Earlier in 2024, the World Health Organization reported that ten types of cancer were responsible for two-thirds of new cancer cases and deaths globally in 2022.

 Most common among them was lung cancer, with 2.5 million new cases – or 12.4% of new cancer cases.

 Lung cancer continues to have the highest incidence and mortality rate of any cancer today, with non-small cell lung cancer (NSCLC) making up the overwhelming majority – approximately 85% – of diagnoses.

 While much progress has been made in this space in recent years, there remains an urgent need for new and effective therapies for these patients.

Chemotherapy-free combination therapy for lung cancer is an emerging treatment option that has quickly become one of the most promising advances in quite some time. The 2024 U.S. Food and Drug Administration (FDA) 

 (amivantamab-vmjw) plus LAZCLUZE™ (lazertinib) for the first-line treatment of adults with locally advanced or metastatic NSCLC with epidermal growth factor receptor (

) exon 19 deletions or exon 21 L858R mutations represents a major milestone and long-awaited turning point in the lung cancer treatment landscape.

 View the full Indication and Important Safety Information for RYBREVANT

 are among the most common driver mutations seen in NSCLC, but treatment options have long been limited and there is no known cure.

 EGFR tyrosine kinase inhibitors (TKIs) have served as the standard of care, which can be effective for months or even a few years, depending on the individual patient and the specific drug in use, but they will not eliminate the disease.

 Despite initial response, resistance to the treatment may develop (acquired resistance), rendering the treatment ineffective as well as potentially limiting future treatment selection and benefit.

-mutated NSCLC never receive second-line therapy due to disease progression, and the five-year survival rate for these patients is less than 20%.

 We have been in need of new, more aggressive therapeutic approaches that may be used earlier, delay the occurrence of resistance, and potentially offer better outcomes to patients with lung cancer.

Achieving a Novel Targeted Approach in the First Line

 plus LAZCLUZE™ is the first and only chemotherapy-free regimen showing median progression-free survival (primary endpoint) of 23.7 months compared to 16.6 months for osimertinib (HR=0.70; 95% CI, 0.58–0.85; p=0.0002) in the first line, marking an important step forward for patients with 

 The approval was based on positive results from the Phase 3 

 study, which showed that this combination therapy reduced the risk of disease progression or death by 30% compared to osimertinib. The median duration of response for RYBREVANT

 plus LAZCLUZE™ was also 25.8 months versus 16.7 months for osimertinib.

In the study, the safety profile of RYBREVANT

 plus LAZCLUZE™ was consistent with previous reports from Phase 1-2 studies. A high incidence of EGFR- and MET-related adverse events was found in the RYBREVANT

 The most common adverse reactions were rash, nail toxicity, infusion-related reaction, musculoskeletal pain, stomatitis, edema, venous thromboembolic (VTE) events, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea and ocular toxicity.

 Serious adverse reactions included VTE, pneumonia, rash, ILD/pneumonitis, COVID-19, pleural effusion and infusion-related reaction.

 Serious adverse reactions occurred in 49% of patients who received RYBREVANT

 in combination with LAZCLUZE™, and permanent discontinuation of RYBREVANT

 due to an adverse reaction occurred in 34% of patients.

 Permanent discontinuation of LAZCLUZE™ due to an adverse reaction occurred in 21% of patients.

 plus LAZCLUZE™, if there is an adverse reaction requiring dose reduction after withholding treatment and resolution, it is recommended to reduce the dose of RYBREVANT

The introduction of a first-line, chemotherapy-free combination treatment regimen for adults with 

-mutated lung cancer allows us to treat the world’s leading cause of cancer death more aggressively, which I hope in turn will bring a more positive outlook to these patients and their families. It’s also critical that we look at how we can treat our patients holistically. In my career, the decision on what treatment to use is among the patient, their loved ones and myself. I connect the patients with resources so they are empowered to advocate for themselves. Together, we make a personalized treatment decision for each patient.

I am inspired by the evolution of the lung cancer treatment landscape. We have made significant strides in the past decade and with this approval, I am confident we will continue to make a positive impact on appropriate individuals faced with lung cancer.

*EGFR exon 19 deletions or exon 21 L858R mutations

 can cause infusion-related reactions (IRR) including anaphylaxis; signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. The median time to IRR onset is approximately 1 hour.

 in combination with LAZCLUZE™ can cause infusion-related reactions. In MARIPOSA (n=421), IRRs occurred in 63% of patients treated with RYBREVANT

 in combination with LAZCLUZE™, including Grade 3 in 5% and Grade 4 in 1% of patients. The incidence of infusion modifications due to IRR was 54% of patients, and IRRs leading to dose reduction of RYBREVANT

 occurred in 0.7% of patients. Infusion-related reactions leading to permanent discontinuation of RYBREVANT

 occurred in 4.5% of patients receiving RYBREVANT

Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT

 via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. Monitor patients for 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. If an anaphylactic reaction occurs, permanently discontinue RYBREVANT

 can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.

In MARIPOSA, ILD/pneumonitis occurred in 3.1% of patients treated with RYBREVANT

 in combination with LAZCLUZE™, including Grade 3 in 1.0% and Grade 4 in 0.2% of patients. There was one fatal case (0.2%) of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). For patients receiving RYBREVANT

 in combination with LAZCLUZE™, immediately withhold both drugs in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT

 in combination with LAZCLUZE™ can cause serious and fatal venous thromboembolic (VTEs) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first four months of therapy.

 In MARIPOSA, VTEs occurred in 36% of patients receiving RYBREVANT

 in combination with LAZCLUZE™, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT

, and 7% of patients had VTE leading to dose interruptions of LAZCLUZE™; 1% of patients had VTE leading to dose reductions of RYBREVANT

, and 0.5% of patients had VTE leading to dose reductions of LAZCLUZE™; 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT

, and 1.9% of patients had VTE leading to permanent discontinuation of LAZCLUZE™. The median time to onset of VTEs was 84 days (range: 6 to 777).

Administer prophylactic anticoagulation for the first four months of treatment. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate.

 and LAZCLUZE™ based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT

 and LAZCLUZE™ at the same dose level at the discretion of the healthcare provider. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT

 and continue treatment with LAZCLUZE™ at the same dose level at the discretion of the healthcare provider.

 can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin.

In MARIPOSA, rash occurred in 86% of patients treated with RYBREVANT

 in combination with LAZCLUZE™, including Grade 3 in 26% of patients. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose interruptions occurred in 37% of patients for RYBREVANT

 and 30% for LAZCLUZE™, rash leading to dose reductions occurred in 23% of patients for RYBREVANT

 and 19% for LAZCLUZE™, and rash leading to permanent discontinuation occurred in 5% of patients for RYBREVANT

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT

 or LAZCLUZE™ in combination with RYBREVANT

. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.

 treatment with or without LAZCLUZE™, administer alcohol-free emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g. use of oral antibiotics) to reduce the risk of dermatologic reactions. 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. For patients receiving RYBREVANT

 in combination with LAZCLUZE™, withhold, dose reduce or permanently discontinue both drugs based on severity.

 can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis.

In MARIPOSA, ocular toxicity occurred in 16% of patients treated with RYBREVANT

 in combination with LAZCLUZE™, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT

 and continue LAZCLUZE™ based on severity.

Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT

Based on its mechanism of action and findings from animal models, RYBREVANT

 and LAZCLUZE™ 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 last dose of RYBREVANT

Advise females of reproductive potential to use effective contraception during treatment with LAZCLUZE™ and for 3 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LAZCLUZE™ and for 3 weeks after the last dose.

For the 421 patients in the MARIPOSA clinical trial who received RYBREVANT

 in combination with LAZCLUZE™, the most common adverse reactions (≥20%) were rash (86%), nail toxicity (71%), infusion-related reactions (RYBREVANT

, 63%), musculoskeletal pain (47%), stomatitis (43%), edema (43%), VTE (36%), paresthesia (35%), fatigue (32%), diarrhea (31%), constipation (29%), COVID-19 (26%), hemorrhage (25%), dry skin (25%), decreased appetite (24%), pruritus (24%), nausea (21%), and ocular toxicity (16%). The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased albumin (8%), decreased sodium (7%), increased ALT (7%), decreased potassium (5%), decreased hemoglobin (3.8%), increased AST (3.8%), increased GGT (2.6%), and increased magnesium (2.6%).

Serious adverse reactions occurred in 49% of patients who received RYBREVANT

 in combination with LAZCLUZE™. Serious adverse reactions occurring in ≥2% of patients included VTE (11%), pneumonia (4%), ILD/pneumonitis and rash (2.9% each), COVID-19 (2.4%) and pleural effusion and infusion-related reaction (RYBREVANT

) (2.1% each). Fatal adverse reactions occurred in 7% of patients who received RYBREVANT® in combination with LAZCLUZE™ due to death not otherwise specified (1.2%); sepsis and respiratory failure (1% each); pneumonia, myocardial infarction, and sudden death (0.7% each); cerebral infarction, pulmonary embolism (PE), and COVID-19 infection (0.5% each); and ILD/pneumonitis, acute respiratory distress syndrome (ARDS), and cardiopulmonary arrest (0.2% each).

Avoid concomitant use of LAZCLUZE™ with strong and moderate CYP3A4 inducers. Consider an alternate concomitant medication with no potential to induce CYP3A4.

Monitor for adverse reactions associated with a CYP3A4 or BCRP substrate where minimal concentration changes may lead to serious adverse reactions, as recommended in the approved product labeling for the CYP3A4 or BCRP substrate.

in combination with LAZCLUZE™ (lazertinib) for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.

 World Health Organization. Global cancer burden growing, amidst mounting need for services. Accessed September 2024. Available at: 

https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing--amidst-mounting-need-for-services

American Cancer Society. What is lung cancer? Accessed September 2024. Available at: 

https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html

(amivantamab-vmjw) Prescribing Information. Horsham, PA: Janssen Biotech, Inc.

 O’Leary C, et al. Epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). 

 Non-small cell lung cancer treatment (PDQ

https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq

 Sakharkar P, et al. Investigating the efficacy of EGFR-TKIs and anti-VEGFR combination in advanced non-small cell lung cancer: a meta-analysis. 

 Garg P, et al. Emerging therapeutic strategies to overcome drug resistance in cancer cells. 

 Lee JY, et al. Treatment patterns and outcomes of first-line osimertinib-treated advanced EGFR mutated NSCLC patients: a real-world study [IASLC abstract EP08.02-082]. Presented at the IASLC 2022 World Lung Conference on Lung Cancer. August 6-9, 2022; Vienna, Austria.

 Girard N, et al. Mortality among EGFR-mutated advanced NSCLC patients after starting frontline osimertinib treatment: a real-world, US attrition analysis. Presented at the European Lung Cancer Congress. March 29-April 1, 2023; Copenhagen, Denmark. Poster 19P.

 Ashrafi A, et al. Current landscape of therapeutic resistance in lung cancer and promising strategies to overcome resistance. 

 LAZCLUZE™ (lazertinib) Prescribing Information. Horsham, PA: Janssen Biotech, Inc.

 Cho BC, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. 

Alexander Spira, MD, PhD, FACP, Director, Virginia Cancer Specialists Research Institute

Articles

Raising the Bar in the First-Line Treatment of EGFR+* mNSCLC Advanced Lung Cancer