Author: RR

Sustained Benefit with Adjuvant VERZENIO® in High-Risk Early Breast Cancer

RR

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. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. 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. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years, while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK 4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity. Phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of CDKs in the cell cycle, has paved the way for the development of CDK inhibitors.

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against Cyclin D1/CDK 4 and Cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

The International monarchE trial, is an open-label, randomized, Phase III study, which included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The goal of monarchE was to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk, early breast cancer. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, or histologic Grade 3 disease (Cohort 1). A smaller group of patients with 1-3 positive axillary lymph nodes and centrally determined Ki-67 score of 20% or more were enrolled in Cohort 2. Ki-67 score was also determined centrally in Cohort 1 patients, but Ki-67 determination was not required for enrollment in this cohort. Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5-10 years of physician’s choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease-Free Survival (IDFS) in the Intent to Treat (ITT) population (Cohorts 1 and 2). Secondary end points included IDFS in patients with high Ki-67 score (in the ITT population and in the Cohort 1 population), Distant Relapse-Free Survival (DRFS), Overall Survival (OS), and Safety. The researchers reported updated results from an interim analysis to assess overall survival, as well as Invasive Disease-Free Survival and Distant Relapse-Free Survival, with additional follow-up.

At a median follow-up of 42 months (3.5 years), the median Invasive Disease-Free Survival (IDFS) was not reached in either group, and the IDFS benefit previously reported was sustained. The risk of developing invasive disease was reduced by 33.6% (HR=0.664; nominal P<0.0001). The 4-year IDFS rate was 85.8% for patients treated with VERZENIO® plus endocrine therapy, compared to 79.4% for patients treated with endocrine therapy alone, reflecting an absolute difference of 6.4% (compared to 2.8% at two years). The majority of the IDFS events were distant metastatic disease. Adjuvant VERZENIO® also reduced the risk of developing metastatic disease by 34.1% (HR=0.659; nominal P<0.0001). The 4-year DRFS rate was 88.4% for patients treated with VERZENIO® plus endocrine therapy, compared to 82.5% for patients treated with endocrine therapy alone, an absolute difference of 5.9% (compared to 2.5% at two years). As was noted in the previous analyses, a high Ki-67 score correlated with increased risk of recurrence, but this IDFS and DRFS benefit was seen across all prespecified subgroups, regardless of Ki-67 score. Overall Survival (OS) data were immature at the time of this analyses. However, fewer deaths were observed in the VERZENIO® plus endocrine therapy group, compared to endocrine therapy alone. There were no new safety findings, and overall results were consistent with the safety profile for VERZENIO®.

It was concluded that adjuvant VERZENIO® combined with endocrine therapy continued to demonstrate statistically significant and clinically meaningful improvement in Invasive Disease Free Survival and Distant Relapse Free Survival, among patients with HR-positive, HER2-negative, node-positive, high risk, early breast cancer, regardless of Ki-67 status. These benefits were sustained after patients completed 2 years of adjuvant treatment with VERZENIO®, with an absolute increase at 4 years. The authors added that further follow-up is needed to establish whether Overall Survival can be improved with VERZENIO® plus endocrine therapy in this patient group.

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Johnston SRD, Toi M, O’Shaughnessy J, et al. The Lancet Oncology. Published:December 06, 2022. DOI:https://doi.org/10.1016/S1470-2045(22)00694-5

Unprecedented Progression Free Survival with SARCLISA® plus KYPROLIS® and Dexamethasone in Relapsed Multiple Myeloma

RR

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, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will 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 CD 38 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 2022 remains an incurable disease.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. CD38 is a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, and was approved for use in combination with KYPROLIS® and Dexamethasone in 2020, for the treatment of patients with multiple myeloma, who had received 1-3 prior lines of therapy. This was based on the CANDOR open label, Phase III trial, in which the triplet combination of DARZALEX®, KYPROLIS® and Dexamethasone resulted in a 37% reduction in the risk of progression or death, compared with KYPROLIS® and Dexamethasone. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation, by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

SARCLISA® (Isatuximab-irfc) is a CD38-targeting IgG1monoclonal antibody, similar to DARZALEX®, but unlike DARZALEX®, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, SARCLISA® targets a specific epitope on the CD38 receptor, and this distinction from DARZALEX® allows use of SARCLISA® in cases when DARZALEX® fails. Additionally, SARCLISA® infusions are less cumbersome. The FDA in 2021, approved SARCLISA® in combination with KYPROLIS® (Carfilzomib) and Dexamethasone, for the treatment of adult patients with Relapsed or Refractory multiple myeloma who have received one to three prior lines of therapy.

IKEMA trial is a multicenter, randomized, open label, Phase III study, in which the efficacy and safety of SARCLISA® in combination with KYPROLIS® and Dexamethasone was evaluated among patients with relapsed and/or refractory multiple myeloma, who had received 1-3 prior lines of therapy. In this study, 302 eligible patients were randomized 3:2 to receive SARCLISA® plus KYPROLIS® and Dexamethasone (N=179) or KYPROLIS® and Dexamethasone alone (N=123). SARCLISA® was given at 10 mg/kg IV weekly for 4 weeks and then every 2 weeks. KYPROLIS® was given at 20 mg/m2 IV on days 1 and 2 and then at 56 mg/m2 IV thereafter twice weekly for 3 of 4 weeks and Dexamethasone was given at 20 mg twice weekly. Treatment was continued until disease progression or unacceptable toxicity. The median age was 64 years, 23% had 3 or more prior lines of therapy, 90% of patients had prior treatment with Proteasome Inhibitor, 78% had prior treatment with Immunomodulatory drug (IMiD) and 24% had high-risk cytogenetics. The Primary endpoint was Progression Free Survival (PFS) as determined by an Independent Review Committee (IRC). Key Secondary endpoints included Overall Response Rate (ORR), rate of Very Good Partial Response (VGPR) or better, Complete Response (CR) rate, Minimal Residual Disease (MRD) negativity rate (10-5 by NGS), and Overall Survival (OS). The authors have now reported updated efficacy and safety results from IKEMA trial.

At a median follow-up of 44 months, the median PFS was 35.7 months in the SARCLISA® group and 19.2 months in the KYPROLIS® and Dexamethasone group (HR=0.58; 95.4% CI). The PFS benefit with SARCLISA® group was consistent across subgroups, including among patients with high-risk cytogenetics and those who were refractory to Lenalidomide. SARCLISA® plus KYPROLIS® and Dexamethasone also delayed the time to next treatment and prolonged PFS2. The median time to next treatment was 44.9 months with SARCLISA® combination and 25.0 months with KYPROLIS® and Dexamethasone (HR=0.55; 95% CI). The median PFS2 was 47.2 months and 35.6 months respectively (HR=0.68; 95% CI). The Complete Response (CR) rate or stringent CR rate was 44.1% in the SARCLISA® combination group and 28.5% in the KYPROLIS® and Dexamethasone group. MRD negativity was achieved in 33.5% of patients in the SARCLISA® combination group and 15.4% in the KYPROLIS® and Dexamethasone group. The rate of MRD negativity among patients with a CR or stringent CR was 26.3% in the SARCLISA® combination group and 12.2% in the KYPROLIS® and Dexamethasone group. No new safety signals were identified.

It was concluded that the addition of SARCLISA® to KYPROLIS® and Dexamethasone resulted in unprecedented median Progression Free Survival, Complete Response Rate and MRD negativity with a non-Lenalidomide regimen, and is the longest Progression Free Survival with a Proteasome Inhibitor backbone in the relapsed multiple myeloma setting. The authors added that SARCLISA® combination was well tolerated with manageable safety and a favorable benefit-risk profile, and this updated efficacy data support SARCLISA® in combination with KYPROLIS® and Dexamethasone as a standard of care treatment for patients with relapsed or refractory multiple myeloma.

VP5-2022: Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Moreau P, Dimopoulos MA, Mikhael J, et al. ESMO Virtual Plenary. May 19-20, 2022. DOI:https://doi.org/10.1016/j.annonc.2022.04.013

IMBRUVICA® (Ibrutinib)

RR

The FDA on August 24, 2022, approved IMBRUVICA® (Ibrutinib) for pediatric patients ≥ 1 year of age with chronic Graft Versus Host Disease (cGVHD) after failure of 1 or more lines of systemic therapy. Formulations include capsules, tablets, and oral suspension. IMBRUVICA® is a product of Pharmacyclics LLC.

ENHERTU® (fam-trastuzumab deruxtecan-nxki)

RR

The FDA on August 11, 2022, granted accelerated approval to ENHERTU® (fam-trastuzumab deruxtecan-nxki) for adult patients with unresectable or metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have activating human Epidermal Growth Factor Receptor 2 HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC. ENHERTU® is a product of Daiichi Sankyo, Inc.

Long Term Lung Cancer Survival Rates with Low Dose CT Screening

RR

SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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 and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

In the National Lung Screening Trial (NLST) with Low Dose CT (LDCT) screening for lung cancer, there was a 20% reduction in mortality. Following the publication of the results of NLST, the NCCN issued guideline in 2011, and the United States Preventive Services Task Force (USPSTF) recommended lung cancer screening with Low Dose CT scan in high-risk patients. The CMS in 2015 determined that there was sufficient evidence to reimburse for this preventive service. The USPSTF expanded the criteria for lung cancer screening in 2021 and recommended annual screening with Low-Dose CT for adults aged 50-80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years.

Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the implementation of lung cancer screening programs. Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. Despite the favorable stage shift as a result of lung cancer screening, low Health Care Provider knowledge of the lung cancer screening guidelines represents a potential barrier to implementation.

The Early Lung Cancer Action Project (ELCAP) in 1992 initiated a study of the early diagnosis of lung cancer in cigarette smokers using annual spiral CT screening. This study showed that more than 80% of individuals diagnosed with lung cancer as a result of annual CT screening had clinical Stage I cancer (Lancet 1999;354:99-105). In a subsequent large collaborative study (International Early Lung Cancer Action Program-IELCAP), 31,567 asymptomatic individuals at risk for lung cancer were screened with Low-Dose CT from 1993 through 2005. This study suggested that for those participants with Stage I lung cancer, the estimated 10-year survival rate was 88%, and among those with clinical Stage I lung cancer who underwent surgical resection within 1 month after the diagnosis, the survival rate was 92%. This study provided strong evidence that annual spiral CT screening can detect lung cancer that is curable (N Engl J Med 2006; 355:1763-1771).

The researchers herein provided the 20-year lung cancer-specific survival of participants, IELCAP enrolled, since its start in 1992. This prospective, international, multicenter study enrolled 87,416 participants, current, former and never smokers, 40 years of age and older, as of December 31, 2021. Participants were screened for lung cancer using Low-Dose CT for early detection of lung cancer with particular attention to lung cancer manifesting on CT images as solid, part solid and nonsolid consistency.

The 20-year lung cancer-specific survival for patients who underwent CT screenings and were diagnosed with early-stage lung cancer was 80%. The lung cancer-specific survival for patients with nonsolid and part-solid consistency cancerous lung nodules who underwent CT screenings was 100%, and 73% for patients with solid nodules. The lung cancer-specific survival for clinical Stage IA participants was 86%, regardless of consistency. For participants with pathologic Stage IA lung cancers 10 mm or less in average diameter, the 20-year lung cancer-specific survival was 92%.

The researchers concluded that after 20 years, their previous estimates of lung cancer survival rates are now confirmed, and this study adds further evidence of the high curability of lung cancer diagnosed by CT screening. These data demonstrate the importance of routine and early lung cancer screening.

20-year Lung Cancer Survival Rates in the International Early Lung Cancer Action Program (IELCAP). Henschke C, Yankelevitz DF, Libby DM, et al. Presented at: Radiological Society of North America; November 27-December 1, 2022; Chicago, IL.

FDA Approves REZLIDHIA® for Acute Myeloid Leukemia

RR

SUMMARY: The FDA on December 1, 2022, approved REZLIDHIA® (Olutasidenib) capsules for adult patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test. The FDA on the same day also approved the Abbott RealTime IDH1 Assay to select patients for REZLIDHIA®.

The American Cancer Society estimates that for 2022, about 20,050 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,540 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior Myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. AML mainly affects older adults and the median age at diagnosis is 68 years. A significant majority of patients with AML are unable to receive intensive induction chemotherapy due to comorbidities and therefore receive less intensive, noncurative regimens, with poor outcomes.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression, thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle.

Approximately 20-25% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic Cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-Cell Lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations. IDH2 mutations are more common than IDH1 mutations, occurring in approximately 15% to 20% of patients with AML. The presence of IDH mutations has both prognostic and predictive value. Patients with an IDH mutation and a Nucleo¬phosmin (NPM1) mutation usually have a better prognosis whereas patients with mutations in IDH and FMS-like tyrosine kinase 3 (FLT3) do not. Further IDH mutations predict response to specific IDH1 and IDH2 inhibitors in the Relapsed and Refractory setting. The presence of an IDH mutation is therefore not only prognostic, but also predictive of response to certain therapies.

The two IDH inhibitors presently available in the US include IDHIFA® (Enasidenib), approved for the treatment of patients with Relapsed or Refractory AML with IDH2 mutation and TIBSOVO® (Ivosidenib), approved for AML patients with the IDH1 mutation who have Relapsed/Refractory disease, as well as monotherapy for newly diagnosed AML patients 75 years or older with comorbidities that preclude the use of intensive induction chemotherapy. IDHIFA® can be associated with indirect hyperbilirubinemia, which is of no clinical consequence, whereas with TIBSOVO® there is a small risk of QT interval prolongation. Both agents can lead to Differentiation Syndrome in 10-15% of patients which requires systemic steroids and hemodynamic monitoring for at least 3 days.

REZLIDHIA® is a potent, selective, oral, brain-penetrant, small molecule inhibitor of mutant IDH1, that has exhibited favorable tolerability and clinical activity in high-risk AML patients in a Phase 1 trial (Watts JM, et al. Blood 2019). The present FDA approval was based on the Phase 1/2 Study 2102-HEM-101 trial (NCT02719574), which included 147 adult patients with Relapsed or Refractory AML with an IDH1 mutation, confirmed using the above now approved assay. Enrolled patients had pathologically proven AML, except those with Acute Promyelocytic Leukemia with the t(15;17) translocation, or intermediate high, or very high-risk MDS as defined by the WHO criteria or Revised International Prognostic Scoring System. REZLIDHIA® 150 mg was given orally, twice daily, until disease progression, unacceptable toxicity, or Hematopoietic Stem Cell Transplantation. The median treatment duration was 4.7 months. Sixteen (11%) patients underwent Hematopoietic Stem Cell Transplantation following treatment with REZLIDHIA®. The Primary end points included the rate of Complete Remission (CR) plus Complete Remission with partial hematologic recovery (CRh). Secondary end points included time to response, Duration of Response, Event-Free Survival, Overall Survival, and Relapse-Free Survival.

The Complete Remission plus Complete Remission with partial hematologic recovery rate with REZLIDHIA® was 35%, with 32% CR and 2.7% CRh. The median time to CR+CRh was 1.9 months and the median duration of CR+CRh was 25.9 months. Among the 86 patients who were Red Blood Cell (RBC) and/or platelet transfusions dependent at baseline, 34% became RBC and platelet transfusion independent during any 56-day post-baseline period. Of the 61 patients who were RBC and platelet transfusions independent at baseline, 64% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions were nausea, diarrhea, constipation, mucositis, fatigue/malaise, arthralgia, fever, rash, leukocytosis, dyspnea, and transaminitis. Health care professionals and patients should be aware of the risk of Differentiation Syndrome, which can be fatal.

REZLIDHIA® is the third IDH inhibitor currently approved for the treatment of Acute Myeloid Leukemia.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olutasidenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-idh1-mutation.

FDA Approves Biomarker-Driven ELAHERE® for Platinum-Resistant Ovarian Cancer

RR

SUMMARY: The FDA on November 14, 2022, granted accelerated approval to ELAHERE® (mirvetuximab soravtansine-gynx) for adult patients with Folate Receptor alpha (FR alpha) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. The FDA also on the same day approved the VENTANA FOLR1 (FOLR-2.1) RxDx Assay (Ventana Medical Systems, Inc.), as a companion diagnostic device to select patients for the above indication.

It is estimated that in the United States, approximately 19,880 women will be diagnosed with ovarian cancer in 2022, and 12,810 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%. Treatment options for patients with platinum-resistant ovarian cancer are limited, and patients are often treated with single-agent chemotherapy, with an Overall Response Rate of between 4% and 13%, short duration of response, and significant toxicities.

Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha, and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue.

ELAHERE® (mirvetuximab soravtansine-gynx) is a first-in-class Antibody Drug Conjugate (ADC), directed against FR alpha, a cell-surface protein highly expressed in ovarian cancer. It is comprised of a Folate Receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, which is a potent tubulin inhibitor, disrupting microtubule formation, and thereby designed to kill the targeted cancer cells. Microtubules are major components of the cytoskeleton that give shape and structure to cells. ELAHERE® is the first FDA approved ADC for platinum-resistant disease.

The FDA approval was based on the pivotal SORAYA trial, which is a single-arm study in 106 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, whose tumors expressed high levels of Folate Receptor alpha, and who had been treated with 1-3 prior lines of systemic treatment regimens. All patients were required to have received prior treatment with AVASTIN® (Bevacizumab). Enrolled patient’s tumors were positive for FR alpha expression as determined by the above-mentioned FDA approved assay. Patients were eligible for the study if at least 75% of cells had 2+ staining intensity or greater, based on immunohistochemistry-based scoring. Patients were excluded if they had corneal disorders, ocular conditions requiring ongoing treatment, more than Grade 1 peripheral neuropathy, or noninfectious interstitial lung disease. Patients received ELAHERE® 6 mg/kg (based on adjusted ideal body weight) IV infusion every three weeks, until disease progression or unacceptable toxicity. Assessments were made for tumor response every six weeks for the first 36 weeks, and every 12 weeks thereafter. The Primary endpoint was investigator-assessed Overall Response Rate (ORR), and key Secondary endpoint was Duration of Response (DOR).

The confirmed ORR was 31.7% including five Complete Responses, and the median Duration of Response was 6.9 months. Response rates were consistently seen regardless of the number of prior therapies or the use of a prior PARP inhibitor. The most common adverse reactions including laboratory abnormalities, were vision impairment, keratopathy, fatigue, nausea, peripheral neuropathy, increase in ALT and AST and cytopenias. Product labeling includes a boxed warning for ocular toxicity. The authors reported that the ocular events were reversible and primarily included low-grade blurred vision and keratopathy, which were managed with protocol-defined dose modifications. Approximately 60% of patients with symptoms had resolution prior to their next cycle of treatment, and less than 1% of patients discontinued therapy due to an ocular event.

It was concluded that ELAHERE® had impressive anti-tumor activity, durability of response, and overall tolerability, and may be a new therapeutic option for patients with Folate Receptor alpha-positive platinum-resistant ovarian cancer.

Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: Results from the SORAYA study. Matulonis UA, Lorusso D, Oaknin A, et al: 2022 SGO Annual Meeting on Women’s Cancer. Abstract 242. Presented March 19, 2022.