with the investigation and development of targeted treatments.”

As with any cancer, understanding of the biology of NSCLC and how to identify the appropriate treatment for each patient is evolving. RYBREVANT® is an option for NSCLC treatment for patients with EGFR exon 20 insertion mutations and is FDA-approved with both liquid biopsy blood and tissue-based tests.21,27,28

INDICATION

RYBREVANT® (amivantamab-vmjw) is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum based chemotherapy.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

RYBREVANT® can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.

Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT®. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion.

The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT® due to IRR.

Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT® as recommended. Administer RYBREVANT® via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT® infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT® based on severity.

Interstitial Lung Disease/Pneumonitis

RYBREVANT® can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT®, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT® due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT® in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Dermatologic Adverse Reactions

RYBREVANT® can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT®, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT® was permanently discontinued due to rash in 0.7% of patients.

Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT®.

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT®. Advise patients to wear protective clothing and use broad spectrum UVA/UVB sunscreen. Alcohol-free emollient cream is recommended for dry skin.

If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT® based on severity.

Ocular Toxicity

RYBREVANT® can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT®. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT® based on severity.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal models, RYBREVANT® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT®.

Adverse Reactions

The most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma‑glutamyl transferase (4%), and decreased sodium (4%).

Please read full Prescribing Information for RYBREVANT®.

References

  1. Lung Cancer Statistics. How Common is Lung Cancer? Accessed January 19, 2022. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html
  2. Cancer of the Lung and Bronchus - Cancer Stat Facts. SEER. Accessed January 19, 2022. https://seer.cancer.gov/statfacts/html/lungb.html
  3. American Cancer Society. What is Lung Cancer? Accessed January 19, 2022. https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html
  4. O’Leary C, Epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Pharmaceuticals. 2020, 13, 273; doi:10.3390/ph13100273/
  5. Lung Cancer Survival Rates. 5-Year Survival Rates for Lung Cancer. Accessed January 19, 2022. https://www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/survival-rates.html
  6. Carper M, et al. Clinical potential of gene mutations in lung cancer. Clin Transl Med. 2015; 4:33.
  7. Vyse S. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther. Published online 2019:10.
  8. Riess JW, Gandara DR, Frampton GM, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol. 2018;13(10):1560-1568. doi:10.1016/j.jtho.2018.06.019
  9. Arcila M, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013; Feb; 12(2):220-9.
  10. Bazhenova L, Minchom A, Viteri S, et al. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung Cancer. 2021;162:154-161. doi:10.1016/j.lungcan.2021.10.020
  11. Lin JJ, Cardarella S, Lydon CA, Dahlberg SE, Jackman DM, Jänne PA, et al. Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs. J Thorac Oncol. 2016 Apr;11(4):556-65.
  12. Wang F, et al. EGFR exon 20 insertion mutations in non-small cell lung cancer. Transl Cancer Res. 2020; 9:14.
  13. Baraibar I, et al. Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC. Crit Rev Onc. 2020.
  14. Remon J, et al. EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treatment Rev. 90 (2020).
  15. Bauml JM, Viteri S, Minchom A, et al. Underdiagnosis of EGFR exon 20 insertion mutation variants: Estimates from NGS-based real-world datasets. J Thorac Oncol. 2021 Mar;16(3):S208-S209.
  16. Robichaux JP, Elamin YY, Tan Z, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med. 2018;24(5):638-646.
  17. Yasuda H, Park E, Yun CH, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer [published correction appears in Sci Transl Med. 2014 Feb 26;6(225):225er1]. Sci Transl Med. 2013;5(216):216ra177
  18. Oxnard GR, Lo PC, Nishino M, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2013;8(2):179-184.
  19. Naidoo J, Sima C, Rodriguez K, et al. Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib. Cancer. 2015;121(18):3212-3220.
  20. Chen D, Song Z, Cheng G. Clinical efficacy of first-generation EGFR-TKIs in patients with advanced non-small-cell lung cancer harboring EGFR exon 20 mutations. Onco Targets Ther. 2016;9:4181-4186.
  21. RYBREVANT®. U.S. Prescribing Information.
  22. Burnett H, Emich H, Carroll C, Stapleton N, Mahadevia P, Li T. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore.
  23. Pennell et al. Biomarker testing for patients with advanced non small cell lung cancer: Real world issues and tough choices. Am Soc Clin Oncol Educ Book. 2019;39(39):531-542.
  24. Del Re M, Crucitta S, Gianfilippo G, et al. Understanding the mechanisms of resistance in EGFR positive NSCLC: from tissue to liquid biopsy to guide treatment strategy. Int J Mol Sci. 2019;20(16):3951.
  25. Stein et al. Sociodemographic disparities in the management of advanced lung cancer: a narrative review. J Thorac Dis. 2021;13(6):3772-3800.
  26. Bruno S, et al. Racial disparities in biomarker testing and clinical trial enrollment in non-small cell lung cancer (NSCLC). J of Clinc Oncol. 2021;39(15):9005
  27. Thermo Fisher Scientific. FDA approves NGS-based companion diagnostic for EGFR exon 20 insertion mutant non-small cell lung cancer tumor tissue. Accessed April 1, 2022. https://corporate.thermofisher.com/content/tfcorpsite/us/en/index/newsroom/press-releases/2021/ Dec/09-FDA-Approves-NGS-Based-Companion-Diagnostic-for-EGFR-Exon20-Insertion-Mutant-Non-Small-Cell-Lung-Cancer-Tumor-Tissue.html
  28. Guardant Health. Guardant360® CDx Receives FDA Approval as Companion Diagnostic for Janssen’s RYBREVANT™ (amivantamab-vmjw) for Use in Patients with Advanced Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. Accessed April 2022. https://investors.guardanthealth.com/press-releases/press-releases/2021/Guardant360-CDx-Receives-FDA-Approval-as-Companion-Diagnostic-for-Janssens-RYBREVANT-amivantamab-vmjw-for-Use-in-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer-with-EGFR-Exon-20-Insertion-Mutations/default.aspx