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Cancer is a complex disease that causes abnormal cell growth and spread. DNA mutations, chemical or environmental exposure, viral infections, chronic inflammation, hormone abnormalities, etc., are underlying factors that can cause cancer. Drug resistance and toxicity complicate cancer treatment. Additionally, the variability of cancer makes it difficult to establish universal treatment guidelines. Next-generation sequencing has made genetic testing inexpensive. This uncovers genetic mutations that can be treated with specialty drugs. AI (artificial intelligence), machine learning, biopsy, next-generation sequencing, and digital pathology provide personalized cancer treatment. This allows for patient-specific biological targets and cancer treatment. Monoclonal antibodies, CAR-T, and cancer vaccines are promising cancer treatments. Recent trial data incorporating these therapies have shown superiority in clinical outcomes and drug tolerability over conventional chemotherapies. Combinations of these therapies with new technology can change cancer treatment and help many. This review discusses the development and challenges of targeted therapies like monoclonal antibodies (mAbs), bispecific antibodies (BsAbs), bispecific T cell engagers (BiTEs), dual variable domain (DVD) antibodies, CAR-T therapy, cancer vaccines, oncolytic viruses, lipid nanoparticle-based mRNA cancer vaccines, and their clinical outcomes in various cancers. We will also study how artificial intelligence and machine learning help find new cancer treatment targets.

Non-small-cell lung cancer (NSCLC) frequently harbors mutations in the epidermal growth factor receptor (EGFR), with exon 20 insertions comprising 1–10% of these mutations. EGFR exon 20 insertions are less responsive to conventional tyrosine kinase inhibitors (TKIs), leading to the development of targeted agents. This review explores key therapeutic agents, such as Amivantamab, Mobocertinib, Poziotinib, Zipalertinib, and Sunvozertinib, which have shown promise in treating NSCLC with EGFR exon 20 insertions. Amivantamab, a bispecific antibody-targeting EGFR and c-MET, demonstrates significant efficacy, particularly when combined with chemotherapy. Mobocertinib, a TKI, selectively targets EGFR exon 20 mutations but faces limitations in efficacy. Poziotinib, another oral TKI, shows mixed results due to mutation-specific responses. Zipalertinib and Sunvozertinib have emerged as potent TKIs with promising clinical data. Despite these advances, challenges in overcoming resistance mutations and improving central nervous system penetration remain. Future research should focus on optimizing first-line combination therapies and enhancing diagnostic strategies for comprehensive mutation profiling.

Amivantamab is a bispecific antibody against epidermal growth factor receptor (EGFR) and MET that has been approved for nonsmall cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations and common EGFR mutations, such as exon 19 deletion and L858R. MET has attracted attention as a therapeutic target for lung cancer; however, its role in EGFR binding and amivantamab‐induced antibody‐dependent cellular toxicity (ADCC) remains unclear. We used high‐speed atomic force microscopy (HS‐AFM) to observe the real‐time binding of amivantamab to the EGFR‐extracellular domain (ECD) and MET‐ECD and visualized the binding of amivantamab to the EGFR domain 3 and MET Sema domain. Furthermore, we observed the trimer comprising amivantamab bound to EGFR and MET. Western blot analysis of the gel filtration fractions revealed that the MET‐ECD enhanced the binding of amivantamab to the EGFR‐ECD, which promoted trimer formation. Moreover, amivantamab‐induced mononuclear cell‐mediated ADCC in NSCLC cells with common EGFR mutations. ADCC activity was positively correlated with EGFR expression in tumor cells. Studies using MET‐knockout NSCLC cells revealed that MET enhanced ADCC activity with low concentrations of amivantamab. Thus, MET augments amivantamab binding to EGFR and augments ADCC activity at low amivantamab concentrations. These results indicate that binding to MET contributes to the increased efficacy of amivantamab in NSCLC with common EGFR mutations. Amivantamab binds to EGFR domain 3 and the MET Sema domain, and the EGFR‐MET‐amivantamab trimer was successfully visualized using high‐speed atomic force microscopy (HS‐AFM). MET enhances the binding of amivantamab to EGFR and increases antibody‐dependent cellular cytotoxicity (ADCC) even at low concentrations of amivantamab. These findings suggest that MET binding contributes to the enhanced therapeutic efficacy of amivantamab against EGFR‐mutated nonsmall cell lung cancer (NSCLC).

The combination of amivantamab and lazertinib has demonstrated clinically significant and sustained antitumor effects in both treatment-naïve and osimertinib-pretreated advanced non-small cell lung cancer (NSCLC) patients harboring previously untreated epidermal growth factor receptor (EGFR) mutations. A cost-effectiveness analysis was conducted to compare three therapeutic strategies, namely, amivantamab with lazertinib combination therapy, lazertinib monotherapy, and osimertinib monotherapy, for advanced NSCLC patients with EGFR mutations; the patients included both treatment-naïve individuals and those previously treated with osimertinib. Based on a previous multicenter randomized double-blind phase III trial (NCT04487080) for evaluating amivantamab-lazertinib versus osimertinib in EGFR-mutated advanced NSCLC patients (both treatment-naïve and osimertinib-pretreated), we constructed a Markov model for 3-week cycles over a 5-year horizon. The primary outcomes of the model included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER), where all economic parameters were discounted at 3.0% annually. The cost-utility analyses employed China's gross domestic product for 2023 (ranging from $12,295.7 to $36,887.0) as the willingness-to-pay (WTP) threshold supplemented by comprehensive sensitivity and scenario analyses to verify the model robustness. The economic evaluations demonstrated that compared to osimertinib monotherapy, the amivantamab-lazertinib combination yielded an additional 1.11 QALYs at an incremental cost of $1,342,374, producing an ICER of $1,211,236/QALY that substantially exceeds the $36,887 WTP threshold. Similarly, lazertinib monotherapy showed a QALY gain of 0.71 with $224,248 of additional costs (ICER = $315,640/QALY), also surpassing the lower threshold of $12,296. The sensitivity analysis showed that the predominant model driver was drug acquisition costs. The economic analyses indicate that neither amivantamab-lazertinib combination therapy nor lazertinib monotherapy represents a cost-effective first-line option for EGFR exon 20 insertion-positive NSCLC compared to osimertinib monotherapy. The substantial drug acquisition costs are the primary contributors to the unfavorable economic profiles of these treatments. Hence, future clinical implementations should carefully weigh the considerable therapeutic benefits against the significant financial burdens to achieve an optimal risk-benefit equilibrium.

Non-small cell lung cancer (NSCLC) patients with sensitizing oncogenic driver mutations benefit from targeted therapies. Tyrosine kinase inhibitors are highly effective against classic sensitizing epidermal growth factor receptor ( EGFR ) mutations, such as exon 19 deletions and exon 21 L858R point mutations. Conversely, EGFR exon 20 insertions (exon20ins) are resistant to the traditional EGFR tyrosine kinase inhibitors (TKIs). In May 2021, the US Federal Drug Administration (FDA) provided accelerated approval to amivantamab (Rybrevant) in adults with locally advanced or metastatic NSCLC with EGFR exon20ins after treatment with platinum-based chemotherapy. Amivantamab was the first EGFR/MET bispecific antibody to be approved specifically for EGFR exon20ins where there was an unmet need. Furthermore, amivantamab is being evaluated in additional settings such as post osimertinib in sensitizing EGFR mutations as well as in MET altered NSCLC. Here we discuss amivantamab in regard to its mechanism of action, preclinical and clinical data, and clinical impact for patients with EGFR exon20ins NSCLC and beyond.

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (EGFR Exon 20ins) are the third most common mutations in non‐small cell lung cancer (NSCLC) and are associated with a poorer prognosis and resistance to conventional EGFR‐tyrosine kinase inhibitors. This subpopulation analysis of the open‐label phase 3 trial (PAPILLION) evaluates the efficacy and safety of amivantamab–chemotherapy versus chemotherapy among Japanese patients with locally advanced or metastatic NSCLC with EGFR Exon 20ins mutation (ClinicalTrials.gov, NCT04538664). Patients were randomized 1:1 to either intravenous amivantamab plus carboplatin/pemetrexed chemotherapy or chemotherapy alone. The primary endpoint was progression‐free survival (PFS) by blinded independent central review; the secondary endpoints included objective response rate, duration of response, PFS after first subsequent therapy, overall survival, and safety. The overall population (n = 308) included 34 Japanese patients (amivantamab–chemotherapy, n = 19; chemotherapy, n = 15). Median PFS was 15.5 (95% CI 8.0, NE) months with amivantamab–chemotherapy compared with 5.6 (95% CI 3.0, 7.0) months (HR = 0.22 [0.09, 0.53]) for chemotherapy alone. Improvements in secondary endpoints were also greater in the amivantamab–chemotherapy arm than the chemotherapy arm. The predominant adverse events associated with amivantamab–chemotherapy were reversible hematologic and EGFR‐related toxic effects; 2 of 19 patients discontinued all study agents due to treatment‐emergent adverse events. Efficacy and safety results in this Japanese subpopulation were consistent with those in the overall population and support the first‐line use of amivantamab–chemotherapy in this setting. Early identification of patients with EGFR Exon 20ins mutations, preferably with more sensitive next‐generation sequencing‐based methods, is important to ensure appropriate patient access to amivantamab–chemotherapy. Trial Registration: ClinicalTrials.gov, NCT04538664. This subpopulation analysis of the open‐label phase 3 trial (PAPILLION) evaluates the efficacy and safety of amivantamab–chemotherapy versus chemotherapy among Japanese patients with locally advanced or metastatic NSCLC with EGFR Exon 20ins mutation. Efficacy and safety results in this Japanese subpopulation were consistent with those in the overall population.

Dysregulation of the MET tyrosine kinase receptor is a known oncogenic driver, and multiple genetic alterations can lead to a clinically relevant oncogenesis. Currently, a number of drugs targeting MET are under development as potential therapeutics for different cancer indications, including non-small cell lung cancer (NSCLC). However, relatively few of these drugs have shown sufficient clinical activity and obtained regulatory approval. One of the reasons for this could be the lack of effective predictive biomarkers to select the right patient populations for treatment. So far, capmatinib is the only MET-targeted drug approved with a companion diagnostic (CDx) assay, which is indicated for the treatment of metastatic NSCLC in patients having a mutation resulting in MET exon 14 skipping. An alternative predictive biomarker for MET therapy is MET amplification, which has been identified as a resistance mechanism in patients with EGFR-mutated NSCLC. Results obtained from different clinical trials seem to indicate that the MET/CEP7 ratio detected by FISH possesses the best predictive properties, likely because this method excludes MET amplification caused by polysomy. In this article, the concept of CDx assays will be discussed, with a focus on the currently FDA-approved MET targeted therapies for the treatment of NSCLC.

Improved efficacy has been shown for amivantamab and amivantamab-based combination therapies in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) compared to established treatment options in clinical trials. However, a high risk of venous thromboembolism (VTE) was observed in patients treated with amivantamab-based therapies, with considerable differences in VTE risk according to the line of systemic treatment, concomitant treatment with lazertinib, and intravenous vs. subcutaneous amivantamab administration. Based on early reports of high VTE rates, prophylactic anticoagulation has been implemented in ongoing clinical trials for the first 4 months of amivantamab–lazertinib therapy. However, open questions remain concerning the type, dosing, and duration of primary pharmacological thromboprophylaxis in patients treated with amivantamab-based therapies. Therefore, the aim of this clinical opinion piece is to provide provisional guidance on how to mitigate VTE risk in patients treated with amivantamab-based therapies following existing clinical practice guidelines on primary thromboprophylaxis and treatment of VTE in ambulatory patients with cancer.

Background Epidermal growth factor receptor ( EGFR ) mutations represent one of the most frequent oncogenic driver in non-small cell lung cancer (NSCLC). Amivantamab, a bispecific antibody targeting EGFR and MET proto-oncogene, receptor tyrosine kinase (MET), has demonstrated clinical benefit in EGFR -mutant NSCLC through dual blockade, but its immunological role in human clinical specimens, especially tumor-infiltrating lymphocytes (TILs), has not been directly evaluated. Methods We analyzed surgically resected tumor samples from 40 patients with NSCLC to investigate immune responses and their associations with EGFR and MET expression. TILs were characterized by flow cytometry (FCM) and immunohistochemistry (IHC). To assess the immunomodulatory potential of amivantamab, fresh tumor digests containing live tumor cells and TILs were cultured ex vivo with CD3 and CD28 stimulation in the absence or presence of amivantamab, followed by FCM. EGFR and MET expression were also evaluated by IHC. Results EGFR mutations and high EGFR protein expression were associated with a trend toward reduced CD8⁺ T-cell and dendritic cell (DC) infiltration. In ex vivo TIL assays, exposure to amivantamab significantly activated CD8⁺ T cells, such as programmed cell death-1 expression and cytokine production, and promoted DC maturation. These effects were most pronounced in tumors with high EGFR or MET protein expression rather than EGFR mutations. Conclusions This study provides the first direct evidence from ex vivo fresh TIL assays using human NSCLC clinical specimens that amivantamab can activate immune responses. EGFR and MET expression may serve as potential biomarkers for amivantamab-induced immune responses.

Osimertinib has been the standard treatment for advanced Epidermal Growth Factor Receptor (EGFR)-driven non-small cell lung cancer (NSCLC) for many years. However, even with remarkable response rate, progression-free survival (PFS) and survival benefit as compared to the old generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, treatment outcomes for these subsets of patients remain a challenge. Recently, in order to go beyond osimertinib, new treatment strategies have been developed. In particular, in the FLAURA 2 phase III randomized trial, the combination of platin-based chemotherapy and osimertinib showed impressive PFS benefits as compared to single-agent osimertinib. Furthermore, in the MARIPOSA phase III randomized study, the combination of the anti-EGFR and anti-MET monoclonal antibody amivantamab combined with the new anti-EGFR TKI lazertinib demonstrated remarkable PFS benefit as compared to single agent osimertinib. This paper will discuss these new treatment options and potential selection criteria for personalized treatment of patients.