Tag: Lung Cancer: Non-Small Cell

TAGRISSO® after Chemoradiotherapy in Stage III EGFR Mutated Non-Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Approximately one third of all patients with NSCLC have Stage III, locally advanced disease at the time of initial presentation and 60 to 90% of these patients have unresectable disease. These patients are treated with concurrent chemoradiotherapy (CRT) followed by consolidation therapy with Durvalumab (IMFINZI®) in patients without progression, as this regimen confers an Overall Survival advantage, and is considered the standard of care (PACIFIC trial).

EGFR (Epidermal Growth Factor Receptor) mutations are found in up to one third of patients with unresectable Stage III NSCLC. There are currently no approved targeted treatments for patients with unresectable Stage III EGFR-mutated NSCLC. The current standard of care, which includes consolidation therapy with Durvalumab, may not offer clear benefits to this subset of patients with EGFR mutations.

Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (TKI), presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Osimertinib is also approved by the FDA as adjuvant treatment for resected Stage IB–IIIA EGFR-mutated NSCLC. Further, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.

LAURA was a global, randomized, double-blind, placebo-controlled, multicenter Phase III trial conducted to assess the efficacy and safety of Osimertinib in patients with unresectable Stage III NSCLC harboring EGFR mutations (EGFR exon 19 deletion or exon 21 L858R mutation). The trial enrolled patients who had not experienced disease progression during or after definitive platinum-based chemoradiotherapy (CRT). A total of 216 patients who had undergone CRT were randomly assigned 2:1 to receive Osimertinib 80 mg orally once daily (N=143) or placebo once per day (N=73). Treatment was continued until Blinded Independent Central Review (BICR)–assessed disease progression, unacceptable toxicity, or other discontinuation criteria were met. Upon disease progression, patients in the placebo arm were permitted to receive Osimertinib, allowing for crossover therapy. Stratification factors included method of CRT (concurrent versus sequential) and disease Stage (IIIA versus IIIB/C). Both treatment groups were well balanced. The median patient age was 63 years, approximately 60% of participants were female, 83% were Asian, 69% had never smoked and 85% had Stage IIIA and B disease. Majority of patients received concurrent CRT rather than sequential CRT. The Primary end point was Progression Free Survival (PFS) as assessed by BICR. Key Secondary end points included Overall Survival (OS), survival without progression of CNS disease (CNS Progression Free Survival), Objective Response Rate (ORR), Duration of Response, Quality of Life, and Safety.

Treatment with Osimertinib resulted in significant PFS improvement compared to placebo. The median PFS was 39.1 months in the Osimertinib group versus 5.6 months in the placebo group, representing an 84% reduction in the risk of disease progression or death (HR=0.16; P<0.001). Additionally, a higher percentage of patients in the Osimertinib group remained alive and progression-free at 12 months compared to the placebo group (74% versus 22% respectively). Subgroup analyses were conducted to evaluate the consistency of treatment effects across various demographic and clinical factors. The benefits of Osimertinib were observed across all prespecified subgroups, indicating a consistent treatment effect, regardless of patient characteristics. The incidence of new lesions was lower with Osimertinib compared to placebo (22% versus 68%), and this included new brain lesions (8% versus 29%) and new lung lesions (6% versus 29%) respectively. The Objective Response Rate was higher with Osimertinib than with placebo (57% versus 33%). The median Duration of Response was longer with Osimertinib (36.9 months) than with placebo (6.5 months). Interim OS data showed a favorable trend for Osimertinib, although maturity was limited at the time of analysis. Further follow-up will be conducted to assess OS as a secondary endpoint. The adverse event profile of Osimertinib was generally consistent with previous studies. Grade 3 or higher adverse events occurred more frequently in the Osimertinib group, with radiation pneumonitis being the most common. However, no new safety concerns emerged during the trial.

In summary, treatment with Osimertinib resulted in significantly longer Progression Free Survival than placebo in patients with unresectable Stage III EGFR-mutated NSCLC following definitive CRT, and should be considered the new standard of care for this group of patients. Overall, the LAURA study represents a major breakthrough in the treatment of EGFR-mutated Stage III NSCLC, addressing an unmet need for targeted therapies in this setting. Further follow-up will provide additional insights into the long-term efficacy and safety of Osimertinib in this patient population.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. Lu S, Kato T, Dong X, et al. for the LAURA Trial Investigators. N Engl J Med 2024;391:585-597

Lung Cancer Risk with Vaping and Cigarette Smoking

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SUMMARY: According to the American Cancer Society, tobacco use is responsible for nearly 1 in 5 deaths in the United States and accounts for at least 30% of all cancer deaths. Smokeless tobacco products are a major source of cancer causing nitrosamines, and increase the risk of developing cancer of the oropharynx, esophagus, and pancreas. Cigarette smoke contains more than 7,000 chemicals, many of which are toxic and some linked to cancer.

The use of e-cigarettes (electronic cigarettes) often referred to as “vaping” was introduced to the U.S. market in 2007 after e-cigarettes were first developed in China. When a smoker inhales through the mouth piece of an e-cigarette, the air flow triggers a sensor that switches on a small lithium battery powered heater, which in turn vaporizes liquid nicotine along with PolyEthylene Glycol (PEG) present in a small cartridge. The PEG vapor looks like smoke. The potent liquid form of nicotine extracted from tobacco is tinctured with fragrant flavors such as chocolate, cherry and bubble gum, coloring substances, as well as other chemicals and these e-liquids are powerful neurotoxins. With the rapid growth of the e-cigarette industry and the evidence of potential dangers and risk to public health, particularly children, experts from the world’s leading lung organizations were compelled to release a POSITION statement on e-cigarettes, specifically focusing on their potential adverse effects on human health, and calling on government organizations to ban or restrict the use of e-cigarettes, until their impact on health is better understood. With epidemiological data demonstrating that nicotine use is a gateway to the use of cocaine and marijuana and subsequent lifelong addiction, the Forum of International Respiratory Societies (FIRS), an organization composed of the world’s leading international respiratory societies including American Thoracic Society (ATS) and the American College of Chest Physicians (ACCP) made several important recommendations (not included here).

The health risks associated with vaping might be compounded by the presence of harmful substances in e-cigarette aerosols, such as diacetyl, diethylene glycol, aldehydes, cadmium, benzene, and heavy metals like nickel, tin, and lead. These components are known to be toxic and carcinogenic, raising concerns about their contribution to lung cancer risk.

Recent concerns have emerged about the potential health risks associated with vaping, particularly in relation to lung cancer. Although nicotine exposure from electronic delivery systems (vaping) has been linked to elevated risks of lung conditions, the impact on lung cancer risk has remained relatively unexplored. To address this gap, the researchers in this publication conducted a comprehensive case-control study at The Ohio State University in Columbus, Ohio, examining the association between vaping, cigarette smoking, and lung cancer risk. The researchers in this study analyzed medical records from the James Cancer Hospital and Solove Research Institute, encompassing data from 4,975 patients diagnosed with pathologically confirmed lung cancer between 2013 and 2021. This patient cohort was meticulously matched to 27,294 control individuals without cancer on a 5:1 ratio based on age, gender, race, and year of ascertainment. The researchers utilized descriptive statistics and performed logistic regression analyses to evaluate the associations between vaping, smoking, and lung cancer risk. This analysis aimed to determine how these factors individually and synergistically contributed to the likelihood of developing lung cancer.

The results of this analysis demonstrated that the demographic profile of the lung cancer cases showed a predominance of males (55%), with a majority being White (88%). The mean age at diagnosis was 62 years. There was a significantly higher risk of lung cancer among individuals who both vaped and smoked compared to those who only smoked. Specifically, the adjusted Odds Ratio (OR) for those who reported both vaping and smoking was 21.1 (95% CI = 17.1, 26.1), while for smoking alone, it was 6.3 (95% CI = 5.8, 6.8). Further stratification by gender and histologic cell type demonstrated that the risk associated with combined vaping and smoking was consistently over 3X higher compared to smoking alone (P<0.001). This elevated risk persisted even after adjusting for comorbidities, Chronic Obstructive Pulmonary Disease (COPD), and cardiovascular disease.

The researchers added that these findings underscore a markedly higher risk of lung cancer associated with the combination of vaping and smoking compared to smoking alone. This synergistic effect is reminiscent of the risks associated with known carcinogens such as radon or asbestos. The results suggest that the addition of vaping to smoking significantly accelerates the risk of developing lung cancer.

The limitations of this study are that this analysis did not include a vaping-only group, as nearly 97% of those who vaped also reported smoking. Additionally, there was no detailed temporal data on the duration and frequency of vaping versus smoking. However, the consistent significant increase in lung cancer risk observed with combined vaping and smoking indicates a potentially substantial interaction effect.

In conclusion, this case-control study provides compelling evidence suggesting that vaping combined with smoking may significantly elevate lung cancer risk. While these preliminary findings highlight the potential dangers of e-cigarettes, further research is necessary to confirm these results and explore the long-term implications of vaping on lung cancer risk. Physicians should reconsider harm-reduction messages related to vaping, as it may NOT be safer than smoking. Further studies are needed to quantify the exact risks associated with vaping and smoking, as well as to understand the long-term effects.

Vaping, smoking and lung cancer: A case-control study. Bittoni MA, Carbone D, Harris R. Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract 2213.

Five Year Outcomes with First Line OPDIVO® plus YERVOY® and a Limited Course of Chemotherapy

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SUMMARY: The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States and accounts for about 13% of all new cancers and 21% of all cancer deaths. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. Ipilimumab (YERVOY®) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4. In the CheckMate-227, Part 1, Phase III trial, a combination of Nivolumab plus Ipilimumab significantly improved Overall Survival (OS), Progression Free Survival (PFS), Objective Response Rates (ORR) and Duration of Response, compared to chemotherapy, independent of PD-L1 expression level. The authors in this study hypothesized that a limited course of chemotherapy combined with Nivolumab plus Ipilimumab could provide rapid disease control, while building on the durable Overall Survival benefit seen with dual PD-1 and CTLA-4 inhibition, as well as minimizing the toxicities associated with a full course of chemotherapy.

CheckMate-9LA is a pivotal, randomized, open-label, global, multi-center, Phase III trial, designed to evaluate the long-term efficacy and safety of a combination of immunotherapy and chemotherapy compared to chemotherapy alone in patients with metastatic NSCLC. In this study, 719 adults treatment naïve patients with histological confirmed Stage IV/recurrent NSCLC, with ECOG Performance Status 0-1, and no known sensitizing EGFR/ALK alterations, were randomly assigned 1:1 to receive either Nivolumab 360 mg every 3 weeks IV plus Ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy (N=361), or 4 cycles of platinum-doublet chemotherapy alone (N=358). Chemotherapy was based on histology. Patients with non-squamous NSCLC in the chemo-only randomized group could receive optional Pemetrexed maintenance treatment. Patients were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 years. Patients were stratified by PD-L1 status (less than 1% versus 1% or more), sex, and histology (squamous versus non-squamous). Demographics in treatment groups were well balanced. Crossover between treatment groups was not permitted. However, at physician discretion, patients could receive subsequent immunotherapy upon discontinuation of study treatment in either group. The Primary end point was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR) and efficacy by PD-L1 subgroups. Exploratory Endpoints included Treatment-Free Interval (TFI), efficacy in patients who discontinued due to Treatment-Related Adverse Events (TRAEs), and outcomes among 5-year survivors. This trial met its Primary and Secondary endpoints, showing statistically significant improvements in OS, PFS, and Objective Response Rate (ORR), when compared to chemotherapy alone. This clinical benefit was noted across tumor PD-L1 expression levels and histology. The researchers herein reported updated efficacy and safety data with a 5-year follow up, and outcomes in 5-year survivors.

At a median follow up of 64.5 months, the combination of Nivolumab, Ipilimumab, and chemotherapy demonstrated a continued survival benefit over chemotherapy alone. The 5-year OS rate was 18% for the experimental group compared to 11% for the control group, with a Hazard Ratio (HR) of 0.73. In patients with tumor PD-L1 expression less than 1%, a subgroup with historically poorer outcomes, the 5-year OS rate was 22% in the experimental group versus 8% in the control group (HR=0.63). The 5-year PFS rate in this subgroup was also significantly better with Nivolumab plus Iipilimumab and chemotherapy (9% versus 3%).

The median DOR in the experimental arm was 12.4 months compared to 5.6 months in the control arm. The 5-year DOR rates were 19% for the experimental group and 8% for the control group. Regarding Treatment-Free Interval (TFI), among patients who survived to 5 years, 72% of those in the experimental group were treatment-free compared to 35% in the control group. The TFI rates underscore the durability of the response achieved with the combination therapy.

In Squamous NSCLC patients, the median OS was 14.5 months with the experimental regimen compared to 9.1 months with chemotherapy alone (HR, 0.63). For non-squamous NSCLC patients, the median OS was 17.8 months versus 12.0 months (HR, 0.77). In patients with PD-L1 expression less than 1%, the experimental regimen had a median OS of 17.7 months compared to 9.8 months for the control group. For those with PD-L1 expression 1% or greater, the median OS was 15.8 months versus 10.9 months. Among patients who discontinued the experimental regimen due to TRAEs (N=61), 37% were alive at 5 years. The median OS in this subgroup was 27.5 months, with a 5-year OS rate of 37%.

No new safety signals emerged with extended follow up. Grade 3 and 4 immune-mediated AEs were relatively low across different Ipilimumab dosing groups. The most common severe AEs were hepatitis, rash, pneumonitis, and adrenal insufficiency, with incidence varying by the number of Ipilimumab doses.

Exploratory Analyses suggested that among the 5-year survivors, the median PFS was not reached in the experimental group compared to 16.8 months in the control group (HR, 0.52). The ORR at 5 years was 73% in the experimental group versus 60% in the control group.

In conclusion, the 5-year follow-up results from the CheckMate -9LA trial reinforce the long-term efficacy of Nivolumab plus Ipilimumab combined with chemotherapy as a first-line treatment for metastatic NSCLC. The combination therapy not only improved OS and PFS compared to chemotherapy alone, but also showed a significant benefit in patients with low PD-L1 expression and Squamous histology. The extended follow-up underscores the durability of the response and supports the combination as a robust treatment option for patients with metastatic NSCLC, with manageable safety profiles over the long term.

Five-year outcomes with first-line (1L) nivolumab + ipilimumab + chemotherapy (N + I + C) vs C in patients (pts) with metastatic NSCLC (mNSCLC) in CheckMate 9LA. Reck M, Ciuleanu TE, Schenker M, et al. J Clin Oncol. 2024;42(suppl 16):8560-8560. doi:10.1200/JCO.2024.42.16_suppl.8560.

Late Breaking Abstract – ASCO 2024: Subcutaneous versus Intravenous RYBREVANT® in Refractory EGFR Mutated Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21.

Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib target the EGFR signaling cascade. However, patients eventually will develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of 5 months.

Amivantamab (RYBREVANT®) is a fully-human bispecific antibody directed against EGFR and MET receptors. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, and is approved for the treatment of patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.

Lazertinib (LECLAZA®) is a highly selective, third-generation TKI that penetrates the CNS, with demonstrated efficacy in activating EGFR mutations and acquired T790M “gatekeeper” point mutation. Combining Amivantamab with Lazertinib has been shown to provide a synergistic benefit by targeting the extracellular and catalytic EGFR domains.

Amivantamab given intravenously along with Lazertinib demonstrated antitumor activity in EGFR-mutated advanced NSCLC. PALOMA-3 study evaluated the efficacy, PharmacoKinetics (PK), and safety of a subcutaneous formulation of Amivantamab given along with Lazertinib, compared to intravenous (IV) administration given along with Lazertinib, in patients with EGFR Exon 19 deletion or L858R-mutated advanced NSCLC.

PALOMA-3 is a randomized, controlled Phase III trial in which 418 patients who had disease progression on Osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous (SC) or intravenous (IV) Amivantamab, both combined with Lazertinib, with 206 patients (N=206) assigned to the SC arm and 212 patients (N=212) assigned to the IV arm. SC Amivantamab was administered at 1600 mg weekly for the first 4 weeks and then every 2 weeks, while IV Amivantamab was given at the approved dose of 1050 mg. Lazertinib was administered at 240 mg orally daily in both groups. Prophylactic anticoagulation was recommended for the first 4 months. The median age of patients was 61 years, 67% were female, 61% were Asian, patients had received a median of two prior lines of therapy, and 34% had a history of brain metastases. Co-primary pharmacokinetic noninferiority endpoints were trough concentrations (C trough on Cycle 2 Day 1 or Cycle 4 Day 1) and Cycle 2 AUC Day1-Day 15. Secondary endpoints included Objective Response Rate (ORR) and Progression Free Survival (PFS). Overall Survival (OS) was an exploratory endpoint.

At a median follow up of 7 months, the trial met both co-primary PK endpoints. SC Amivantamab demonstrated non-inferiority compared to IV in terms of trough concentrations and AUC, with geometric mean ratios favoring SC administration. SC Amivantamab along with Lazertinib showed a non-inferior ORR (30.1%) compared to IV (32.5%), meeting the predefined noninferiority criteria (RR=0.92; P=0.001). Among confirmed responders, SC administration resulted in a longer median DoR (11.2 months) compared to 8.3 months with IV administration. Although not statistically significant, SC Amivantamab along with Lazertinib showed a favorable trend in PFS (median 6.1 months versus 4.3 months for IV; HR 0.84, P=0.20). Overall Survival was notably longer with SC administration (HR 0.62; P=0.017), with 65% alive at 12 months in the SC arm versus 51% in the IV group.

SC administration significantly reduced Infusion-Related Reactions by 5 fold (13% versus 66% for IV), with no severe reactions leading to hospitalization in the SC arm. Prophylactic anticoagulation reduced Venous Thromboembolism (VTE) risk (9% SC versus 14% IV) and the overall incidence was lower in the SC group, emphasizing safety benefits. Across both treatment groups, VTE incidence was 10% for patients who received prophylactic anticoagulants versus 21% for patients who did not. With regards to patient experience, SC administration took less than 5 minutes, significantly shorter than IV (initial infusion 5 hours), contributing to higher patient satisfaction (85% versus 35% found SC convenient at end of treatment).

It was concluded that the PALOMA-3 trial demonstrated that SC administration of Amivantamab is non-inferior to IV in terms of PK and efficacy endpoints and represents a paradigm shift towards more patient-friendly and effective treatment options for EGFR-mutated NSCLC, with lower rates of Infusion-Related Reactions and VTE.

Subcutaneous amivantamab vs intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results, including overall survival (OS), from the global, phase 3, randomized controlled PALOMA-3 trial. Leighl NB, Akamatsu H, Lim SM, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA8505)

Late Breaking Abstract – ASCO 2024: Long Term Outcomes with LORBRENA® in ALK-Positive Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The discovery of chromosomal rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, and their sensitivity to ALK inhibitors, paved the way to the development of small-molecule ALK Tyrosine Kinase Inhibitors. It has become clear that appropriate, molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8%, as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET, NTRK and ROS oncogenes. These mutations are mutually exclusive, and the presence of two simultaneous mutations, are rare.

ALK inhibitors include first-generation XALKORI® (Crizotinib) and second-generation ALK inhibitors such as ZYKADIA® (Ceritinib), ALECENSA® (Alectinib) and ALUNBRIG® (Brigatinib). Despite the improved efficacy of second-generation ALK inhibitors, recurrent disease due to drug resistance including CNS disease progression can still develop.

Lorlatinib (LORBRENA®) is a novel third-generation ALK inhibitor that is more potent than second-generation inhibitors, and has the broadest coverage of ALK resistance mutations that have been identified. Lorlatinib crosses the blood-brain barrier and has marked intracranial activity in previously treated patients with baseline CNS disease, including leptomeningeal disease.

The CROWN study is an ongoing, multicenter, global, open-label, randomized Phase III trial, conducted to compare the efficacy and safety of Lorlatinib versus Crizotinib in treatment-naive patients with advanced Stage IIIB/IV or recurrent ALK-positive NSCLC. In this study, 296 eligible patients were randomly assigned 1:1 to receive Lorlatinib 100 mg orally once daily (N=149) versus Crizotinib 250 mg orally twice daily (N=147) in cycles of 28 days. Treatment was continued until disease progression or unacceptable toxicities. Eligible patients were required to have ALK-positive tumors detected by the Ventana ALK (D5F3) CDx assay. Patients with asymptomatic treated or untreated CNS metastases were eligible and had to have at least one extracranial measurable target lesion that had not been previously irradiated. Patients were stratified according to the presence of brain metastases and ethnic group (Asian or non-Asian) and crossover between the treatment groups was not permitted. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Secondary end points included independently assessed Overall Survival (OS), Objective Response Rate (ORR) and intracranial objective response, time to intracranial progression, Duration of Response, and duration of intracranial response. At a planned interim analysis, treatment with Lorlatinib resulted in statistically significant and clinically meaningful improvement in PFS as assessed by BICR, with a Hazard Ratio of 0.28 (P<0.001), corresponding to a 72% reduction in the risk of disease progression or death. The median PFS was Not Reached in the Lorlatinib arm and was 9.3 months for those treated with Crizotinib. Based on these results, the FDA in 2021, the FDA granted regular approval to Lorlatinib for patients with previously untreated, advanced metastatic NSCLC, whose tumors are ALK-positive.

Given that the median PFS was Not Reached (NR) after 3 years of follow-up, the researchers conducted this post hoc analysis of the Phase III CROWN study, to evaluate the long-term outcomes of Lorlatinib versus Crizotinib at the clinically meaningful landmark follow-up of 5 years, and updated investigator-assessed efficacy outcomes, safety, and biomarker analyses.

With a median follow-up for PFS of 60.2 months for Lorlatinib and 55.1 months for Crizotinib, the median PFS was Not Reached (NR) with Lorlatinib after 5 years and was 9.1 months with Crizotinib (HR=0.19; 95% CI 0.13 to 0.27), The 5-year PFS was 60% and 8% respectively. This represents the longest reported PFS with any molecular targeted therapy in advanced NSCLC and across metastatic solid tumors. The median time to intracranial progression was NR with Lorlatinib and 16.4 months with Crizotinib (HR=0.06; 95% CI, 0.03 to 0.12). New ALK resistance mutations were not detected in circulating tumor DNA collected at the end of Lorlatinib treatment.

The confirmed ORR by investigator assessment was 81% with Lorlatinib and 63% with Crizotinib and the median Duration of Response was NR and 9.2 months respectively. In patients with measurable and/or nonmeasurable baseline brain metastases, intracranial objective response was also greater with Lorlatinib than with Crizotinib (60% versus 11%, respectively) and intracranial complete response was reported in 49% and 5% of patients, respectively. The median duration of intracranial response was NR with Lorlatinib and 12.8 months with Crizotinib.

Treatment related Grade 3-4 adverse events were noted in 66% of patients in the Lorlatinib group and 39% of patients in the Crizotinib group leading to dose reduction in 21% and 13% respectively. However, dose reduction did not impact median PFS or time to intracranial progression in these patients.

In summary, the CROWN study represents a pivotal trial that establishes Lorlatinib as a milestone in ALK-targeted therapy, providing unprecedented Progression Free Survival and intracranial efficacy in treatment-naive patients with advanced ALK-positive NSCLC, setting a new standard in the treatment landscape of this disease. Overall Survival data were not mature at the time of this analysis and continued research into optimal sequencing of ALK inhibitors and exploration of biomarkers are essential to predict treatment response and resistance.

Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non–Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. Solomon BJ, Liu G, Felip E, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA8503). DOI:10.1200/JCO.2024.42.17_suppl.LBA8503

Late Breaking Abstract – ASCO 2024: KRAZATI® Superior to Docetaxel in KRAS G12C Mutated Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers.

The KRAS (kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase, and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous.

KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 25% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers, and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.

Adagrasib (KRAZATI®) is a potent, orally available, small molecule covalent inhibitor of KRAS G12C. This drug irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Unlike Sotorasib (LUMAKRAS®), which is also a selective covalent inhibitor of KRAS G12C, Adagrasib has a longer drug half-life of 23 hours, as compared to 5 hours for Sotorasib, has dose-dependent extended exposure, and can penetrate the CNS. Approximately, 27-42% of patients with NSCLC harboring KRAS G12C mutations have CNS metastases, with poor outcomes. The U.S. FDA granted accelerated approval for Adagrasib as a targeted treatment for patients with KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy in December 2022.

KRYSTAL-12 trial is a pivotal, open-label, multicenter, randomized, Phase III study designed to compare Adagrasib against standard-of-care chemotherapy (Docetaxel) in patients with KRASG12C-mutated NSCLC who had received prior platinum-based chemotherapy concurrently or sequentially with anti-PD-(L)1 therapy. In this study, 453 patients were randomized 2:1 to receive either Adagrasib 600 mg orally twice a day (N=301) or Docetaxel 75 mg/m2 IV every 3 weeks (N=152). Importantly, patients in the Docetaxel arm had the option to crossover to Adagrasib upon confirmed disease progression. Patients were stratified by region (non-Asia Pacific versus Asia Pacific) and by whether they received concurrent or sequential chemoimmunotherapy. Patients with stable brain metastases were allowed. Both treatment groups were well balanced. The median age was 64.5 years, 95% of patients had adenocarcinoma histology with metastatic disease and approximately 75% of patients were former smokers and previously received concurrent chemoimmunotherapy. The Primary endpoint of the study was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), Safety assessments and Patient-Reported Outcomes. At the time of this analysis, 29% of patients had crossed over from Docetaxel treatment to receive Adagrasib.

With a median follow-up of 9.4 months, the trial met its Primary endpoint, with Adagrasib demonstrating a significant improvement in PFS over Docetaxel (median PFS 5.5 versus 3.8 months; HR=0.58, P<0.0001). The benefit of Adagrasib over Docetaxel was maintained across key subgroups. The ORR was also significantly higher with Adagrasib compared with Docetaxel (32% versus 9%; Odds Ratio 4.68; P<0.0001). The median Duration of Response was 8.3 months versus 5.4 months respectively, and responses were sustained at least 6 months in 64% and 39% of patients, respectively. Among those patients with CNS metastases at baseline, intracranial responses were observed in 24% of patients receiving Adagrasib and 11% of patients receiving Docetaxel, with intracranial Disease Control Rate of 82% and 56%, respectively. There was also a significant benefit in the Patient-Reported Outcomes of median time to deterioration. There were no new safety signals noted with Adagrasib and the safety data was consistent with the known safety profile. Grade 3 or more treatment-related adverse events occurred in 47% of patients treated with Adagrasib and 45.7% of patients treated with Docetaxel and treatment discontinuation rates were 7.7% versus 14.3%, respectively.

In summary, the KRYSTAL-12 trial confirmed Adagrasib as a superior treatment option compared to Docetaxel in patients with previously treated KRASG12C-mutated locally advanced or metastatic NSCLC. Adagrasib significantly improved Progression Free Survival, Overall Response Rate, and Duration of Response, with a notable impact on intracranial disease control rates. Its safety profile was manageable, aligning with expectations from earlier studies. These findings underscore the potential of Adagrasib in this patient population and highlight ongoing research efforts to further optimize treatment strategies in this challenging patient population.

KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Mok TSK, Yao W, Duruisseaux M, et al. J Clin Oncol. 2024;42(suppl 17):LBA8509.

Late Breaking Abstract – ASCO 2024: TAGRISSO® after Chemoradiotherapy in Stage III EGFR Mutated Non-Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Approximately one third of all patients with NSCLC have Stage III, locally advanced disease at the time of initial presentation and 60 to 90% of these patients have unresectable disease. These patients are treated with concurrent chemoradiotherapy (CRT) followed by consolidation therapy with Durvalumab (IMFINZI®) in patients without progression, as this regimen confers an Overall Survival advantage, and is considered the standard of care (PACIFIC trial).

EGFR (Epidermal Growth Factor Receptor) mutations are found in up to one third of patients with unresectable Stage III NSCLC. There are currently no approved targeted treatments for patients with unresectable Stage III EGFR-mutated NSCLC. The current standard of care, which includes consolidation therapy with Durvalumab, may not offer clear benefits to this subset of patients with EGFR mutations.

Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (TKI), presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Osimertinib is also approved by the FDA as adjuvant treatment for resected Stage IB–IIIA EGFR-mutated NSCLC. Further, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.

LAURA was a global, randomized, double-blind, placebo-controlled, multicenter Phase III trial conducted to assess the efficacy and safety of Osimertinib in patients with unresectable Stage III NSCLC harboring EGFR mutations (EGFR exon 19 deletion or exon 21 L858R mutation). The trial enrolled patients who had not experienced disease progression during or after definitive platinum-based chemoradiotherapy (CRT). A total of 216 patients who had undergone CRT were randomly assigned 2:1 to receive Osimertinib 80 mg orally once daily (N=143) or placebo once per day (N=73). Treatment was continued until Blinded Independent Central Review (BICR)–assessed disease progression, unacceptable toxicity, or other discontinuation criteria were met. Upon disease progression, patients in the placebo arm were permitted to receive Osimertinib, allowing for crossover therapy. Stratification factors included method of CRT (concurrent versus sequential) and disease Stage (IIIA versus IIIB/C). Both treatment groups were well balanced. The median patient age was 63 years, approximately 60% of participants were female, 83% were Asian, 69% had never smoked and 85% had Stage IIIA and B disease. Majority of patients received concurrent CRT rather than sequential CRT. The Primary end point was Progression Free Survival (PFS) as assessed by BICR. Key Secondary end points included Overall Survival (OS), survival without progression of CNS disease (CNS Progression Free Survival), Objective Response Rate (ORR), Duration of Response, Quality of Life, and Safety.

Treatment with Osimertinib resulted in significant PFS improvement compared to placebo. The median PFS was 39.1 months in the Osimertinib group versus 5.6 months in the placebo group, representing an 84% reduction in the risk of disease progression or death (HR=0.16; P<0.001). Additionally, a higher percentage of patients in the Osimertinib group remained alive and progression-free at 12 months compared to the placebo group (74% versus 22% respectively). Subgroup analyses were conducted to evaluate the consistency of treatment effects across various demographic and clinical factors. The benefits of Osimertinib were observed across all prespecified subgroups, indicating a consistent treatment effect, regardless of patient characteristics. The incidence of new lesions was lower with Osimertinib compared to placebo (22% versus 68%), and this included new brain lesions (8% versus 29%) and new lung lesions (6% versus 29%) respectively. The Objective Response Rate was higher with Osimertinib than with placebo (57% versus 33%). The median Duration of Response was longer with Osimertinib (36.9 months) than with placebo (6.5 months). Interim OS data showed a favorable trend for Osimertinib, although maturity was limited at the time of analysis. Further follow-up will be conducted to assess OS as a secondary endpoint. The adverse event profile of Osimertinib was generally consistent with previous studies. Grade 3 or higher adverse events occurred more frequently in the Osimertinib group, with radiation pneumonitis being the most common. However, no new safety concerns emerged during the trial.

In summary, treatment with Osimertinib resulted in significantly longer Progression Free Survival than placebo in patients with unresectable Stage III EGFR-mutated NSCLC following definitive CRT, and should be considered the new standard of care for this group of patients. Overall, the LAURA study represents a major breakthrough in the treatment of EGFR-mutated Stage III NSCLC, addressing an unmet need for targeted therapies in this setting. Further follow-up will provide additional insights into the long-term efficacy and safety of Osimertinib in this patient population.

Osimertinib after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage  III epidermal growth factor receptor-mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. Ramalingam SS, Kato T, Dong X, et al. J Clin Oncol. 2024;42(suppl 17):LBA4.

Benefits of Neoadjuvant Chemoimmunotherapy in Early Stage Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Approximately 50% of NSCLC patients are diagnosed at an early stage, when surgical resection is a viable treatment option. Among patients with early stage disease, 20% present with Stage I or II disease, while 30% present with Stage IIIA or IIIB disease. These patients are often treated with platinum-based neoadjuvant or adjuvant chemotherapy to eradicate micrometastatic disease and decrease the risk of recurrence. However, conventional neoadjuvant or adjuvant chemotherapy provides only a 5% absolute improvement in Overall Survival (OS) at 5 years and 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Combining cytotoxic chemotherapy with a PD-1 inhibitor therapy may augment the antitumor immune response through cell-death induced increased tumor antigenicity and reduction of Treg mediated immune suppression.

Neoadjuvant Immune Checkpoint Inhibitors (ICIs) have emerged as a promising approach to enhance the surgical resectability of tumors and reduce the risk of distant relapse. Clinical trials investigating the combination of neoadjuvant ICIs with platinum-based chemotherapy (ICI-chemotherapy) in resectable NSCLC have demonstrated improvements in Event-Free Survival (EFS) and a notable increase in pathologic Complete Response (pCR), which is considered a potential surrogate for Overall Survival. Consequently, regulatory agencies such as the US FDA and the European Medicines Agency have approved neoadjuvant ICI regimens for resectable NSCLC.

Several studies have suggested greater benefits in EFS and/or pCR in patients with higher PD-L1 expression in tumor cells. As a result, the European Medicines Agency has limited the use of neoadjuvant ICI therapy in combination with platinum-based chemotherapy to NSCLC patients with tumor cell PD-L1 expression of at least 1%. Other factors potentially influencing treatment outcomes include histologic features, disease stage, and smoking history. However, uncertainties remain regarding the necessity of adjuvant postoperative ICI treatment for all patients receiving neoadjuvant ICIs with chemotherapy, and the optimal duration of preoperative treatment.

The researchers therefore conducted a systematic review and meta-analysis of Randomized Clinical Trials with neoadjuvant Immune Checkpoint Inhibitors (ICIs) plus chemotherapy (ICI-chemotherapy) with or without adjuvant ICIs, to evaluate the collective benefits of neoadjuvant ICI-chemotherapy in Event-Free Survival (EFS) and pathologic Complete Response (pCR) among early-stage NSCLC patients, and additionally investigate the impact of various clinical, pathologic, and treatment-related factors. The analysis included 8 Phase II and III Randomized Clinical Trials involving 3387 previously untreated Stage IB-IIIB NSCLC patients. It compared 2-year EFS and pCR rates between patients receiving neoadjuvant chemoimmunotherapy and those patients receiving neoadjuvant chemotherapy alone. The current analysis unlike other meta-analyses that aimed to compare different perioperative ICI-based therapies, focused on limiting heterogeneity and providing consistent and clinically helpful evidence from the subgroup analysis.

The results indicated that neoadjuvant chemoimmunotherapy significantly improved both 2-year EFS and pCR rates, compared to chemotherapy alone. Neoadjuvant chemoimmunotherapy was associated with improved 2-year EFS (HR=0.57; P<0.001) and increased pCR rate (RR=5.58; P<0.001), compared to neoadjuvant chemotherapy alone. This benefit was noted regardless of age, sex, ECOG performance status, smoking history, histologic features including tumor PD=L1 status, tumor stage, type of platinum-compound chemotherapy, number of cycles of neoadjuvant chemoimmunotherapy, or addition of adjuvant Immune Checkpoint Inhibitors. Patients with tumor cells negative for PD-L1 were at higher risk of relapse (HR=0.75), than were those with low PD-L1 (HR=0.61) or high PD-L1 (HR=0.40) and this was statistically significant (P=0.005).

In conclusion, this systemic review and meta-analysis suggests that 3 cycles of neoadjuvant platinum-based Immune Checkpoint Inhibitors plus chemotherapy for early-stage NSCLC patients leads to meaningful improvements in 2-year Event Free Survival and pathologic Complete Response. It underscores the potential of this treatment approach in enhancing outcomes for NSCLC patients and provides valuable insights into optimizing treatment strategies.

Neoadjuvant Chemo-Immunotherapy for Early-Stage Non–Small Cell Lung Cancer; A Systematic Review and Meta-Analysis. Banna GL, Hassan MA, Signori A, et al. JAMA Netw Open. 2024;7(4):e246837. doi:10.1001/jamanetworkopen.2024.6837.

FDA Approves ALECENSA® as Adjuvant Treatment for ALK-Positive Non Small Cell Lung Cancer

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SUMMARY: The FDA on April 18, 2024, approved ALECENSA® (Alectinib) for adjuvant treatment following tumor resection in patients with Anaplastic Lymphoma Kinase (ALK)-positive Non Small Cell Lung Cancer (NSCLC), as detected by an FDA-approved test. Lung cancer is the second most common cancer in both men and women and accounts for about 12% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024 about 234,580 new cases of lung cancer will be diagnosed and about 125,070 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 25% are Squamous cell carcinomas, 40% are Adenocarcinomas and 10% are Large cell carcinomas.

The discovery of rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, led to the development of agents such as XALKORI® (Crizotinib), ZYKADIA® (Ceritinib), ALECENSA® (Alectinib), ALUNBRIG® (Brigatinib) and LORBRENA® (Lorlatinib), with promising results. It has become clear that appropriate molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 5%, as well as other mutations in BRAF, HER2, AKT1, fusions involving RET and ROS oncogenes and MET gene alterations. These mutations are mutually exclusive and the presence of two simultaneous mutations, are rare.

Patients with ALK-positive NSCLC tend be younger nonsmokers and present with more advanced disease. Approximately 50-60% of these patients develop brain metastases. These patients are often treated with ALK TKIs that cross the blood brain barrier. Patients with early stage resected ALK-positive NSCLC receive adjuvant treatment with platinum-based combination chemotherapy, with 5-year survival ranging from 70% for Stage IB disease to about 35% for Stage IIIA disease, with associated chemotherapy related toxicities.

Alectinib is a potent, second-generation ALK Tyrosine Kinase Inhibitor, and is effective against several ALK mutations that confer resistance to Crizotinib. In the Phase III, randomized ALEX trial, treatment naïve patients with advanced ALK-positive NSCLC who received Alectinib had significantly longer Progression Free Survival and 5-year Overall Survival, compared to those who received Crizotinib, with substantial CNS activity.

The ADAURA trial investigated adjuvant TAGRISSO® (Osimertinib), a third-generation EGFR TKI, in patients with resected EGFR-mutated NSCLC of stage IB, II, or IIIA. Results showed benefits in Disease-Free and Overall Survival, along with reduced CNS recurrence. The ALINA trial similarly assessed the efficacy of Alectinib, in resected ALK-rearranged NSCLC.

ALINA is a global, open-label, randomized, Phase III trial, conducted to investigate the efficacy and safety of adjuvant Alectinib as compared with standard chemotherapy in patients with resected ALK-positive NSCLC. In this study, 257 eligible enrolled patients (N=257) were randomly assigned 4-12 weeks after patients had undergone complete surgical resection (lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy) in a 1:1 ratio to receive Alectinib 600 mg orally twice daily or platinum-based chemotherapy IV every 21 days for 4 cycles. Alectinib was given for 24 months. Chemotherapy consisted of Cisplatin 75 mg/m2 IV on day 1 of each cycle, plus Vinorelbine 25 mg/m2 IV on days 1 and 8, Gemcitabine 1250 mg/m2 IV on days 1 and 8, or Pemetrexed 500 mg/m2 on day 1. In the event of Cisplatin intolerance, Carboplatin AUC 5 or 6 IV was substituted. Eligible patients had completely resected, histologically confirmed Stage IB (tumors 4 cm or more), II, or IIIA NSCLC, and randomization was stratified according to disease stage and race (Asian versus non-Asian). A total of 231 patients had Stage II or IIIA disease, 116 in the Alectinib group and 115 in the chemotherapy group. The Primary end point was Disease Free Survival (DFS), tested hierarchically among patients with Stage II or IIIA disease and then in the Intention-To-Treat (ITT) population. Secondary end points included CNS Disease Free Survival, Overall Survival, and Safety. The median duration of follow up was 28 months.

The DFS among patients with Stage II or IIIA disease at 2 years was 93.8% in the Alectinib group and 63.0% in the chemotherapy group, and 88.3% and 53.3% respectively at 3 years. The Hazard Ratio for disease recurrence or death was 0.24 (P<0.001), which corresponds to a 76% lower risk with adjuvant Alectinib than with chemotherapy. This DFS benefit was seen consistently across prespecified subgroups, including those defined according to disease stage, race, sex, and smoking status. An exploratory analysis showed a clinically meaningful prolongation of CNS Disease Free Survival with Alectinib. Fewer patients in the Alectinib group had CNS recurrence compared to the chemotherapy group (3.1% versus 11%), consistent with the intracranial efficacy of Alectinib in advanced NSCLC. Overall Survival data were immature at the time of data-cutoff.

The authors concluded that Adjuvant Alectinib significantly improved Disease Free Survival, as compared with platinum-based chemotherapy, among patients with resected ALK-positive NSCLC of Stage IB, II, or IIIA, with few discontinuations due to adverse events. The researchers added that this study reinforces the need for implementation of biomarker testing for ALK alterations, across all stages of NSCLC.

Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer. Wu Y-L, Dziadziuszko R, Ahn JS, et al. for the ALINA Investigators. N Engl J Med 2024;390:1265-1276.

FDA Approves RYBREVANT® in Combination with Chemotherapy for Advanced NSCLC with EGFR Exon 20 Insertion Mutations

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SUMMARY: The FDA on March 1, 2024, approved Amivantamab-vmjw (RYBREVANT®) with Carboplatin and Pemetrexed for the first-line treatment of 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. The FDA also granted traditional approval to Amivantamab-vmjw for adult patients 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. FDA previously granted accelerated approval for this indication based on Phase 1 CHRYSALIS study.

The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations, and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions and occur in about 2-3% patients with NSCLC and are insensitive to EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5-year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. There is therefore a clinically unmet need for this patient group, as there are no approved targeted therapies available, and platinum-doublet chemotherapy remains the standard of care for these patients.

Amivantamab (RYBREVANT®) is a fully human bispecific antibody directed against EGFR and MET receptors, with immune cell-directing activity. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Additionally, Amivantamab has been shown to engage macrophages, monocytes, and Natural Killer cells through its Fc domain. Amivantamab in combination with Carboplatin and Pemetrexed demonstrated synergy, with improvement in Response Rates, in previously published studies.

PAPILLON trial is an international, randomized, Phase III study, conducted to assess the efficacy and safety of Amivantamab plus chemotherapy as compared with standard chemotherapy alone, as first-line treatment, in patients with advanced NSCLC with EGFR exon 20 insertions. In this study, 308 patients (N=308) were randomly assigned 1:1 to receive Amivantamab plus chemotherapy (N=153) or chemotherapy alone (N=155), given in 3 week cycles. Amivantamab was given at a dose of 1400 mg (1750 mg for a body weight of 80 kg or more) IV weekly for the first 4 weeks, with the first infusion split over 2 days (at a dose of 350 mg on cycle 1, day 1, and the remainder on cycle 1, day 2). Starting at cycle 3 (week 7), the dose of Amivantamab was increased to 1750 mg IV (2100 mg for a body weight of 80 kg or more) administered every 3 weeks until disease progression. Carboplatin was administered at AUC 5 IV every 3 weeks for up to 4 cycles. Pemetrexed was administered at a dose of 500 mg/m2 IV every 3 weeks until disease progression. Both treatment groups were well balanced and the patients mutational status was determined by local testing of tissue samples in 92% of cases, and plasma samples in 8% of cases. Patients with treated brain metastases were eligible if they were asymptomatic. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive Amivantamab monotherapy. The Primary end point was Progression Free Survival (PFS) as determined by Blinded Independent Central Review. Secondary end points included Objective Response Rate (ORR), Overall Survival (OS), Duration of Response and Safety.

At a median follow-up of 14.9 months, the median PFS was significantly longer in the Amivantamab plus Chemotherapy group and was 11.4 months, compared to 6.7 months in the chemotherapy alone group (HR=0.40; P<0.001). At 18 months, the PFS in the Amivantamab plus chemotherapy group was 31% and 3% in the chemotherapy group. The Objective Response was 73% in the Amivantamab plus chemotherapy group and 47% in the chemotherapy alone group (P<0.001). Overall Survival results were immature at the time of current analysis, with a trend toward improvement in Overall Survival despite a high rate of crossover for the control arm (42%).

The most common adverse events associated with Amivantamab plus chemotherapy were reversible hematologic and EGFR-related toxic effects and included rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, diarrhea, nausea and vomiting. Approximately 7% of patients discontinued Amivantamab due to adverse reactions.

It was concluded that Amivantamab in combination with chemotherapy resulted in superior efficacy as compared with chemotherapy alone, in previously untreated advanced NSCLC patients with EGFR exon 20 insertions.

Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. Zhou C, Tang K-J, Cho BC, et al. for the PAPILLON Investigators. N Engl J Med 2023;389:2039-2051.