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MARIPOSA SPOTLIGHT EV-302 NATALEE

MARIPOSA: amivantamab plus lazertinib for the treatment of advanced EGFR mutant NSCLC

 

With lung cancer the most diagnosed cancer globally, and non-small cell lung cancer (NSCLC) representing approximately 75% of these cases1, it is essential to address populations of unmet clinical need. The most prevalent actionable driver mutations are those activating epidermal growth factor receptor (EGFR)2, which regulates proliferation signaling pathways. Sustained EGFR activation is thought to drive more aggressive tumor phenotypes and, in lung cancer, is characterized by a significant response to tyrosine kinase inhibitors (TKIs)1. The current first-line treatment is monotherapy with the TKI osimertinib, approved by the American Food and Drug Administration (FDA) in 2018 following the results of the FLAURA trial (NCT02296125)3.

Primary results from the Phase III global, randomized MARIPOSA trial (NCT04487080) on amivantamab plus lazertinib versus osimertinib for the treatment of patients with EGFR-mutated

 

advanced NSCLC were presented at the European Society for Medical Oncology (ESMO) 2023 Congress. Amivantamab is a novel, bispecific monoclonal antibody that targets the extracellular domains of both EGFR and mesenchymal-epithelial transition (MET) receptors, which can drive tumor growth2. It is traditionally administered when platinum-based therapies have been ineffective4. Its pairing with CNS-penetrant lazertinib is apt as this TKI selectively targets the T790M and activating Ex19del and L858R EGFR mutations, sparing wild-type-EGFR. Lazertinib saw its first approval for second-line NSCLC treatment in January 20215.

1074 patients were randomized to receive amivantamab with lazertinib, osimertinib, or lazertinib alone. With endpoints determined through a blinded independent central review, the primary endpoint of mean progression-free survival (PFS) was 23.7 months, compared to 16.6 months in the osimertinib cohort, resulting in a statistically significant 30% reduction in progression or death (HR, 0.70; 95% CI, P<0.001). Secondary endpoints included overall survival and depth of response and, although this data is still interim, it shows favorable results for amivantamab plus lazertinib. Generally mild and manageable side-effects consistent with previous trials were additionally reported6.

These results have changed the trajectory of NSCLC treatment, providing new opportunities for first-line therapy in patients with EGFR-mutant NSCLC. Following the success of this trial, amivantamab plus lazertinib treatment of osimertinib-relapsed EGFR-mutant advanced NSCLC Phase II doses have been determined, for which there is currently no approved targeted treatment7.

SPOTLIGHT: targeted immunotherapy for advanced HER2-negative gastrointestinal cancers

 

Following on from lung cancers, gastric cancer is the third leading cause of death worldwide, with increasing prevalence. Having a greater risk of peritoneal metastasis, advanced gastric cancers represent a patient population of unmet need8, which is further emphasized in human epidermal growth factor (HER) 2 negative cases, where patients are ineligible for immunotherapies that target the proliferation-regulator9. Gastric and gastroesophageal junction (GEJ) tumors express a unique set of tight-junction proteins called claudin 18 isoform 2 (claudin 18.2)10, identifying a potential target for their treatment; the Phase III SPOTLIGHT trial (NCT03504397) has tested this in patients with HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinomas11.

5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is a current treatment option for HER2-negative gastric and GEJ adenocarcinomas, but this fails to selectively target tumor cells. The SPOTLIGHT trial tested the claudin18.2 antibody zolbetuximab (which binds the protein and mediates cell death through antibody and complement-dependent cytotoxicity12) in conjunction with mFOLFOX6.Findings from the trial, which were presented at American Society of Clinical Oncology (ASCO) 2023 Gastrointestinal Cancers (GI) Symposium, saw a significant increase in overall (HR 0.75, 95% CI 0.60–0.94; p=0.0053) and progression-free survival (95% CI 8.90–12.48; 8.21–10.28). However, there was a significant increase in treatment-related adverse events (TRAEs) with 87% of the patients experiencing grade 3 or above side effects (compared to 78% with mFOLFOX6 monotherapy)

 

which were mainly nausea. Doctors believe that these may be mitigated by dose adjustment, as they were most prevalent at high treatment cycles11.

Its side effects notwithstanding, zolbetuximab presents a promising option for targeted therapy in HER2-negative, locally advanced gastric and GEJ adenocarcinomas, and with refined dosage, is likely to change the clinical approaches to these malignancies and improve patient outcomes and attitudes towards these specific forms of the disease. This trial also highlights the need and begins the search for stomach cancer biomarkers aside from HER2.

EV-302: FDA approves enfortumab vedotin for metastatic or locally advanced bladder cancer

 

Bladder cancer is the most common neoplasm of the urinary system13, with urothelial carcinomas representing almost all cases14. Platinum-based chemotherapy is the standard of care for most cases following any possible surgical intervention. However, long-term outcomes remain poor, with the 5-year overall survival statistics sitting at just 20% once metastasis to the perivesical fat has occurred13, meaning patients represent a large population of unmet need15.

The global, randomized Phase III EV-302 (NCT04223856) study assessed enfortumab vedotin and pembrolizumab versus standard chemotherapy in patients with untreated advanced/metastatic urothelial cancer who were eligible for cisplatin- or carboplatin- containing chemotherapy. Enfortumab vedotin is an antibody-drug conjugate that inserts the antimitotic agent monomethyl auristatin E

 

(MMAE) into tumor cells, disrupting their cytoskeleton and selectively killing the cancer cells16, whereas pembrolizumab (whose success is notable in several other emerging cancer treatments17,18,19) is an anti-PD-1 immunotherapy20. Findings from the trial were presented at the ESMO 2023 Congress.

Over approximately 3 years, enfortumab vedotin and pembrolizumab significantly prolonged progression-free (median PFS, 12.5 mo vs 6.3 mo, respectively; HR 0.45 [95% CI: 0.38-0.54]; P<0.00001) and overall (median OS, 31.5 mo vs 16.1 mo, respectively; HR 0.47 [95% CI: 0.38-0.58]; P<0.0000) survival, reducing the risk of death by a skyrocketing 53%. The confirmed overall response rate in the enfortumab vedotin and pembrolizumab  arm was 67.7%, compared to just 44.4% in the chemotherapy arm. In addition to these substantial efficacy results, EV+P treatment was associated with fewer grade 3 and above TRAEs than chemotherapy (occurring in 55.9% and 69.5% of recipients respectively15). This data represents enfortumab vedotin and pembrolizumab as a more effective, safer and overall preferred therapeutic intervention compared to traditional platinum chemotherapy for the treatment of advanced urothelial cancer.

Following the overwhelming success of this trial, the FDA approved EV+P therapy on December 15th 2023 for second-line intervention in locally advanced or metastatic urothelial cancer21; the trial is now entering its fourth and final stage. The EV-302 trial has reshaped the course of genitourinary cancer treatment and clinical practice and is predicted to have further positive influence in other, wider areas of cancer treatment in the near future.

NATALEE: ribociclib plus endocrine therapy for the first-line treatment of early breast cancers

 

Finally, breakthroughs in breast cancer this year included the Phase III NATALEE trial (NCT03701334). With an unmet need for patients who are HER2-negative and therefore do not respond well to drugs targeting the infamous HER2 protein, there is a call for more standard-of-care treatment options. Previous studies22 have shown the targeted cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib to be effective in treating postmenopausal women with metastatic breast cancers, resulting in its FDA approval in 201823. CDKs’ cell-cycle regulation means that, when overexpressed, CDKs can stimulate cell proliferation, aiding tumor growth. Thus, in patients with high CDK 4/6 expression, inhibiting the action of these proteins can slow disease progression by retarding this tumor growth24,25. However, the standard of care for early breast cancer (EBC) remains endocrine therapy alone, NATALEE demonstrated that adding ribociclib to endocrine therapy as adjuvant treatment improved survival outcomes across a wide range of patients with EBC.

In this trial, whose primary results were presented at the ASCO 2023 Annual Congress, pre- and post-menopausal men and women with stage II or III HR-positive /HER2-negative EBC were treated either with ribociclib and endocrine therapy  or standard endocrine therapy monotherapy. The study’s primary endpoint was invasive disease-free survival (iDFS), which was significantly higher in the ribociclib and endocrine therapy versus endocrine therapy arms (HR, 0.748; 95% CI, 0.618-0.906; P = .0014), with the 3-year iDFS rates sitting at 90.4% and 87.1% respectively. Secondary endpoints of overall, recurrence-free and distant disease-free survival also consistently favored the addition of RIB26.

 

With clinically meaningful results across all patient strata, NATALEE has rendered RIB effective at not only treating metastatic breast cancer in post-menopausal women but also wide ranges and stages of breast cancer in varied patient cohorts. This presents ribociclib and endocrine therapy as a promising new standard of care in HR-positive/HER2-negative EBC, and with no new safety concerns, a forthcoming expansion of the FDA’s approval of ribociclib is highly anticipated.

It’s been a successful year for developments in oncology, from conferences such as ESMO and ASCO collating the collective knowledge and innovation from leading experts in each and every field. With many novel drug agents, diagnostic methods and not to mention the rise in artificial intelligence and emerging roles in clinical settings we look forward to seeing what 2024 will bring…

References

  1. Bethune G, Bethune D, Ridgway N, Xu Z. Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. Journal of thoracic disease. 2010;2(1):48–51.
  2. ClinicalTrials.gov [Internet]. Bethesda (MD). National Library of Medicine (US). 2000. Identifier: NCT04487080. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). 2023 [Cited 2023 Dec 19]; Available from: https://www.clinicaltrials.gov/study/NCT04487080?term=NCT04487080&rank=1.
  3. NCI Staff. Osimertinib in Advanced Lung Cancer with EGFR Mutations [Internet]. National Cancer Institute. Cancer.gov; 2019 [cited 2023 Dec 19]. Available from: https://www.cancer.gov/news-events/cancer-currents-blog/2019/osimertinib-lung-cancer-improves-survival-flaura.
  4. European Medicines Agency. Rybrevant | amivantamab [Internet]. Europa.eu. European Union Agencies Network; 2022 [cited 2023 Dec 19]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/rybrevant.
  5. Dhillon S. Lazertinib: First Approval. Drugs [Internet]. 2021 May 24 [cited 2023 Dec 19];81(9):1107–13. Available from: https://pubmed.ncbi.nlm.nih.gov/34028784/.
  6. Cho BC, Felip E, Spira AI, Girard N, Js L, Sh L, et al. LBA14 Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Annals of Oncology. 2023 Oct 1;34:S1306–6.
  7. Cho BC, Kim D, Spira AI, Gomez J, Haura EB, Kim S, et al. Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial. Nature Medicine. 2023 Sep 14;29(10):2577–85.
  8. Osumi H, Takahari D, Chìn K, Ogura M, Ichimura T, Wakatsuki T, et al. Modified FOLFOX6 as a first-line treatment for patients with advanced gastric cancer with massive ascites or inadequate oral intake. OncoTargets and Therapy. 2018 Nov 1;Volume 11:8301–7.
  9. Lordick F, Al‐Batran SE, Dietel M, Gaiser T, Hofheinz R, Kirchner T, et al. HER2 testing in gastric cancer: results of a German expert meeting. Journal of Cancer Research and Clinical Oncology. 2017 Mar 11; 143(5):835–41.
  10. ClinicalTrials.gov [Internet]. Bethesda (MD). National Library of Medicine (US). 2000. Identifier: NCT03504397. A Phase 3 Efficacy, Safety and Tolerability Study of Zolbetuximab (Experimental Drug) Plus mFOLFOX6 Chemotherapy Compared to Placebo Plus mFOLFOX6 as Treatment for Gastric and Gastroesophageal Junction (GEJ) Cancer (Spotlight). 2023 [Cited 2023 Dec 19]; Available from: https://clinicaltrials.gov/study/NCT03504397.
  11. Shitara K, Lordick F, Bang Y, Enzinger PC, Ilson DH, Shah MA, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. The Lancet. 2023 May 1;401(10389):1655–68.
  12. Sclafani F, Fontana E, Wyrwicz L, Wagner AD, Valle JW, Smyth E, et al. Highlights from the 2022 ASCO gastrointestinal cancer symposium: An overview by the EORTC gastrointestinal tract cancer group. Clinical Colorectal Cancer. 2022 Sep;21(3):188–97.
  13. Kaseb H, Aaddula NR. Bladder Cancer. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536923/.
  14. National Cancer Institute. What Is Bladder Cancer? [Internet]. National Cancer Institute. National Institutes of Health; 2023 [cited 2023 Dec 19]. Available from: https://www.cancer.gov/types/bladder.
  15. Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits JH, et al. LBA6 EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Annals of Oncology. 2023 Oct 1;34:S1340–0.
  16. European Medicines Agency. Padcev | European Medicines Agency [Internet]. Europa.eu. European Union Agencies Network; 2022 [cited 2023 Dec 19]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/padcev.
  17. Cunningham J, Drake K. Merck to Present Extensive New Research Demonstrating Significant Progress in the Treatment of Certain Earlier Stage Cancers and in Advancing Broad Oncology Pipeline at 2023 ASCO Annual Meeting – Merck.com [Internet]. Merck.com. Merck & Co.; 2023 [cited 2023 Dec 19]. Available from: https://www.merck.com/news/merck-to-present-extensive-new-research-demonstrating-significant-progress-in-the-treatment-of-certain-earlier-stage-cancers-and-in-advancing-broad-oncology-pipeline-at-2023-asco-annual-meeting/.
  18. Goodman A. Pembrolizumab Added to Chemotherapy Improves Survival in Advanced Cervical Cancer Regardless of PD-L1 Expression – The ASCO Post [Internet]. Ascopost.com. HSP News Service LLC; 2023 [cited 2023 Dec 19]. Available from: https://ascopost.com/issues/june-10-2023/pembrolizumab-added-to-chemotherapy-improves-survival-in-advanced-cervical-cancer-regardless-of-pd-l1-expression/.
  19. Robert C, Carlino MS, McNeil CM, Ribas A, Grob JJ, Schachter J, et al. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. Journal of Clinical Oncology. 2023 Aug 20;41(24):3998–4003.
  20. Cancer Research UK. Pembrolizumab (Keytruda) [Internet]. Cancerresearchuk.org. 2023 [cited 2023 Dec 19]. Available from: https://www.cancerresearchuk.org/about-cancer/treatment/drugs/pembrolizumab.
  21. U.S. Food & Drug Administration. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer [Internet]. U.S. Food and Drug Administration. Oncology Center of Excellence; 2023 [cited 2023 Dec 19]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer.
  22. Hortobágyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch‐Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Annals of Oncology. 2018 Jul 1;29(7):1541–7.
  23. U.S. Food & Drug Administration. FDA approves first cancer drug through new oncology review pilot that enables greater development efficiency [Internet]. U.S. Food and Drug Administration. 2018 [cited 2023 Dec 20]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-cancer-drug-through-new-oncology-review-pilot-enables-greater-development.
  24. European Medicines Agency. Kisqali (ribociclib) [Internet]. Europa.eu. European Union Agencies Network; 2020 Jun [cited 2023 Dec 20]. Available from: https://www.ema.europa.eu/en/documents/overview/kisqali-epar-medicine-overview_en.pdf.
  25. Drugs.com. FDA Approves Kisqali (ribociclib) for HR+/HER2- Metastatic Breast Cancer [Internet]. Drugs.com. Drugs.com; 2017 [cited 2023 Dec 20]. Available from: https://www.drugs.com/newdrugs/fda-approves-kisqali-ribociclib-hr-her2-metastatic-breast-cancer-4496.html.
  26. Slamon DJ, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial. Journal of Clinical Oncology. 2023 Jun 10;41(17_suppl):LBA500–0.

Written by Sophie Cruddas

Edited by Simon Ng

The content of VJOncology is intended for healthcare professionals