The antibody, linker, and payload moieties all play a significant role in giving the ADC its unique therapeutic potential. The antibody subclass employed in ADCs is determined based on relative individual receptor affinities and pharmacokinetics. Meanwhile, the linker used in an ADC can either be cleavable or non-cleavable. ADC therapy comprises antibody-dependent mechanisms in addition to the direct cytotoxic effects of the payload. These include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, as well as the “bystander effect”, which refers to the diffusion of a portion of the cytotoxic molecules out of the target cell, exerting its cytotoxic effect on the adjacent cells. Target antigens of ADCs are expected to be expressed on the membranes of the cancer cells facing the external matrix, although new approaches utilize antigens regarding tumor-associated cells, the tumor microenvironment, or the tumor vasculature. These target antigens of ADCs not only determine the efficacy of these agents but also impact the off-targets and related adverse effects. The majority of ADC-related toxicities are associated with off-targets. The proposed mechanisms of ADC resistance include disrupted intracellular drug trafficking, dysfunctional lysosomal processing, and the efflux of the cytotoxic molecule via ATP-binding cassette (ABC) transporters. The latter mechanism is especially prominent for multi-drug-resistant tumors. An important limitation of ADCs is the penetration of the conjugate into the tumor microenvironment and their delivery to target cancer cells. Cancerous tissues’ vascular profile and the steric “binding site barrier” formed around the peripheral vessels of tumors stand as potential challenges of ADC therapy for solid tumors. As research efforts focus on reducing toxicities, overcoming resistance, and improving pharmacokinetics, ADC options for cancer therapy are expected to continue to diversify, including standalone approaches and combination therapies.

The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

Background: Lung cancer is a leading cause of cancer-related deaths, with Non-Small Cell Lung Cancer (NSCLC) comprising 85–90% of cases, most commonly adenocarcinoma. Key mutations include EGFR Exon 19 deletions and Exon 21 L858R. While third-generation TKIs like osimertinib, lazertinib, and aumolertinib are effective, resistance often arises. Amivantamab, a bispecific monoclonal antibody targeting EGFR and c-MET, shows promise, particularly against EGFR Exon 20 insertions. Objective: To provide a comprehensive evaluation of the adverse effects associated with amivantamab in EGFR-mutant NSCLC, including their underlying pathophysiological mechanisms and evidence-based management strategies. In addition, this review aims to contextualize the clinical relevance of amivantamab by briefly outlining the therapeutic evolution of EGFR-targeted treatments, highlighting the rationale for its development, and current positioning in treatment paradigms. Methods: A comprehensive review of clinical trials, including CHRYSALIS, PAPILLON, MARIPOSA, and PALOMA-III, was conducted to assess the safety and efficacy of amivantamab. Practical and early insights into managing adverse effects of amivantamab are critical to better adherence and quality of life. Results: Adverse effects were observed in most of the patients treated with amivantamab. Common side effects included cutaneous toxicities, diarrhea, infusion-related reactions (IRRs), vascular thrombosis and pneumonitis. The most frequent cutaneous side effects were rash, paronychia, pruritis, and stomatitis. Diarrhea occurred in patients primarily due to EGFR inhibition. IRRs were predominantly mild to moderate, occurring mainly during the first cycle. Thrombosis was a notable adverse effect observed, even in patients receiving anticoagulant prophylaxis. Pneumonitis was less common but severe. Management: Adverse effects of amivantamab are managed based on severity. Cutaneous toxicities are treated with antibiotics, topical steroids, and dose adjustments. Diarrhea is managed with hydration, loperamide, and dose interruption. Infusion-related reactions (IRRs) are treated symptomatically, with epinephrine in severe cases. Anticoagulants are used for deep vein thrombosis or thromboembolism, and fibrinolytics or thrombectomy may be considered. Pneumonitis is managed by discontinuing amivantamab and using glucocorticoids. Conclusions: Amivantamab is effective for EGFR mutant NSCLC but can cause adverse effects. Understanding these effects and implementing management strategies can optimize outcomes, maintaining treatment efficacy.

The antibody, linker and payload moieties all play a significant role in rendering the ADC its unique therapeutic potential. The antibody subclass employed in ADCs is determined based on relative individual receptor affinities and pharmacokinetics. Meanwhile, the linker used in an ADC can either be cleavable or non-cleavable. ADC therapy comprises antibody-dependent mechanisms in addition to the direct cytotoxic effects of the payload. These include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, as well as the “bystander effect,” which refers to the diffusion of a portion of the cytotoxic molecules out of the target cell, exerting its cytotoxic effect on the adjacent cells. Target antigens of ADCs are expected to be expressed on the membranes of the cancer cells facing the external matrix, although new approaches utilize antigens regarding tumor-associated cells, tumor microenvironment, or tumor vasculature. These target antigens of ADCs not only determine the efficacy of these agents but also impact the off-targets and related adverse effects. The majority of ADC-related toxicities are associated with off-targets. Proposed mechanisms of ADC resistance include disrupted intracellular drug trafficking, dysfunctional lysosomal processing, and the efflux of the cytotoxic molecule via ATP-binding cassette (ABC) transporters. The latter mechanism is especially prominent for multi-drug resistant tumors. An important limitation of ADCs is the penetration of the conjugate into the tumor microenvironment and their delivery to target cancer cells. Cancerous tissues’ vascular profile and the steric “binding site barrier” formed around the peripheral vessels of a tumor stand as potential challenges of ADC therapy for solid tumors. As research efforts focus on reducing toxicities, overcoming resistance, and improving pharmacokinetics, ADC options for cancer therapy are expected to continue to diversify, including standalone approaches and combination therapies.

Background: Although CDK4/6 inhibitors combined with endocrine therapies have improved outcomes in HR+ HER2-negative metastatic breast cancer, predictive biomarkers for treatment response and adverse effects remain limited. This study assessed the prognostic and predictive value of large unstained cells (LUC), a subset of white blood cells that may reflect immune status or treatment response. Methods: A retrospective analysis of 210 patients with HR+ HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors between 2021 and 2024 was conducted. Clinical data, including demographics, tumor characteristics, and treatment regimens, were analyzed. Based on LUC levels, progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. Results: The cohort had a median age of 57, of which 78% were postmenopausal. Common metastatic sites included bone (67%) and liver (24%). At a median follow-up of 18.5 months, the PFS and OS rates were 65% and 83%. Patients with low LUC levels had significantly shorter PFS (OR: 1.91; p = 0.014) and OS (OR: 2.39; p = 0.012), while high LUC levels correlated with a lower incidence of grade 3 neutropenia (OR: 0.49; p = 0.017). Liver metastasis and prior treatments were also linked to shorter survival. Conclusions: LUC levels emerge as a promising biomarker for predicting survival outcomes and the risk of neutropenia in HR+ HER2-negative metastatic breast cancer patients treated with CDK 4/6 inhibitors and endocrine therapy, showing their potential to guide personalized treatment approaches.

Purpose: CDK4/6 inhibitors require meticulous monitoring due to their potential to cause hematological toxicities and hepatotoxicity. This study evaluates the safety of combining CDK4/6 inhibitors with palliative radiotherapy in patients with metastatic hormone receptor-positive and HER2-negative breast cancer. Patients and Methods: This study included 188 patients treated with CDK4/6 inhibitors between January 2021 and June 2024. Data on patient demographics, tumor characteristics, and treatment interventions were extracted from medical records. The primary focus was on the incidence of grade ≥ 3 hematologic toxicities and hepatotoxicity, assessed according to CTCAE 5.0 criteria, in those receiving concurrent palliative radiotherapy. Results: With a median follow-up of 18.5 months, the 18-month PFS and OS rates were 67% and 85%, respectively. The median age was 57.5 years, and 79% of patients were post-menopausal. Bone and liver metastases were present in 66% and 23% of patients, respectively. Concurrent palliative radiotherapy was administered in 25% of the cohort. The incidence of grade ≥ 3 hematologic toxicity was comparable between those who received radiotherapy and those who did not. Ribociclib use was associated with lower rates of grade 3 hematologic toxicity (OR: 0.37), neutropenia (OR: 0.41), dose interruptions (OR: 0.30), and dose reductions (OR: 0.37). Pre-menopausal status was linked to fewer dose reductions (OR: 0.17). Rates of treatment interruption, dose reduction, and withdrawal were 55%, 24%, and 2%, respectively. Conclusions: The concurrent use of CDK4/6 inhibitors and palliative radiotherapy does not increase the incidence of hematological adverse events in patients with metastatic breast cancer.