Category: Meeting Updates

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: BLENREP®, Pomalidomide and Dexamethasone in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024 and 12,540 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease.

Patients with newly diagnosed multiple myeloma often receive triplet and quadruplet regimens that incorporate proteasome inhibitors, immunomodulators, and anti-CD38 antibodies as first line therapy, as these regimens are associated with prolonged Progression Free Survival and Overall Survival. However, most patients relapse and frontline use of Lenalidomide therapy has increased the number of patients with Lenalidomide-refractory disease at the time of the first relapse. New novel combinations are needed for patients who have relapsed or refractory myeloma, after disease progression during frontline therapy.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and multiple myeloma. B-Cell Maturation Antigen is therefore an established target in myeloma.

Belantamab mafodotin (BLENREP®) is a BCMA-targeting antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. Among patients with relapsed or refractory myeloma, data from a Phase I-II trial involving Belantamab mafodotin, Pomalidomide, and Dexamethasone (BPd) showed some safety concerns but promising clinical activity.

The DREAMM-8 is an ongoing, global, open-label, randomized, multicenter Phase III trial, conducted to evaluate the efficacy and safety of Belantamab mafodotin in combination with Pomalidomide and Dexamethasone (BPd) compared to the standard of care, Pomalidomide, Bortezomib, and Dexamethasone (PVd), in patients with relapsed or refractory multiple myeloma (RRMM) who had received at least one prior line of therapy, including a Lenalidomide-containing regimen, and experienced disease progression. In this study, 302 patients were randomized 1:1 to BPd regimen (N=155) or PVd regimen (N=147). Patients in the BPd group received Belantamab mafodotin 2.5 mg/kg IV on Day 1 of Cycle 1, then 1.9 mg/kg on Day 1 of subsequent cycles, plus Pomalidomide 4 mg orally daily on Days 1-21 of each cycle, and Dexamethasone 40 mg orally weekly on Day 1 of each cycle. Patients in the PVd group received Pomalidomide 4 mg orally daily on Days 1-14 of each 21-day cycle, Bortezomib 1.3 mg/m² subcutaneously on Days 1, 4, 8, 11 (Cycles 1-8) and Days 1, 8 (Cycle 9+), and Dexamethasone 20 mg orally on the day of and day after Bortezomib. The median age was 67 years, 86% were Caucasian, 33% had high risk cytogenetics, 28% had previous anti-CD38 antibodies and approximately 60% of patients had Autologous Stem-Cell Transplantation (ASCT). The Primary Endpoint was Progression-Free Survival (PFS) evaluated by an Independent Review Committee (IRC) and Secondary Endpoints included Overall Survival (OS), Overall Response Rate (ORR) defined as the proportion of patients achieving Partial Response (PR) or better according to the International Myeloma Working Group (IMWG) criteria, Duration of Response and Safety.

At a median follow-up of 21.8 months, the median PFS was not reached (NR) in the BPd arm versus 12.7 months in the PVd arm (HR=0.52; P<0.001). The 12-month estimated PFS rate was 71% with BPd versus 51% with PVd. The ORR in the BPd group was 77% and in the PVd group was 72%. The Complete Response (CR) or better was 40% in the BPd group and 16% in the PVd group, and the median Duration of Response was Not Reported with BPd versus 17.5 months with PVd. With regards to Overall Survival, a positive trend favoring BPd was observed (HR 0.77; 95% CI 0.53-1.14), although data were immature at the time of analysis. Follow-up for OS is ongoing.

Adverse Events occurred in more than 99% of patients in the BPd arm and 96% in the PVd arm. Ocular adverse events were common with BPd (89%, Grade 3/4 in 43%) versus PVd (30%, Grade 3/4 in 2%). These adverse events were mitigated by Belantamab mafodotin dose modifications. Treatment was discontinued due to adverse events in 9% of patients in the BPd arm versus none in the PVd arm.

In summary, the DREAMM-8 trial provides robust evidence of the clinical efficacy and safety of Belantamab mafodotin in combination with Pomalidomide and Dexamethasone for relapsed or refractory multiple myeloma patients, addressing the critical need for effective therapies post-Lenalidomide exposure. Despite higher rates of ocular adverse events with Belantamab mafodotin, these toxicities can be effectively managed with dose adjustments, ensuring continued patient safety and treatment compliance.

Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM). Trudel S, Beksac M, Pour L, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA105). DOI: 10.1200/JCO.2024.42.17_suppl.LBA105

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: ENHERTU® Improves PFS in HR-Positive, HER2-Low and HER-Ultralow Metastatic Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with high levels of HER2 expression (IHC 3+ or 2+/FISH+) are classified as HER2-positive. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. Tumors that are not classified as HER2-positive are classified as HER2-negative. Despite being classified as HER2-negative, majority these tumors still have some level of HER2 expression.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. It is estimated that approximately 60-65% of HR-positive/HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action. Further, there are no targeted therapies specifically approved for patients with HER2-low or HER2-ultralow expression, prior to chemotherapy.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), another ADC targeting HER2, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

DESTINY-Breast06 is a global, randomized, open-label Phase III trial evaluating the efficacy and safety of ENHERTU® versus chemotherapy in patients with HR-positive, HER2-low, or HER2-ultralow advanced or metastatic breast cancer. This study enrolled 866 patients (N=713 for HER2-low and N=153 for HER2-ultralow). HER2-low was defined as IHC 1+ or 2+ or FISH negative and HER2-ultralow was defined as IHC 0 with membrane staining. Patients were randomized 1:1 to receive ENHERTU® 5.4 mg/kg every 3 weeks (N=436) or physicians choice of chemotherapy which included Capecitabine, Paclitaxel, or nab-Paclitaxel (N=430). Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment, or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months. Patients were stratified based on prior CDK4/6 inhibitor use, HER2 expression and prior taxane use in the non-metastatic setting. Patients in the trial had received a median of two prior lines of endocrine therapy. In the overall trial population, 14.9% of patients in the ENHERTU® group and 19.2% in the chemotherapy group had received one prior line of endocrine therapy. No patients had received prior chemotherapy for metastatic disease. The Primary endpoint was Progression Free Survival (PFS) in the HER2-low patient population as measured by Blinded Independent Central Review (BICR). Key Secondary endpoints included Progression Free Survival (PFS) in the overall trial population (HER2-low and HER2-ultralow), Overall survival (OS) in the HER2-low patient population, Objective Response Rate (ORR), Duration of response (DOR) and Safety. The median duration of follow-up was 18.2 months.

In the primary analysis of this study, results showed that in the HER2-low expression patients, ENHERTU® reduced the risk of disease progression or death by 38%, with a median PFS was 13.2 months in the ENHERTU® group, compared to 8.1 months for chemotherapy (HR=0.62; P<0.0001). For the overall trial population (HER2-low and HER2-ultralow), the median PFS results were similar and the median PFS was 13.2 months for ENHERTU® versus 8.1 months for chemotherapy (HR=0.63; P<0.0001). ENHERTU® reduced the risk of disease progression or death by 37% compared to chemotherapy.

A prespecified exploratory analysis showed that the improvement in PFS was consistent between patients with HER2-low and HER2-ultralow expression. In patients with HER2-ultralow expression, ENHERTU® reduced the risk of disease progression or death by 22% compared to chemotherapy, with a median PFS of 13.2 months versus 8.3 months, respectively (HR=0.78).

The Objective Response Rate (ORR) in HER2-Low Population was 56.5% for ENHERTU® compared to 32.2% for chemotherapy, in the Overall Trial Population was 57.3% for ENHERTU® versus 31.2% for chemotherapy, and in the HER2-Ultralow Subgroup was 61.8% for ENHERTU® versus 26.3% for chemotherapy. The median duration of response across these three groups was 14.3 months.

The safety profile of ENHERTU® was consistent with previous breast cancer clinical trials and no new safety concerns identified. The most common Grade 3 or higher treatment-related adverse events occurring in 5% or more of patients treated with ENHERTU® were neutropenia (20.7%) and anemia (5.8%). Interstitial Lung Disease (ILD), adjudicated as drug-related by an independent committee, occurred in 11.3% of patients treated with ENHERTU®. The majority of ILD events were low grade.

The results from the DESTINY-Breast06 trial underscore the significant clinical benefits of ENHERTU® in improving PFS and ORR in patients with HR-positive, HER2-low, and HER2-ultralow metastatic breast cancer, offering a promising alternative to standard chemotherapy. These findings highlight the potential of ENHERTU® to become a new standard of care for this patient population, pending further investigation and regulatory approval. The detailed positive outcomes underscore the clinical benefits and reinforce the promise of ENHERTU® in treating this challenging cancer subtype.

Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). Curigliano G, Hu X, Dent RA, et al. J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000.

Late Breaking Abstract – ASCO 2024: IMFINZI® as Consolidation Treatment for Limited Stage Small Cell Lung Cancer

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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 about 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) accounts for approximately 13-15% of all lung cancers and is aggressive.

Limited Stage-Small Cell Lung Cancer – LS-SCLC (Stage I-III) accounts for approximately 30% of SCLC diagnoses and the disease is confined to one hemithorax. These patients are often treated with a combination of Carboplatin or Cisplatin with Etoposide and radiotherapy. Despite initial response, LS-SCLC typically recurs and progresses rapidly, and only 15-30% of patients are alive five years after diagnosis.

Based on the premise that SCLC has a high mutation rate, it was hypothesized that these tumors may be immunogenic and more recently immunotherapy with checkpoint inhibitors has demonstrated clinical activity in SCLC. IMFINZI® (Durvalumab) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) receptor and CD80, thereby unleashing the T cells to recognize and kill tumor cells. IMJUDO® (Tremelimumab) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses.

The rationale for the ADRIATIC trial was supported by findings from the pivotal Phase III PACIFIC and CASPIAN trial. In the PACIFIC trial, Durvalumab after concurrent chemoradiotherapy for Stage III Non-Small Cell Lung Cancer, improved both Overall Survival (OS) and Progression Free Survival (PFS), whereas in the CASPIAN trial, Durvalumab with Platinum and Etoposide chemotherapy significantly improved OS, compared to chemotherapy alone, in newly diagnosed patients with extensive-stage SCLC.

The ADRIATIC trial is a Phase III, randomized, double-blind, placebo-controlled, multicenter, global study that assessed the efficacy and safety of Durvalumab (IMFINZI®) as consolidation therapy in patients with Limited-Stage Small Cell Lung Cancer (LS-SCLC) who had not progressed after concurrent platinum-based chemoradiotherapy. This trial enrolled 730 patients with Stage I to III LS-SCLC, including those with inoperable Stage I/II disease. Eligible patients had a WHO Performance Status of 0 or 1, and had not experienced disease progression after completing concurrent chemoradiotherapy. Chemotherapy consisted of a combination of Platinum plus Etoposide for up to 4 cycles, and the radiation therapy could either be once daily up to 66 Gy, or twice a day up to 45 Gy. Prophylactic Cranial Irradiation (PCI) was allowed before randomization. Patients were randomized within 6 weeks after completing concurrent chemoradiotherapy to experimental arms Durvalumab monotherapy 1500 mg IV every 4 weeks with or without Tremelimumab 75 mg IV every 4 weeks for up to 4 cycles each, followed by Durvalumab every four weeks for up to 24 months or Placebo every 4 weeks. Baseline characteristics and prior treatment were well balanced between groups. This analysis compared the outcomes in patients assigned to receive Durvalumab monotherapy (N=264) with patients who received placebo (N=266). The dual Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) for Durvalumab monotherapy versus placebo. Key secondary endpoints included OS and PFS for Durvalumab plus Tremelimumab versus placebo, Safety, and Quality of Life measures. The median duration of follow-up for OS and PFS in censored patients at this first planned interim analysis was 37.2 and 27.6 months, respectively.

The median OS with Durvalumab was 55.9 months, compared to 33.4 months with placebo. Durvalumab demonstrated a statistically significant improvement in OS compared to placebo (HR=0.73; P=0.0104), translating to a 27% reduction in the risk of death. The median PFS was 16.6 months with Durvalumab versus 9.2 months with placebo, representing a 24% reduction in the risk of disease progression or death (HR=0.76; P=0.0161). The 24-month OS rate was 68% with Durvalumab versus 58.5% with placebo, and the 36-month OS rate was 56.5% versus 47.6%, respectively. The 18-month PFS rate was 48.8% with Durvalumab versus 36.1% with placebo, and the 24-month PFS rate was 46.2% with Durvalumab versus 34.2% with placebo. Treatment benefit was generally consistent across predefined patient subgroups for both OS and PFS.

Grade 3/4 Adverse Events (AEs) were similar in both treatment groups at 24.3%, but treatment discontinuation due to AEs was slightly higher in the Durvalumab arm (16.3% versus 10.6% in the placebo arm). Any grade pneumonitis was reported in 38.0% of patients in the Durvalumab arm compared to 30.2% in the placebo arm.

The results of the ADRIATIC trial represent a significant advancement in the treatment of Limited Stage-Small Cell Lung Cancer (LS-SCLC). Durvalumab consolidation therapy demonstrated a statistically significant and clinically meaningful improvement in both OS and PFS compared to placebo. These findings support Durvalumab as a new standard of care for patients with LS-SCLC following concurrent chemoradiotherapy, potentially changing the treatment landscape for this aggressive disease. Further analyses, including subgroup analyses and assessment of the Durvalumab plus Tremelimumab combination, are ongoing to optimize treatment strategies for LS-SCLC patients.

ADRIATIC: Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). Spigel DR, Cheng Y, Cho BC, et al. J Clin Oncol. 2024;42(suppl 17):LBA5. doi.org/10.1200/JCO.2024.42.17_suppl.LBA5

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.

Late Breaking Abstract – ASCO 2024: SCEMBLIX® Superior to Other TKIs in Newly Diagnosed Chronic Myeloid Leukemia

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SUMMARY: The American Cancer Society estimates that about 9,280 new CML cases will be diagnosed in the United States in 2024 and about 1,280 patients will die of the disease. Chronic Myeloid Leukemia (CML) constitutes about 15% of all new cases of leukemia and the average age at diagnosis of CML is around 64 years. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells.

The Tyrosine Kinase Inhibitors (TKIs) approved for newly diagnosed chronic phase CML in the United States share the same therapeutic target, which is the ATP-binding site of BCR-ABL1 kinase. They include first-generation TKI Imatinib (GLEEVEC®) or second-generation TKIs Nilotinib (TASIGNA®), Dasatinib (SPRYCEL®), or Bosutinib (BOSULIF®). Imatinib is associated with lower patient response and a higher incidence of disease progression than those with second-generation TKIs, whereas treatment with second-generation TKIs can result in faster, deeper molecular responses than Imatinib in frontline therapy, but are associated with more adverse events, necessitating dose modifications and switching treatments. Further, close to 50% of clinical resistance is associated with the acquisition of mutations in this region of the kinase, resulting in conformational changes that render TKIs inactive. Therefore resistance to one of the TKIs, will likely result in resistance to the others as well. Further, the “gatekeeper” T315I mutation, which has been reported in 20% of patients with mutations, confers resistance to all clinically available TKIs except Ponatinib (ICLUSIG®). There is therefore an unmet need for a safe and effective frontline therapy for patients with newly diagnosed chronic phase CML

Asciminib (SCEMBLIX®) is a novel, first-in-class, potent and specific, oral BCR-ABL1 inhibitor that does not bind to the ATP-binding site of the kinase. Instead, it specifically targets the ABL1 myristoyl pocket, also known as a STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, with activity against native unmutated BCR-ABL1, and all clinically observed ATP-site mutants, including T315I. In a Phase I study, Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom Ponatinib had failed, and those with a T315I mutation.

Asciminib is approved in the US for the treatment of adults with Philadelphia Chromosome positive chronic phase CML who have previously been treated with two or more TKIs. It is also approved in patients with Philadelphia Chromosome positive chronic phase CML with the T315I mutation.

The ASC4FIRST study is a pivotal Phase III, multi-center, open-label, randomized trial aimed at evaluating the efficacy and safety of Asciminib compared to investigator-selected Tyrosine Kinase Inhibitors (TKIs) in adult patients with newly diagnosed Philadelphia chromosome positive Chronic Myeloid Leukemia in chronic phase (CML-CP). A total of 405 patients were enrolled and were randomly assigned in a 1:1 ratio to receive either Asciminib 80 mg orally once daily (N=201) or investigator-selected TKIs which included Imatinib and second generation TKIs such as Bosutinib, Dasatinib or Nilotinib given at approved doses (N=204). Before randomization, investigators after discussing with patients selected a TKI (either Imatinib or one of the second-generation TKIs a patient would take, if randomly assigned to the comparator group-prerandomization selected TKI), considering treatment goals, disease and patient characteristics, and coexisting conditions. Randomization was stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk), and by TKI selected by investigators before randomization. The two Primary objectives of this study were to compare the efficacy of Asciminib with that of investigator-selected TKIs (all members of this class considered together as a group), and to compare the efficacy of Asciminib with that of Imatinib. Asciminib was not compared with second-generation TKIs as a primary objective. The Primary end point for both objectives was Major Molecular Response (defined as BCR/ABL1 transcript levels 0.1% or less on the International Scale at week 48 that did not meet any treatment failure criteria. The Secondary objective of this study was assessment of Major Molecular Response (MMR) at week 48 with Asciminib, as compared with investigator-selected TKIs among patients with second-generation TKIs as their prerandomization-selected TKI. The median follow-up was 16.3 months in the Asciminib group and 15.7 months in the investigator-selected TKI group.

At the 48-week mark, Asciminib demonstrated a significantly higher MMR rate compared to investigator-selected TKIs (67.7% versus 49.0%; P<0.001). Deep molecular response rates (BCR/ABL1 transcript levels 0.01% or less, were also superior in the Asciminib group compared to investigator-selected TKIs (38.8% versus 20.6%). Patients preselected for Imatinib who were randomized to Asciminib achieved an MMR rate of 69.3% compared to 40.2% in the Imatinib group. Among those preselected for second-generation TKIs, the MMR rate was 66.0% for Asciminib versus 57.8% for the second-generation TKI group.

Asciminib exhibited a favorable safety profile with fewer Grade 3 or higher Adverse Events and lower rates of treatment discontinuation due to Adverse Events. Grade 3 or higher Adverse Events for Asciminib was 38%, for Imatinib was 44.4% and for second-generation TKIs was 54.9%. Discontinuation due to Adverse Events for Asciminib was 4.5%, for Imatinib was 11.1% and for Second-generation TKIs was 9.8%.

It was concluded that Asciminib is the only agent to demonstrate superiority over investigator selected standard-of-care TKIs in achieving higher MMR rates at 48 weeks in newly diagnosed chronic phase CML patients, alongside a better safety and tolerability profile. These findings indicate that Asciminib could significantly improve the treatment landscape for this group of patients, offering hope for better disease control and quality of life, thereby addressing key unmet needs in CML management.

ASC4FIRST, a pivotal phase 3 study of asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed patients (pts) with chronic myeloid leukemia (CML): Primary results. Hughes TP, Hochhaus A, Takahashi N, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA6500)

Bispecific Immune Checkpoint Inhibitor Improves Survival in Gastric and GEJ Cancer Regardless of PD-L1 Status

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SUMMARY: The American Cancer Society estimates that in the US about 26,890 new gastric cancer cases will be diagnosed in 2024 and about 10,880 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for gastric cancer. Additionally, one of the strongest risk factor for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 15%. These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6 or CAPOX. Patients with HER2-positive disease are usually treated with chemotherapy plus Trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor, or checkpoint inhibitor alone, if the tumors express PD-L1.

Cadonilimab (AK104) is a human, bispecific IgG1 antibody with high binding avidity especially to high density of PD-1 and CTLA-4 due to its tetravalent design, and could simultaneously bind different cells expressing PD-1 and CTLA-4, respectively. By effective blocking both PD-1 and CTLA-4 pathways, Cadonilimab activates T cells by increasing interleukin-2 (IL-2) and interferon-gamma secretion to similar extent, as compared with anti-PD-1 and anti-CTLA-4 combination.

COMPASSION-15 is a double-blind, randomized, multicenter, Phase III trial that enrolled 610 patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. They were randomly assigned 1:1 to receive either Cadonilimab in combination with Oxaliplatin and Capecitabine chemotherapy, or placebo plus the same chemotherapy. Chemotherapy with Oxaliplatin and Capecitabine was given every 3 weeks for up to six cycles. Capecitabine was administered at 1000 mg/m2 orally twice daily on days 1 through 14 every 3 weeks and Oxaliplatin IV at 130 mg/m2 every 3 weeks. Cadonilimab 10 mg/kg IV or placebo was given on day 1 of each cycle every 3 weeks. Following the 6 cycles, patients then received Cadonilimab 10 mg/kg IV monotherapy or placebo every 3 weeks. Stratification factors included ECOG performance status (0 versus 1), PD-L1 expression (CPS 5% or more, or less than 5%), and the presence or absence of liver metastasis. The Primary endpoint was Overall Survival (OS) in the Intent to Treat (ITT) population.

The researchers herein presented the interim analysis data of COMPASSION-15 trial. The results revealed a significant improvement in Overall Survival with Cadonilimab combination therapy compared to placebo. The median OS was 15.0 months with Cadonilimab combination, compared with 10.8 months for those in the placebo arm (HR=0.60; P<0.001). The 18-month Overall Survival rate was 45.8% in the Cadonilimab group versus 25.5% in the placebo group.

Subgroup analysis based on PD-L1 expression levels (CPS 5% or more, or less than 5%) also demonstrated favorable outcomes with Cadonilimab across all strata. Among patients with a PD-L1 CPS of less than 5%, Cadonilimab combination achieved a median OS of 14.8 months, compared with 11.1 months in the placebo group. The 18-month OS rates were 44.1% compared with 27.5%, respectively.

Progression-Free Survival (PFS), another critical measure of treatment efficacy, showed consistent benefits with Cadonilimab combination compared to placebo plus chemotherapy, irrespective of PD-L1 expression. Median PFS was 7 months versus 5.3 months in the ITT population, with similar trends observed in CPS 5% or more, and less than 5% subgroups.

The safety analysis revealed no new safety signals. However, Grade 3 or higher treatment-related adverse events were more commonly reported in the combination therapy group compared to the placebo group. Treatment-related adverse events leading to therapy discontinuation were also more frequent in the Cadonilimab group.

It was concluded from this study that Cadonilimab is the first PD-1/CTLA-4 bispecific antibody to demonstrate substantial improvements in Overall Survival and Progression-Free Survival benefit in combination with chemotherapy, offering a potential new standard of care for patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. This study represents a significant milestone in the quest for improved first-line treatments for gastric and GEJ cancers, even for patients with low PD-L1 expression tumors.

Cadonilimab plus chemotherapy versus chemotherapy as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (COMPASSION-15): A randomized, double-blind, phase 3 trial. Ji J, Shen L, Li Z, et al. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA.

Neoadjuvant KEYTRUDA® plus Chemotherapy Significantly Improves EFS in Early Stage High Risk Triple Negative Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival (OS) of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

Neoadjuvant chemotherapy is the preferred treatment approach in this group of patients and can potentially increase the likelihood of tumor resectability and breast conservation. Further, a pathological Complete Response (pCR) after neoadjuvant chemotherapy can result in a longer Event-Free Survival and Overall Survival. Pathological Complete Response is therefore used as an end point for clinical testing of neoadjuvant treatment in patients with early triple-negative breast cancer.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Pembrolizumab when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent Pembrolizumab in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10-21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, Pembrolizumab combination achieved pathological Complete Response rate of 65%, regardless of PD-L1 expression.

KEYNOTE-522 trial is a multicenter, randomized, double-blind, placebo-controlled Phase III trial, conducted to evaluate the efficacy and safety of neoadjuvant Pembrolizumab plus chemotherapy as compared with neoadjuvant placebo plus chemotherapy, followed by adjuvant Pembrolizumab or placebo in patients with early stage, high-risk, Triple Negative Breast Cancer. In this study, total of 1174 patients (N=1174) regardless of tumor PD⁠-⁠L1 expression, were randomly assigned 2:1 to receive Pembrolizumab plus chemotherapy (N=784) or placebo plus chemotherapy (N=390). Eligible patients had newly diagnosed, previously untreated, Triple Negative Breast Cancer, with tumor size more than 1 cm but 2 cm or less in diameter with nodal involvement, or tumor size more than 2 cm in diameter regardless of nodal involvement. Patients in the neoadjuvant phase received four cycles of Pembrolizumab 200 mg IV or placebo once every 3 weeks plus Paclitaxel 80 mg/m2 once weekly plus Carboplatin AUC 5 IV once every 3 weeks or Carboplatin AUC 1.5 IV once weekly in the first 12 weeks (first neoadjuvant treatment), followed by four cycles of Pembrolizumab or placebo along with Doxorubicin 60 mg/m2 IV or Epirubicin 90 mg/m2 IV plus Cyclophosphamide 600 mg/m2 IV once every 3 weeks in the subsequent 12 weeks (second neoadjuvant treatment). Patients then underwent definitive surgery (breast conservation or mastectomy with sentinel lymph-node evaluation or axillary dissection) 3-6 weeks after the last cycle of the neoadjuvant phase. In the adjuvant phase, patients received radiation therapy as indicated and Pembrolizumab or placebo once every 3 weeks for up to nine cycles. Adjuvant Capecitabine was not allowed. The median age was 49 yrs, 64% were white, 56% were premenopausal, and overall 75% had Stage II disease and 25% had Stage III disease. Both treatment groups were well balanced with regard to age, ECOG performance status, PD-L1-positivity, tumor size and nodal involvement. The Primary end points were a pathological Complete Response (pCR) at the time of definitive surgery and Event-Free Survival (EFS) in the intent-to-treat population. Pathological Complete Response was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0), and was assessed by the blinded local pathologist at the time of definitive surgery. EFS was defined as the time from randomization to the first occurrence of progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause.

The pathological Complete Response rate was 63% in the Pembrolizumab plus chemotherapy group and 55.6% in the placebo plus chemotherapy group, and this difference were statistically significant. The EFS after median follow up of 63.1 months showed a 5-year EFS rate of 81.3% with Pembrolizumab plus chemotherapy and 72.3% with placebo plus chemotherapy (HR=0.63). The median EFS had not been reached in either group. The EFS benefit appeared consistent across subgroups, including those assessed by nodal status, disease stage, PD-L1 expression, menopausal status and Carboplatin schedule. A prespecified, exploratory analysis showed higher 5-year EFS rates with Pembrolizumab among patients who achieved pathologic Complete Response (92.2% versus 88.2%) and among those who did not achieve pathologic Complete Response (62.6% versus 52.3%).

It was concluded that the addition of Pembrolizumab with neoadjuvant chemotherapy followed by Pembrolizumab monotherapy in the adjuvant setting resulted in a durable Event Free Survival benefit, for patients with early stage Triple Negative Breast Cancer, and this benefit was noted across key subgroups, as well as among patients who did or did not achieve pathologic Complete Response.

Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage triple-negative breast cancer: updated event-free survival results from the phase 3 KEYNOTE-522 study. Schmid P, Cortés J, Dent R, et al. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX; abstract LBO1-01.