Category: Hem/Onc Updates

FDA Approves TIVDAK® for Recurrent or Metastatic Cervical Cancer

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SUMMARY: The FDA on April 29, 2024, granted traditional approval to Tisotumab vedotin-tftv (TIVDAK®) for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Tisotumab vedotin previously received accelerated approval for this indication in September 2021.

The American Cancer Society estimates that for cervical cancer in the US for 2024, about 13,820 new cases of invasive cervical cancer will be diagnosed and about 4,360 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to develop cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.

Patients with persistent, recurrent, or metastatic cervical cancer in the past often received Platinum-based chemotherapy, (Cisplatin or Carboplatin along with Paclitaxel) plus Bevacizumab. The addition of Bevacizumab to chemotherapy improved the median Overall Survival from 13.3 months to 17 months in a randomized study. Anti-PD1 and anti-PD-L1 therapies such as Pembrolizumab and Atezolizumab, (respectively) in combination with a doublet of platinum and Paclitaxel with or without Bevacizumab have demonstrated an Overall Survival benefit in Phase III studies. Despite these advances, the prognosis for patients with cervical cancer is poor, with 5-year Overall Survival less than 19% among patients with distant disease. There is an unmet need for additional treatment options.

Tissue Factor is a transmembrane glycoprotein highly expressed in multiple cancers including cervical, pancreatic, esophageal, gastric, colorectal cancers and hepatocellular carcinoma. Tissue Factor is the primary initiator of the extrinsic blood coagulation signaling pathway. Tisotumab vedotin is a tissue factor directed Antibody Drug Conjugate (ADC) which consists of a fully humanized IgG1 monoclonal antibody covalently linked to the microtubule-disrupting agent MonoMethyl Auristatin E (MMAE). Tisotumab vedotin selectively binds to tissue factor-expressing cells, internalized, and releases payload MMAE via proteolytic cleavage. Upon binding of MMAE to tubulin, it disrupts the microtubule network of actively dividing cells, resulting in cell cycle arrest and apoptotic death of the tumor cells. Additionally, Tisotumab vedotin also mediates Antibody-Dependent Cellular Phagocytosis and Antibody-Dependent Cellular Cytotoxicity.

The present FDA approval was based on efficacy, evaluated in innovaTV 301 trial. This study is a pivotal, multinational, open-label, randomized Phase III trial, conducted to evaluate the efficacy and safety of Tisotumab vedotin compared to standard chemotherapy regimens in patients with recurrent or metastatic cervical cancer. This study enrolled 502 patients (N=502) with recurrent or metastatic cervical cancer who had previously received up to two systemic regimens, including chemotherapy with or without Bevacizumab and/or an anti-PD-(L)-1 agent. Participants were randomly assigned in a 1:1 ratio to receive either Tisotumab vedotin 2 mg/kg IV every three weeks (N=253) or Investigators choice of chemotherapy which included either Topotecan, Vinorelbine, Gemcitabine, Irinotecan, or Pemetrexed (N=249). Treatment was continued until disease progression or unacceptable toxicity. Both treatment groups were well balanced with respect to demographic and disease characteristics. This study excluded patients with active ocular surface disease, a history of cicatricial conjunctivitis or ocular Stevens-Johnson syndrome, Grade 2 or more peripheral neuropathy, or significant bleeding risks. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS) and Objective Response Rate (ORR).

The median OS for the Tisotumab vedotin group was 11.5 months compared to 9.5 months for the chemotherapy group. This difference represented a 30% reduction in the risk of death with Tisotumab vedotin, with a Hazard Ratio (HR) of 0.70 (P=0.0038). The median PFS was 4.2 months for the Tisotumab vedotin group versus 2.9 months for the chemotherapy group. The HR for PFS was 0.67 (P<0.0001). The ORR was 17.8% in the Tisotumab vedotin group compared to 5.2% in the chemotherapy group, demonstrating a significant therapeutic benefit with a P-value <0.0001.

Grade 3 or higher adverse events occurred in 52.0% of the Tisotumab vedotin group compared to 62.3% of the chemotherapy group. Additionally, 14.8% of patients on Tisotumab vedotin discontinued treatment due to adverse effects. Despite these side effects, no new safety signals were identified, and ocular adverse events were generally manageable with dose modifications.

In conclusion, the innovaTV 301 trial established that Tisotumab vedotin significantly improves survival and response rates in patients with recurrent or metastatic cervical cancer compared to standard chemotherapy regimens. Future research is underway combining Tisotumab vedotin with other therapies such as checkpoint inhibitors, as well as its utilization in earlier lines of treatment.

Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. Vergote I, González-Martín A, Fujiwara K, et al. for the innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. N Engl J Med 2024;391:44-55.

Late Breaking Abstract – ASCO 2024: Sustained Improvement in Relapse Free Survival with Personalized mRNA Cancer Vaccine plus KEYTRUDA® in Resected High Risk Melanoma

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SUMMARY: The American Cancer Society estimates that for 2024, about 100,640 new cases of melanoma of the skin will be diagnosed in the United States and 8,290 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma.

Patients with resected Stage IIB/C disease comprise a significant group of patients at significant risk of recurrence. Patients with Stage IIB disease have primary tumors that are more than 2 mm, and 4 mm or less in thickness, with ulceration (T3b), or more than 4 mm in thickness without ulceration (T4a). Patients with Stage IIC disease have primary tumors more than 4 mm in thickness with ulceration (T4b). Although Stage II melanoma is less advanced than Stage III, the 5-year risk of recurrence in patients with Stage IIB or Stage IIC disease without adjuvant therapy is approximately 35% and 50% respectively. The 5-year Melanoma-Specific Survival (MSS) rates for patients with Stage IIB/IIC disease are similar to those for Stage IIIA, Stage IIIB and Stage IIIC disease.

Immune Checkpoint Inhibitors are the standard of care adjuvant treatment for high-risk resected melanoma. In the KEYNOTE-054 trial, the 5-year Relapse Free Survival (RFS) with adjuvant Pembrolizumab (KEYTRUDA®) was 55.4% versus 38.3% with placebo. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab (OPDIVO®) versus 41.2% for ipilimumab (YERVOY®). Given the high relapse rates with the present adjuvant melanoma therapies, there is an unmet clinical need.

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. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

mRNA-4157 (V940) is a novel messenger RiboNucleic Acid (mRNA)-based individualized neoantigen therapy consisting of a single synthetic mRNA coding for up to 34 neoantigens, that is designed and produced based on the unique mutational signature of the DNA sequence of the patients tumor. Individualized neoantigen therapies are designed to prime the immune system so that a patient can generate a tailored antitumor response specific to their tumor mutation signature. mRNA-4157 (V940) was designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patients tumor. Early clinical studies demonstrated that combining mRNA-4157 (V940) with Pembrolizumab may potentially provide an additive benefit and enhance T cell-mediated destruction of tumor cells.

KEYNOTE-942 is an ongoing randomized, open-label, Phase IIb trial, designed to evaluate the efficacy and safety of mRNA-4157, an individualized neoantigen therapy, in combination with Pembrolizumab, in patients with completely resected high-risk Stage III/IV cutaneous melanoma. This study included 157 patients who were randomly assigned (2:1) to receive mRNA-4157 in combination with Pembrolizumab (N=107) or Pembrolizumab alone (N=50). The vaccine was administered 1 mg every three weeks for a total of nine doses, and Pembrolizumab was given at 200 mg IV every three weeks for up to 18 cycles (approximately one year). All patients had tumor sample (Formalin Fixed Paraffin Embedded-FFPE) available for Next Generation Sequencing and patients were stratified by disease stage. mRNA-4157 was successfully prepared for more than 99% of patients in the combination arm. The median patient age was 62 years and 84% of patients had Stage IIIC disease. Approximately 64% of patients were PD-L1 positive and 74% had high Tumor Mutational Burden-TMB (10 or more mutations/Mb) in the combination treatment group, whereas 54% were PD-L1 positive and 60% had high TMB in the single agent Pembrolizumab group, respectively. HLA genotyping was performed to explore associations between specific HLA alleles and treatment response. Additionally, subgroup analyses were conducted based on TMB, PD-L1 expression, and circulating tumor DNA (ctDNA) status.

The Primary endpoint was Relapse Free Survival (RFS), defined as the time from first dose of Pembrolizumab until the date of first recurrence (local, regional, or distant metastasis), a new primary melanoma, or death from any cause. Secondary endpoints included Distant Metastasis-Free Survival and Safety. Exploratory endpoints included distribution of TMB expression in baseline tumor samples across study arms and their association with the primary RFS endpoint.

At a median follow up of 23 months for the mRNA-4157/V940 plus Pembrolizumab group, and 24 months for Pembrolizumab alone group, the Relapse Free Survival at 18 months was 78.6% for the immunotherapy combination versus 62.2% for Pembrolizumab alone (HR=0.56; P=0.0266), and this equated to a 44% reduction in the risk of recurrence or death with 2 years of follow-up. mRNA-4157/V940 and Pembrolizumab combination treatment demonstrated an improvement in RFS, irrespective of PD-L1 status and TMB status.

In the recent data presented at ASCO 2024, with an additional year of planned follow-up, at a median of approximately 34.9 months, the combination of mRNA-4157 and Pembrolizumab demonstrated a significant clinically meaningful and durable improvement in RFS, the Primary endpoint of the study, compared to Pembrolizumab alone. The risk of recurrence or death was reduced by 49% (HR=0.51; P=0.019), compared to Pembrolizumab monotherapy. The 2.5-year RFS rate for the combination group was 74.8% compared to 55.6% in the Pembrolizumab alone group. The RFS improvement was observed across subgroups irrespective of TMB and PD-L1 levels.

The combination therapy also showed a meaningful improvement in Distant Metastasis-Free Survival, which was a key Secondary endpoint, compared to Pembrolizumab alone (HR=0.38; P=0.015). This represented a 62% reduction in the risk of developing distant metastases or death compared to Pembrolizumab alone.

While not formally tested as a Primary endpoint, Overall Survival trended favorably with the combination therapy, with a 2.5-Year OS Rate of 96.0% for combination versus 90.2% for Pembrolizumab alone (HR=0.425).

The safety profile of mRNA-4157 in combination with Pembrolizumab was consistent with previous analyses and the common adverse events were fatigue (60.6%), injection site pain (56.7%), and chills (49.0%). Grade 3 or higher adverse events occurred in 25% of patients receiving combination therapy and 18% in the Pembrolizumab alone group. Immune-related adverse events were reported by approximately 37.5% of patients in the combination group and 36% in the Pembrolizumab alone group, with no new safety signals identified.

The KEYNOTE-942 trial demonstrated that mRNA-4157 in combination with Pembrolizumab significantly improved Recurrence-Free Survival and Distant Metastasis-Free Survival in patients with resected high-risk Stage III/IV melanoma, compared to Pembrolizumab alone. These findings suggest a potential benefit across various patient subgroups based on TMB, PD-L1 expression, and ctDNA status. The safety profile was manageable and consistent with expectations for both treatments. Based on these positive results, further investigation in the Phase III INTerpath-001 trial is underway to validate these findings and potentially transform the adjuvant treatment landscape for melanoma patients.

Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial.Weber JS, Khattak MA, Carlino MS, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA9512). DOI 10.1200/JCO.2024.42.17_suppl.LBA9512

Radioligand Therapy before Chemotherapy in Castrate Resistant Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPI), which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies. Patients who progress on Androgen Deprivation Therapy are often switched to second line hormonal treatments that block testosterone with a different mechanism of action, and upon further progression, offered taxane based chemotherapy.

Prostate-Specific Membrane Antigen (PSMA) is a Type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer. Lu-177–PSMA-617 (PLUVICTO®) is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, a cytotoxic radionuclide, linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with Lu-177–PSMA-617 targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell.

The FDA in March 2022, approved Lu-177–PSMA-617 for the treatment of adult patients with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic Castration-Resistant Prostate Cancer (mCRPC), who had been treated with Androgen-Receptor Pathway Inhibitors such as Enzalutamide or Abiraterone acetate and 1 or 2 taxane based chemotherapy regimens. This approval was based on the VISION Phase III study.

PSMAfore is a Phase III trial conducted to assess the benefit of Lu-177–PSMA-617 in patients with metastatic Castration-Resistant Prostate Cancer who had progressed on Androgen-Receptor Pathway Inhibitors, but had not received taxane based chemotherapy, with the hope of making this promising therapy available to more patients earlier in the course of their treatment journey. This study enrolled 468 patients with taxane-naive metastatic CRPC who had PSMA-positive disease on gallium-68–PSMA-11 PET/CT, and were candidates for an Androgen-Receptor Pathway Inhibitor change after one progression on prior Androgen-Receptor Pathway Inhibitor. These patients were randomized to receive either Lu-177–PSMA-617 or a change in Androgen-Receptor Pathway Inhibitor therapy (Abiraterone or Enzalutamide). The Primary endpoint was radiographic Progression Free Survival (rPFS). Secondary endpoints included Overall Survival, Prostate-Specific Antigen (PSA) declines of 50% or more from baseline-known as a PSA50 response, Quality of Life measures, and Safety profiles.

At the primary analysis conducted at 7.3 months, patients treated with Lu-177–PSMA-617 demonstrated a median rPFS of 9.3 months compared to 5.55 months in the Androgen-Receptor Pathway Inhibitor change group, showing a statistically significant and clinically meaningful benefit (HR=0.41; 95% confidence interval [CI] = 0.29-0.56). The positive outcomes persisted at the second interim analysis at 15.9 months, where Lu-177–PSMA-617 continued to show superiority in rPFS, PSA50 response rates (57.6% versus 20.4%), Objective Response Rates (50.7% versus 14.9%), and time to PSA progression (10.55 months versus 4.24 months). Moreover, the safety profile of Lu-177–PSMA-617 was manageable and consistent with previous observations from the VISION trial, with fewer Grade or more adverse events compared to the Androgen-Receptor Pathway Inhibitor change group. Common treatment-related adverse events included dry mouth and myelosuppression.

It was concluded that Lu-177–PSMA-617 represents a promising advancement in the armamentarium against advanced prostate cancer, and Lu-177–PSMA-617 has the potential to redefine treatment paradigms for patients with advanced prostate cancer, particularly in the pretaxane setting. The findings from the PSMAfore study suggest that Lu-177–PSMA-617 could provide a viable therapeutic option earlier in the disease course, potentially delaying or obviating the need for more toxic chemotherapy regimens.

Phase 3 trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Sartor O, Herrmann K, Castellano D, et al. Presented at the Society of Nuclear Medicine and Molecular Imaging. June 9, 2024; Toronto, ON, Canada.

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

FDA Approves KRAZATI® with ERBITUX® for KRAS G12C-Mutated Colorectal Cancer

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SUMMARY: The FDA on June 21, 2024, granted accelerated approval to Adagrasib (KRAZATI®) plus Cetuximab (ERBITUX®) for adults with KRAS G12C-mutated locally advanced or metastatic Colorectal Cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy.

Colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 152,810 new cases of colorectal cancer will be diagnosed in the United States in 2024 and about 53,010 patients will die of the disease. The lifetime risk of developing colorectal cancer is about 1 in 23.

Approximately 15-25% of the patients with colorectal cancer present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with colorectal cancer will develop metastatic disease during the course of their illness. First line treatment of metastatic colorectal cancer includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab (VECTIBIX®). Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). These therapies however have shown limited efficacy.

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. 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 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis. Currently, no targeted therapies driven by a positive-selection biomarker are approved specifically for the treatment of patients with KRAS-mutated colorectal cancer.

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. Unlike the efficacy of single-agent KRAS G12C inhibitors in Non Small Cell Lung Cancer with KRAS G12C mutation, KRAS G12C inhibition alone has limited activity in patients with colorectal cancer. This has been attributed to upstream reactivation of the Epidermal Growth Factor Receptor (EGFR) pathway resulting in treatment-induced resistance, following selective inhibition of KRAS G12C. However, dual KRAS G12C and EGFR blockade can overcome treatment resistance in patients with colorectal cancer with KRAS G12C mutation.

Cetuximab (ERBITUX®) is an anti-EGFR monoclonal antibody that is indicated for the treatment of RAS wild-type metastatic colorectal cancer, either as monotherapy or in combination with chemotherapy. Combining Cetuximab with Adagrasib may overcome treatment resistance and enhance the inhibition of KRAS-dependent signaling and improve outcomes.

The present FDA approval was based on the ongoing KRYSTAL-1, multicenter, expansion cohort Phase 1-2 trial, in which the use of Adagrasib as monotherapy or in combination with Cetuximab was evaluated in patients with previously treated metastatic colorectal cancer with mutant KRAS G12C. Eligible patients had locally advanced or metastatic KRAS G12C-mutated colorectal cancer, and had previous treatment with Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy, and a VEGF inhibitor, if eligible. These patients were heavily pretreated, having received a median of three prior lines of therapy, and their disease had shown resistance to previous treatments. Patients received Adagrasib 600 mg orally twice daily along with Cetuximab 500 mg/m2 IV every two weeks, or 400 mg/m2 IV as initial dose followed by 250 mg/m2 IV weekly. Tumor assessments were performed every 6 weeks. Treatment was continued until disease progression or unacceptable toxicity, Adagrasib discontinuation required Cetuximab discontinuation, however patients could continue Adagrasib if Cetuximab was discontinued. The median patient age was 59 years old, and 51% were women and both treatment groups were well balanced. The Primary efficacy endpoint of the study was the confirmed Overall Response Rate (ORR), assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS), and Safety. Efficacy was assessed in 94 (N=94) enrolled patients.

The study met its Primary endpoint and the ORR was 34%. All responses were Partial Responses (PR), indicating a reduction in tumor burden in responding patients. The median Duration of Response was 5.8 months, with 31% of responders experiencing a Duration of Response of at least 6 months. The most common adverse reactions were rash, nausea, vomiting, diarrhea, fatigue, musculoskeletal pain, hepatotoxicity, anemia, headache, dry skin, decreased appetite, abdominal pain, constipation, edema, cough, and peripheral neuropathy.

In conclusion, the KRYSTAL-1 trial has demonstrated that Adagrasib in combination with Cetuximab shows promising clinical activity and a manageable safety profile in heavily pretreated patients with metastatic CRC harboring the KRAS G12C mutation. These findings highlight a potential new treatment option for patients who have limited therapeutic alternatives and underscore the evolving landscape of precision medicine in oncology, particularly in targeting specific mutations that drive tumor growth and survival.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer.

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.

Duration of Androgen Deprivation Therapy with Postoperative Radiotherapy for Prostate Cancer: 24 Months versus 6 Months

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Treatment options for patients with intermediate and high risk prostate cancer include Radical Prostatectomy and External Beam Radiation Therapy. Three Phase III randomized studies have previously assessed the addition of Androgen Deprivation Therapy (ADT) to postoperative radiotherapy after Radical Prostatectomy, but none of these studies compared different durations of ADT and the optimal duration of Androgen Deprivation Therapy has remained unclear.

RADICALS was a multicenter, international, open-label, randomized, controlled, Phase III trial in prostate cancer.
This study addressed two important questions:
1) Which is the best way to use radiotherapy after surgery?
2) Which is the best way to use hormone treatment with any radiotherapy given after surgery?

The full background and other details related to the RADICALS trial is published elsewhere.

RADICALS-HD is a component of the RADICALS trial and the researchers hypothesized that long-course ADT would be more effective than short-course ADT in patients receiving postoperative radiotherapy. They therefore designed a prospective, international, randomized controlled trial to compare long-course versus short-course use of ADT in this setting. In the RADICALS-HD trial, 1523 patients were randomly assigned 1:1 to receive short-course ADT (N=761) or long-course ADT (N=762) in addition to postoperative radiotherapy at 138 centers in Canada, Denmark, Ireland, and the UK. Radiotherapy was started approximately 2 months after the start of hormone treatment, and patients received either 52.5 Gy in 20 fractions over 4 weeks or 66.0 Gy in 33 fractions over 6.5 weeks. Radiotherapy was given in the adjuvant setting for 43% of patients, and in the early salvage setting for 57% patients. Androgen Deprivation Therapy (ADT) consisted of Gonadotropin Releasing-Hormone analog given subcutaneously monthly for 6 months in the short-course ADT group and every 3 months for 24 months in the long-course ADT group. Outside Canada, Bicalutamide monotherapy 150 mg daily or monthly subcutaneous Degarelix were acceptable alternatives. Randomization was stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT. The two treatment groups were well balanced. The median age was 65 years, 93% of patients had Gleason score of 7 or higher and 30% had Stage T3b disease or higher. The Primary outcome measure was Metastasis-Free Survival, defined as metastasis arising from prostate cancer or death from any cause.

With a median follow-up of 8.9 years, the long-course ADT for 24 months resulted in a superior Metastasis-Free Survival compared to short-course ADT for 6 months. The 10-year Metastasis-Free Survival was 78.1% in the long-course ADT group compared to 71.9% in the short-course ADT group (HR=0.77; P=0.029). This finding was consistent across all prespecified subgroups, including baseline PSA. Grade 3 or higher toxicity was reported in 19% of patients in the long-course ADT group, and in 14% of patients receiving short-course ADT (P=0.025).

It was concluded that compared to adding 6 months of ADT, adding 24 months of ADT to patients receiving postoperative radiotherapy after radical prostatectomy for prostate cancer, significantly improved Metastasis-Free Survival. Long-course ADT should therefore be offered in addition to postoperative radiotherapy to individuals who are willing to accept the additional duration of adverse effects. The researchers added that this is the first trial to compare different durations of ADT with postoperative radiotherapy after Radical Prostatectomy in prostate cancer.

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial. Parker CC, Kynaston H, Cook AD, et al. The Lancet. 2024;403:2416-2425

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.