Category: Hem/Onc Updates

Overall Survival Benefit with SARCLISA® Plus POMALYST® and Dexamethasone in Relapsed and Refractory 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, 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 (MM) in 2022 remains an incurable disease.

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 POMALYST® (Pomalidomide) and Dexamethasone in 2017, for the treatment of patients with multiple myeloma, who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. 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) is a CD38-targeting monoclonal 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 approval of SARCLISA® in 2020 was based on ICARIA-MM trial, which is an open-label, randomized, multicentre Phase III study in which 307 adult patients with Relapsed and Refractory multiple myeloma who had received at least two previous lines of treatment, including REVLIMID® and a Proteasome Inhibitor were eligible. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. Patients were randomly assigned 1:1 to receive either SARCLISA® along with POMALYST® and low-dose Dexamethasone (N =154) or POMALYST® and low-dose Dexamethasone alone (N = 153). Treatment consisted of 28-day cycles of SARCLISA® 10 mg/kg given IV on days 1, 8, 15, and 22 in the first cycle and days 1 and 15 in subsequent cycles. Both groups received POMALYST® 4 mg orally on days 1 to 21 of each cycle and Dexamethasone 40 mg (20 mg for patients aged 75 years or older) orally or IV on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression or unacceptable toxicity. The Primary endpoint was Progression Free Survival (PFS), determined by an Independent Response Committee, and assessed in the intent-to-treat population.

At a median follow up of 11.6 months, the median PFS was 11.5 months in the SARCLISA® group versus 6.5 months in the control group (HR= 0.596; P=0.001). This PFS improvement represented an approximately 40% reduction in the risk of disease progression or death in the SARCLISA® group and was noted in all poor prognostic patient subgroups, including patients who were refractory to REVLIMID®, a Proteasome Inhibitor or both.

The researchers in this publication reported prespecified updated Overall Survival analysis, at 24 months after the primary analysis (second interim analysis). The median follow-up at data cutoff was 35.3 months. The median Overall Survival was 24.6 months in the SARCLISA® group and 17.7 months in the control group (HR=0.76; P=0.028, not crossing prespecified stopping boundary). Final Overall Survival analysis follow up is ongoing. Updated median PFS was 11.1 months in the SARCLISA® group versus 5.9 months in the control group (HR= 0.60; P<0.0001).

Approximately 60% of patients in the SARCLISA® group and 72% in the control group received subsequent therapy after disease progression. Median time to next treatment was longer in the SARCLISA® group (P<0.0001). Among these patients, 24% received DARZALEX® as subsequent therapy versus 58% in the control group. In a post hoc analysis, median overall survival was 19.9 months among control group patients who received DARZALEX® and 17.4 months among those who did not. Overall, median PFS on subsequent therapy or death was 17.5 months in the SARCLISA® group versus vs 12.9 months in the control group (HR=0.76; P=0.02).

The most common Grade 3 or worse treatment-related adverse events in the SARCLISA® group versus the control group were neutropenia (50% versus 35%), pneumonia (23% versus 21%), and thrombocytopenia (13% versus 12%). No new safety concerns were identified with SARCLISA® plus POMALYST® and Dexamethasone, with longer follow up.

The authors concluded that the addition of SARCLISA® to POMALYST® and Dexamethasone resulted in an approximately 7 month difference in median Overall Survival compared with POMALYST® and Dexamethasone, and is a new standard of care for REVLIMID® and Proteasome Inhibitor-refractory or relapsed multiple myeloma.

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Richardson PG, Perrot A, San-Miguel J, et al. Lancet Oncol. 2022;23(3):416-427. doi:10.1016/S1470-2045(22)00019-5

PREMMplus Hereditary Cancer Risk Assessment Tool May Identify People Likely to Benefit from Multigene Panel Testing

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SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, and germline testing and targeted surveillance of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics.

With the widespread adoption of Next Generation Sequencing (NGS), multiple genes can be tested simultaneously (MultiGene Panel Testing-MGPT), rather than sequential single-gene testing, making MultiGene Panel Testing cheaper, faster and more efficient. Further, single-test multigene multiplexing strategy analyzes numerous cancer susceptibility genes and frequently detects highly penetrant, clinically actionable Pathogenic Germline Variants (PGV) in individuals whose clinical histories fail to fulfill syndrome-specific testing criteria. This is clinically relevant, as it has become increasingly complex to determine which individuals warrant germline testing.

Several risk assessment models have been developed to provide probability of an individual carrying a germline mutation. However, these models only provide syndrome-specific risk assessment for Lynch Syndrome, Hereditary Breast and Ovarian Cancer syndrome (HBOC)), etc., and there is significant need for a risk assessment model tailored toward MultiGene Panel Testing.

The PREMM (PREdiction Model for gene Mutations) model has been rigorously tested, and is widely recognized and recommended by several professional societies, including the National Comprehensive Cancer Network (NCCN), the American College of Gastroenterology, and the U.S. Multi-Society Task Force on Colorectal Cancer. The PREMMplus model is a clinical prediction algorithm (tool) that estimates the cumulative probability of an individual carrying a germline mutation in 19 genes linked to cancer. Individuals are considered to be high risk if they have a risk score greater than 2.5%, and are eligible for genetic evaluation to determine if they indeed harbor germline mutations, and these individuals in turn could benefit from measures to prevent the cancer, or detect cancer early.

This aim of this study was to develop and validate PREMMplus clinical risk assessment tool (clinical prediction model) that could be used to identify individuals who are likely to have Pathogenic Germline Variant and should undergo MultiGene Panel Testing. PREMMplus was designed to identify individuals carrying Pathogenic Germline Variants in 19 cancer susceptibility genes broadly categorized by phenotypic overlap and/or relative penetrance, and they included 11 Category A genes (APC, BRCA1/2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53) and 8 Category B genes (ATM, BRIP1, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D). Assessment of germline variant pathogenicity was based on the most recent classification made by the clinical laboratory, performing MultiGene Panel Testing. This clinical prediction model was designed to achieve both high sensitivity and Negative Predictive Value (NPV) across a diverse spectrum of syndromes, used clinical data only, did not require tumor tissue thus facilitating scalability, and was adaptable to allow for future expansion, as new genes became incorporated into routine MultiGene Panel Testing.

Clinical predictors for this model included demographics (sex, ancestry, and age at testing), as well as personal, and family history of specific cancers in first- and second-degree relatives. EIGHTEEN cancer types were selected for PREMMplus development, including both common malignancies such as breast cancer and colorectal cancer and uncommon malignancies such as sarcoma and adrenocortical carcinoma, associated with inherited risk. Individuals were excluded from analysis if a personal and family history of any of these 18 cancers were not available, and/or if age at MultiGene Panel Testing was missing. Individuals with 2 or more Pathogenic Germline Variants were excluded from the development cohort.

The performance of this clinical model was validated in nonoverlapping data sets of 8,691 and 14,849 individuals with prior MultiGene Panel Testing ascertained from clinic and laboratory-based settings, respectively.

PREMMplus demonstrated high sensitivity and high Negative Predictive Value for identifying individuals with Pathogenic Germline Variants in the 19 different cancer susceptibility genes. PREMMplus demonstrated a sensitivity of 93.9%, 91.7%, and 89.3% and Negative Predictive Value of 98.3%, 97.5%, and 97.8% for identifying Category A gene Pathogenic Germline Variants carriers, in the development and validation cohorts, respectively. PREMMplus demonstrated a sensitivity of 89.9%, 85.6%, and 84.2% and Negative Predictive Value of 95.0%, 93.5%, and 93.5% for identifying Category A/B gene Pathogenic Germline Variants carriers in the development and validation cohorts, respectively. Overall, 9.4%, 10.8%, and 9.2% of the development, clinic-based validation, and laboratory-based validation cohorts, respectively, harbored a Pathogenic Germline Variant in one of the 19 PREMMplus genes.

It was concluded that PREMMplus accurately identifies individuals with Pathogenic Germline Variants in a diverse spectrum of cancer susceptibility genes, with high sensitivity and Negative Predictive Value. PREMMplus represents a new evidence-based approach and can be used to identify individuals who should undergo MultiGene Panel Testing.

Development and Validation of the PREMMplus Model for Multigene Hereditary Cancer Risk Assessment. Yurgelun MB, Uno H, Furniss CS, et al. DOI: 10.1200/JCO.22.00120 Journal of Clinical Oncology

Efficacy of Low Dose Decitabine and Azacitidine in Lower Risk Myelodysplastic Syndrome

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SUMMARY: It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient’s disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years.

Patients with Low-risk MDS often present with symptomatic anemia and these patients are in chronic need for RBC transfusions. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200U per liter are less likely to respond to ESAs. A majority of patients with higher-risk MDS are treated with hypomethylating agents such as VIDAZA® (Azacitidine) and DACOGEN® (Decitabine) and these agents can favorably modify the natural history of the disease, and have been shown to improve survival. However, the role of the hypomethylating agents in lower-risk MDS has not been established.

To better understand the role of hypomethylating agents in adult patients with previously untreated MDS, with low or Intermediate-1 risk MDS or Chronic MyeloMonocytic Leukemia (CMML), the researchers conducted a long-term analysis, of a previously reported randomized Phase II study of low dose Decitabine versus low dose Azacitidine, in lower-risk MDS and MDS/myeloproliferative neoplasms (Jabbour E, et al. Blood. 2017;130:1514-1522). The aim of this study was to better understand the impact of attenuated hypomethylating agents dosing, in patients with lower-risk MDS.

A total of 113 patients (N=113) were randomly assigned with a Bayesian response-adaptive design to receive either Decitabine 20 mg/m2 IV daily (N=73) or Azacitidine 75 mg/m2 IV daily (N=40) on days 1-3 of every 28-day cycle, between November 2012 and February 2016. Responding patients were allowed to continue therapy indefinitely. Bone marrow aspiration and/or biopsy were performed at the end of course 2 and every 3 months during the first year, and then every 3 to 6 months thereafter. Patients who had received other prior treatments for MDS, including growth factors, were eligible. Hydroxyurea treatment was permitted to control leukocytosis before study therapy. The authors in their previous publication reported that at a median follow up of 20 months, hypomethylating agents induced high response rates in patients with lower-risk MDS. The researchers in this extension analysis of lower-risk MDS patients, evaluated the Duration of Response, Event-Free Survival (EFS), and Overall Survival (OS), with a median follow-up of 68 months. The median number of treatment cycles was 15.

The Overall Response Rate was 67% in the Decitabine group and 48% in the Azacitidine group (P=0.042). Of the 59 patients who were transfusion dependent, 32% became transfusion independent (Decitabine 41% and Azacitidine 15%; P=0.039). The median duration of transfusion independency was 22 months. Among those patients who were transfusion independent at baseline, 9% became transfusion dependent after therapy. With a median follow-up of 68 months, the median overall Event-Free Survival was 17 months and median Overall Survival was 33 months. No early deaths were observed.

The authors concluded that low dose hypomethylating agents can induce durable response of transfusion independency in patients with lower-risk MDS, and response to hypomethylating agents can be associated with favorable clinical outcomes in this patient group.

Low-Dose Decitabine versus Low-Dose Azacitidine in Lower-Risk MDS. Sasaki K, Jabbour E, Montalban-Bravo G, et al. DOI:https://doi.org/10.1056/EVIDoa2200034

Elacestrant in ER-Positive, HER2-Negative, 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. 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. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI in advanced breast cancer. In a previously published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%).

Fulvestrant is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is the only SERD approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer. However, acquired ESR1 mutations can also occur following Fulvestrant treatment, possibly because of poor bioavailability and incomplete ER blockade when administered intramuscularly. There is therefore an urgent unmet need for an alternate SERD that has activity in tumors harboring ESR1 mutations, and has improved bioavailability allowing oral administration.

Elacestrant is an oral, nonsteroidal, Selective Estrogen Receptor Degrader (SERD) that degrades the Estrogen Receptor (ER) in a dose-dependent manner and inhibits estradiol-dependent functions of ER target gene transcription induction and breast cancer cell proliferation. Estradiol-stimulated tumor growth was diminished by Elacestrant in the ER+ xenograft models derived from heavily pretreated patients, including models resistant to CDK 4/6 inhibitors, Fulvestrant and those harboring ESR1 mutations Y537S and D538G. In an early Phase I trial, Elacestrant was noted to have an acceptable safety profile, and demonstrated single-agent activity with confirmed Partial Responses in heavily pretreated patients with ER+ metastatic breast cancer.

EMERALD trial is a multicenter, International, randomized, open-label, Phase III study, designed to evaluate the benefit of Elacestrant in patients with ER+/HER2- advanced or metastatic breast cancer. In this study, 477 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either Elacestrant 400 mg orally daily (N=239) or the Standard of Care which included investigator’s choice of Fulvestrant or an Aromatase Inhibitor including Anastrozole, Letrozole, or Exemestane (N=238). Treatment was given until disease progression. Both treatment groups were well balanced. The median patient age was 63 years, and patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1. In the study, 48% had tumors with mutated ESR1 and 43% received two prior endocrine therapies. These patients were evenly distributed in both treatment groups. Patients were stratified by ESR1-mutation status, prior treatment with Fulvestrant, and visceral metastases. The co-Primary end points were Progression Free Survival (PFS) in the overall population, and in those with ESR1 mutations. Overall Survival (OS) was a Secondary end point.

Treatment with Elacestrant resulted in a statistically significant and clinically meaningful improvement in PFS, compared with Standard of Care. There was a 30% reduction in the risk of progression or death in the Elacestrant group for all patients (HR=0.70; P=0.002) and a 45% reduction in the risk of progression or death among those with ESR1 mutations (HR=0.55; P=0.0005). The researchers in this study used landmark analysis of PFS at 6 months and 12 months which selects for patients who are still sensitive to endocrine therapy and addresses the limited PFS benefit caused by an initial progression, in patients with complete endocrine resistance who do not respond to endocrine therapy. The PFS at 12 months with Elacestrant was 22.3% in all patients compared with 9.4% for those receiving the Standard of Care treatment. Among the ESR1 mutation group, the 12 month PFS rate was more pronounced and was 26.8% with Elacestrant, compared to 8.2% with Standard of Care. The benefits with Elacestrant compared with Standard of Care, was consistent across multiple prespecified subgroups including patients who had received prior Fulvestrant. There also was a trend toward improved Overall Survival in patients who received Elacestrant, compared with Standard of Care. The final Overall Survival data were not mature at the time of this analysis. Nausea of any grade occurred in 35% of patients receiving Elacestrant and 18.8% receiving Standard of Care treatment, and treatment discontinuations due to adverse events were 3.4% in the Elacestrant group versus 0.9% in the Standard of Care group.

It was concluded that Elacestrant is the first oral Selective Estrogen Receptor Degrader that demonstrated significant and clinically meaningful improvement in PFS, compared with Standard of Care endocrine therapy, in patients with ER+/ HER2- metastatic breast cancer, in the second/third line after treatment with a CDK4/6 inhibitor, and has the potential to become the new standard of care in this study population.

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Bidard F-C, Kaklamani VG, Neven P, et al. DOI: 10.1200/JCO.22.00338 Journal of Clinical Oncology. Published online May 18, 2022.

LYNPARZA® Superior to Next-Generation Hormonal Drug in CRPC Patients with Homologous Recombination Repair Gene Alterations

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of Prostate cancer will be diagnosed in 2022 and 34,500 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. 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 malignant transformation of prostatic epithelial cell as well as the development of CRPC has been attributed to deleterious alterations in a variety of genes including loss-of-function alterations in Homologous Recombination Repair (HRR) genes.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes that recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1, BRCA2, PALB2, CHEK2 and ATM genes. Mutations in these genes predispose an individual to develop malignant tumors. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. LYNPARZA® (Olaparib) is a first-in-class PARP inhibitor and blocks DNA damage response in tumors harboring a deficiency in Homologous Recombination Repair, as is noted in those with mutations such as BRCA1 and/or BRCA2. LYNPARZA® showed promising results in a Phase II trial (TOPARP), when given as monotherapy, in patients with BRCA1/2 or ATM gene-mutated mCRPC, who had received a prior Taxane-based chemotherapy, and at least one newer hormonal agent (ZYTIGA® or XTANDI®).

PROfound is a prospective, multicentre, randomized, open-label, Phase III trial in which the efficacy and safety of LYNPARZA® was compared with physician’s choice of either XTANDI® or ZYTIGA® in two groups of patients with mCRPC, who had progressed on prior treatment with new hormonal anticancer treatments, and had a qualifying tumor mutation in one of 15 genes involved in the Homologous Recombination Repair (HRR) pathway. Patients in Cohort A (N=245) had alterations in BRCA1, BRCA2 or ATM genes while those in Cohort B (N=142) had alterations in any one of 12 other genes known to be involved in DNA repair which included BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L. Patients were randomized 2:1 within each cohort to receive LYNPARZA® 300 mg orally BID or physician’s choice of XTANDI® 160 mg orally QD or ZYTIGA® 1000 mg orally QD along with Prednisone 5 mg orally BID. Patient characteristics were well-balanced between arms in each treatment group, median patient age was 68 years, approximately 25% of patients had de novo metastatic disease, about 65% of patients received prior Taxane therapy and more than 20% had received two lines of chemotherapy. Patients were allowed to cross over to LYNPARZA® upon progression. The Primary endpoint was radiographic Progression-Free Survival (rPFS) in Cohort A, assessed by Blinded Independent Central Review (BICR).

The authors had previously reported that in Cohort A, the median PFS was 7.4 months with LYNPARZA®, compared to 3.5 months in the control group (HR=0.34, P<0.0001). This represented a 66% greater delay in disease progression compared to hormonal therapy. The interim Overall Survival analysis in Cohort A showed that median OS was 18.5 months with LYNPARZA® compared to 15 months with control drug treatment (HR=0.64, P=0.0173). In Cohort A, the Objective Response Rate (ORR) was 33.3% with LYNPARZA® compared with 2.3% with control drug therapies (P<0.0001).

The authors in this publication reported the results of the prespecified Secondary endpoints, which included pain, Health-Related Quality of Life (HRQOL), symptomatic Skeletal-Related Events, and time to first opiate use for cancer-related pain in Cohort A group of patients. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Cohort A included 245 patients with alterations in BRCA1, BRCA2, or ATM genes, of whom 162 patients received the investigational agent LYNPARZA®, and 83 patients received control drug. The median duration of follow up at data cutoff was 6.2 months for all LYNPARZA® group patients and 3.5 months for the control group patients. The median time to pain progression was significantly longer with LYNPARZA® and was Not Reached in the LYNPARZA® group versus 9.92 months in the control group (HR=0.44; P=0.019). Pain interference scores were also significantly better in the LYNPARZA® group (difference in overall adjusted mean change from baseline score −0.85; nominal P=0.0004). Median time to progression of pain severity was Not Reached in either group. Among patients who had not used opiates at baseline (113 in the LYNPARZA® group, 58 in the control group), median time to first opiate use for cancer-related pain was 18.0 months in the LYNPARZA® group versus 7.5 months in the control group (HR=0.61; nominal P=0.044).

The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the LYNPARZA® group than the control group (10% versus 1% respectively; odds ratio=8.32; nominal P=0.0065). The median time to first symptomatic Skeletal-Related Event was not reached for either treatment group and the proportions of patients remaining free of symptomatic Skeletal-Related Events were 89.5% versus 77.1% at 6 months and 77.6% versus 53.6% at 12 months, in the LYNPARZA® and control groups respectively.

It was concluded that LYNPARZA® was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs, in patients with metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Repair gene alterations, who had disease progression after a previous next-generation hormonal drug. The authors added that the study findings support the clinical benefit of improved radiographical Progression Free Survival and Overall Survival identified in PROfound trial.

Pain and health-related quality of life with olaparib versus physician’s choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial. Thiery-Vuillemin A, de Bono J, Hussain M, et al. The Lancet Oncology March 2022;23:393-405.

Late Breaking Abstract – ASCO 2022: Landmark Five Year Overall Survival Rates for OPDIVO® and YERVOY® Combination in NSCLC

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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. 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.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.

CheckMate-227 is an open-label, multi-part, global, Phase III trial in which OPDIVO® based regimens were compared with Platinum-doublet chemotherapy in patients with first line advanced NSCLC, across non-squamous and squamous tumor histologies. This study consisted of Part 1a/Part 1b and Part 2. In Part 2 of this trial, OPDIVO® plus chemotherapy was compared with chemotherapy alone, regardless of PD-L1 expression. Part 2 did not meet its Primary endpoint for Overall Survival for OPDIVO® plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC, and is published elsewhere.

Part 1a: Patients received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks (N=396), OPDIVO® monotherapy 240 mg IV every 2 weeks (N=396) or chemotherapy alone given every 3 weeks for up to four cycles (N=397), in patients whose tumors had PD-L1 expression of 1% or more.
Part 1b: Patients received OPDIVO® plus YERVOY® (N=187), OPDIVO® 360 mg IV every 3 weeks plus chemotherapy IV every 3 weeks for up to four cycles (N=177), or chemotherapy alone IV every 3 weeks for up to four cycles (N=186), in patients whose tumors did not express PD-L1 (less than 1%)

Patients were stratified by histology, and treatment was administered until disease progression, unacceptable toxicity, or administered for 2 years for immunotherapy. It should be noted that when this trial was launched, chemotherapy along with immunotherapy or immunotherapy alone was not approved for the front-line treatment of NSCLC. Therefore, dual immunotherapy combination was not compared with current standards of care such as chemotherapy plus immunotherapy.

There were two independent Primary endpoints in Part 1 for OPDIVO® plus YERVOY® versus chemotherapy: Overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and Progression Free Survival (PFS) in patients with TMB of 10 mut/Mb or more, across the PD-L1 spectrum (assessed in patients enrolled across Part 1a and Part 1b). Other assessments included Objective Response Rate (ORR), Duration of Response (DOR), and treatment-free interval. Treatment-free interval was measured in patients who discontinued study therapy and was defined as the time from last study dose to start of subsequent systemic therapy.

The Overall Survival (OS) data was previously reported at a minimum follow up of 29 months, and the median OS was of 17.1 months for the OPDIVO® plus YERVOY® group, compared to 14.9 months in the chemotherapy group (HR=0.79; P=0.007), with a 2-year OS rate of 40.0% and 32.8%, respectively. The researchers here in presented data after a minimum follow up of 61.3 months (5 years).

Patients whose tumors had PD-L1 expression of 1% or more continued to have sustained long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR=0.77), and the 5-year OS rates were 24% with OPDIVO® plus YERVOY® compared to 14% with chemotherapy alone.

Patients with a PD-L1 expression of less than 1% also demonstrated continued long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR = 0.65), and the 5-year OS rates were 19% for OPDIVO® plus YERVOY&reg compared to 7% for chemotherapy alone.

Among patients who survived for 5 years, median PFS was 59.1 months for PD-L1–positive patients and 60.7 months for PD-L1–negative patients who received OPDIVO® plus YERVOY®, compared to 9.5 months and 24.9 months respectively, for those who received chemotherapy.

Among those who responded to treatment, more patients who received OPDIVO® plus YERVOY® remained in response at five years, compared to chemotherapy, in both PD-L1 expression of 1% or more group (28% versus 3%) and PD-L1 expression of less than 1% group (21% versus 0%), respectively.

Among patients treated with OPDIVO® plus YERVOY® who were alive at five years, approximately two-thirds of patients did not receive any subsequent therapy for more than three years after stopping treatment, regardless of PD-L1 expression.

It was concluded that in this longest reported follow up of a Phase III trial of first line, chemotherapy free, combination immunotherapy, in metastatic Non Small cell Lung Cancer, a combination of OPDIVO® plus YERVOY® continued to provide long term durable clinical benefit and increased 5-year survivorship, when compared to chemotherapy, in previously untreated patients with metastatic NSCLC, regardless of PD-L1 expression.

Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227. Brahmer JR, Lee J-S, Ciuleanu T-E, et al. J Clin Oncol. 2022;40(suppl 17):LBA9025. doi:10.1200/JCO.2022.40.17_suppl.LBA9025

Late Breaking Abstract – ASCO 2022: Docetaxel as Radiosensitizer Improves Overall Survival in Cisplatin-Ineligible Head and Neck cancer

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SUMMARY: The American Cancer Society estimates that in the US for 2022, about 54,000 new cases of oral cavity or oropharyngeal cancer will be diagnosed and about 11,230 patients will die of the disease. Patients with squamous cell carcinoma of the head and neck, frequently present with locoregionally advanced disease. For patients in this setting, chemoradiotherapy is an effective non-surgical approach as primary treatment. Alternatively, chemoradiotherapy can be delivered as adjuvant therapy after a curative resection.

Cisplatin-based concurrent chemoradiation is generally accepted as the standard, definitive non-surgical and post-operative approach in selected patients with locoregionally advanced squamous cell carcinoma of the head and neck. This treatment can however be associated with substantial morbidity and lifelong toxicities. Cetuximab is an immunoglobulin G1 chimeric monoclonal antibody against Epidermal Growth Factor Receptor (EGFR), and the only approved targeted agent in locoregionally advanced squamous cell carcinoma of the head and neck. Cetuximab plus Radiotherapy significantly improved Overall Survival at 5 years, when compared with radiotherapy alone, in patients with locoregionally advanced squamous cell carcinoma of the head and neck (Lancet Oncol. 2010). Cetuximab plus Radiotherapy is therefore an important treatment option in this patient group. However, financial barriers make Cetuximab as a Cisplatin substitute, inaccessible to patients, in low and middle-income countries.

Docetaxel is a semisynthetic taxane that affects polymerized tubulin to promote microtubule formation and inhibit its disassembly. Docetaxel has been shown to have significant antitumor activity as a single agent in head and neck cancer, when given in the neoadjuvant setting. Docetaxel is also a potent radiosensitizer. The researchers evaluated Docetaxel as a radiosensitizer in this clinical trial.

The authors in this open-label, randomized, Phase III study enrolled 356 Cisplatin-ineligible patients with locally advanced head and neck squamous cell carcinoma, planned for treatment with radical or adjuvant chemoradiation. The patients were randomly assigned 1:1 to receive Radiation alone (N=176) or Radiation with concurrent Docetaxel 15 mg/m2 IV weekly for a maximum of 7 cycles (N=180). Both treatment groups were well balanced. The median age was 62 yrs, approximately 45% of patients had a ECOG Performance Status of 2, and reasons for Cisplatin ineligibility included low creatinine clearance (26%), and hearing loss (43%). Approximately 33% of patients had oral cavity cancer and about two-thirds of patients had Stage IVA disease. The FACT-G, and Head and Neck questionnaires were completed by patients at baseline, 6 months, 12 months and at 24 months. FACT-G (Functional Assessment of Cancer Therapy-G) is a 27-item questionnaire designed to measure four domains of Health-Related Quality of Life (HRQOL) in cancer patients, which includes physical, social, emotional, and functional well-being. The Primary endpoint was Disease Free Survival (DFS), and key Secondary endpoints included Overall Survival (OS), adverse events and Quality of Life.

It was noted that the 2-year DFS was 30.3% with Radiation alone versus 42% with Docetaxel plus Radiation Therapy (HR=0.67; P=0.002). Docetaxel plus Radiation Therapy also significantly improved Overall Survival. The median Overall Survival was 15.3 months with Radiation Therapy alone, versus 25.5 months in the Docetaxel plus Radiation Therapy group (P=0.035). The 2 -year Overall Survival was also significantly higher in the Docetaxel plus Radiation Therapy group and was 41.7% with Radiation Therapy alone, versus 50.8% in the Docetaxel plus Radiation Therapy group (HR=0.74; P=0.035). These survival outcomes were observed across all preplanned subgroups.

Grade 3 or above adverse events were seen in 58% of patients receiving Radiation Therapy alone and in 81.6% of patients receiving Docetaxel plus Radiation Therapy. The addition of Docetaxel to Radiation Therapy resulted in a higher incidence of Grade 3 and above mucositis (49.7% versus 22.2%; P<0.001), odynophagia (52.5% versus 33.5%; P<0.001) and dysphagia (49.7% versus 33%; P<0.002). The addition of Docetaxel however did not lead to a worsening of Quality of Life, including Trial Outcome Index and FACT-G scores at 6 months.

The authors concluded that the addition of Docetaxel to Radiation Therapy improved Disease Free Survival and Overall Survival, in Cisplatin-ineligible locally advanced head and neck squamous cell carcinoma, and provides an evidence based, financially more viable treatment option, for this patient group.

Results of phase 3 randomized trial for use of docetaxel as a radiosensitizer in patients with head and neck cancer unsuitable for cisplatin-based chemoradiation. Patil VM, Noronha V, Menon NS, et al. DOI: 10.1200/JCO.2022.40.17_suppl.LBA6003 Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022) LBA6003.

ADCETRIS® Improves Overall Survival in Stage III or IV Hodgkin’s Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 8,540 new cases of Hodgkin lymphoma will be diagnosed and about 920 patients will die of the disease. Hodgkin lymphoma is classified into two main groups – Classical Hodgkin lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells, collectively known as Hodgkin and Reed-Sternberg cells (HRS).

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (Stage III-IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

Response-adapted therapy involves the administration of 2 cycles of chemotherapy with ABVD regimen, followed by an interim PET scan, which serves as the basis for either intensifying or de-escalating therapy. If PET negative after the second cycle, patients receive 4 additional cycles of AVD omitting Bleomycin from the ABVD regimen. Radiotherapy is not recommended for patients with negative findings on interim PET scans. This response-adapted therapy resulted in lower incidence of pulmonary toxicities, compared with continued treatment with ABVD, without compromising efficacy (NEJM 2016; 374:2419-2429).

ADCETRIS® (Brentuximab vedotin) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. In a previously published Phase I study, ADCETRIS® in combination with AVD (A+AVD) resulted in a Complete Response rate of 96% and a 5 year Overall Survival rate of 100%. Based on these finding, ECHELON-1 study was conducted, which is an international, open-label, randomized, multicenter, Phase III trial, comparing A+AVD with ABVD, as frontline therapy in patients with Stage III or IV Classical Hodgkin lymphoma. The goal of this study was to maintain the high probability of cure, while reducing the incidence of toxic effects.

ECHELON-1 study included 1334 previously untreated patients with Stage III or IV Classical Hodgkin lymphoma, who were randomly assigned in a 1:1 ratio to receive A+AVD (N=664), which consisted of ADCETRIS® 1.2 mg/kg , Doxorubicin 25 mg/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2 or ABVD (N=670), which consisted of Doxorubicin 25 mg/m2, Bleomycin 10 units/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2, given intravenously, on days 1 and 15 of each 28-day cycle, for up to 6 cycles. Both treatment groups were well balanced and approximately 14% of the patients in the trial were 60 years of age or older. The use of Granulocyte Colony Stimulating Factor (G-CSF), which was initially permitted according to institutional guidelines, was subsequently recommended after an increased incidence of febrile neutropenia with A+AVD therapy during an interim safety analysis. The Primary end point was “modified” Progression Free Survival (mPFS), which, in addition to disease progression or death, included less than Complete Response after the completion of frontline chemotherapy, based on independently assessed PET results. PET scan interpretation was based on Deauville score (The Deauville score is a 5-point scale on which higher scores indicate greater uptake of FDG glucose at involved sites on PET). Patients were stratified according to International Prognostic Score (IPS) risk group (Low risk versus Intermediate risk versus High risk). A PET scan was performed at the end of the second cycle of treatment (PET2) and patients were offered alternative frontline therapy at the discretion of the treating physician, for patients with a PET Deauville score of 5. Secondary end points included Overall Survival.

At a median follow up of 73.0 months, the analysis of Overall Survival significantly favored A+AVD over ABVD across various subgroups (HR for death=0.59; P=0.009). The 6-year Overall Survival estimates were 93.9% in the A+AVD group and 89.4% in the ABVD group. Progression Free Survival (PFS) outcomes also favored A+AVD over ABVD and the 6-year PFS estimates were 82.3% with A+AVD and 74.5% with ABVD (HR for disease progression or death=0.68). The PFS estimates again favored A+AVD over ABVD across various subgroups, including subgroups defined according to disease Stage (III or IV) and PET2-negative status. Further, fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation. Fewer second cancers were reported with A+AVD, but more patients had peripheral neuropathy with A+AVD than with ABVD. However, majority of patients in both treatment groups had resolution or amelioration of neuropathy by the last follow up.

It was concluded from the ECHELON-1 study that, after a median follow up of 6 years, treatment with ADCETRIS® in combination with Doxorubicin, Vinblastine and Dacarbazine (A+AVD) resulted in a significant improvement both in Progression Free Survival as well as Overall Survival.

Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin’s Lymphoma. Ansell SM, Radford J, Connors JM, et al. for the ECHELON-1 Study Group. N Engl J Med 2022; 387:310-320.

Late Breaking Abstract – ASCO 2022: Improved Distant Metastasis-Free Survival with Adjuvant KEYTRUDA® in High Risk Stage II Melanoma

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SUMMARY: The American Cancer Society’s estimates that for 2022, about 99,780 new cases of melanoma of the skin will be diagnosed in the United States and 7,650 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, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. The current standard of care for patients following resection of high-risk Stage II disease is observation, even though patients with Stage IIB and IIC disease presenting with high-risk features (depth of invasion, T-category, ulceration) have 5 and 10 year melanoma-specific survival similar to that of patients with Stage IIIA and IIIB disease.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. 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. The FDA in 2019, approved KEYTRUDA® for the adjuvant treatment of patients with melanoma, with involvement of lymph node(s), following complete resection (Stage III). The present study was conducted to evaluate the role of adjuvant immunotherapy in patients with high risk Stage II melanoma.

KEYNOTE-716 is a randomized, double-blind, Phase III trial, in which 976 patients aged 12 years or older, with completely resected cutaneous Stage IIB or IIC melanoma, and no lymph node involvement, were randomly assigned 1:1 to receive KEYTRUDA® 200 mg IV (2 mg/kg for pediatric patients) or placebo, every 3 weeks for 17 cycles (up to 1 year). Patients were stratified by T category 3b, 4a, 4b (adults) and with a separate stratum for pediatric patients. Approximately 65% had Stage IIB disease and 35% had Stage IIC disease. There was no prespecified analysis for PD-L1 or BRAF status in this study, as there was inconsistent and small amounts of tissue available for testing. This was the first part (Part 1) of this double-blind study. The Primary endpoint was Relapse Free Survival (RFS) per investigator assessment, and Safety. The second part (Part 2) of this study was open-label design, and adults and pediatric patients were eligible to receive up to 35 additional cycles of treatment, only if they had recurrence after receiving the placebo or completed 17 cycles of KEYTRUDA®. Patients in the KEYTRUDA® group who experienced disease recurrence within 6 months of completing the treatment were excluded from Part 2 of the study. Secondary end points included Distant Metastasis Free Survival (DMFS), Overall Survival (OS) and Quality of Life.

At median follow up of 14.4 months, adjuvant KEYTRUDA® significantly prolonged RFS compared to placebo (HR=0.65; P=0.00658), in patients with resected Stage IIB or IIC melanoma. At the time of this analysis, 11.1% of patients on KEYTRUDA® had a recurrence, compared to 16.8% of those receiving placebo. The 12-month RFS rate was 90.5% for KEYTRUDA® versus 83.1% for placebo.

The researchers herein presented new data from the analysis of Distant Metastasis-Free Survival (DMFS) and Recurrence Free Survival (RFS), with a longer median follow up of 26.9 months. Adjuvant KEYTRUDA® significantly improved DMFS when compared to placebo (HR=0.64; P=0.0029), representing a 36% reduction in the risk of recurrence. The 24-month DMFS rate was 88.1% versus 82.2%, respectively. Grade 3 or more Adverse Events occurred in 28.4% of patients in the KEYTRUDA® group, versus 20% in the placebo group. Hypothyroidism was the most common immune mediated Adverse Event with KEYTRUDA®, compared to placebo (17.2% versus 3.7%).

The authors concluded that adjuvant KEYTRUDA® for resected Stage IIB and IIC melanoma, significantly improved Distant Metastasis-Free Survival, with continued reduction in the risk of recurrence, and a favorable benefit-risk profile. KEYNOTE-716 is the first randomized Phase III trial of an anti-PD-1 therapy in resected Stage II melanoma, and these findings represent an important milestone for this patient group.

Distant metastasis-free survival with pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: The phase 3 KEYNOTE-716 study. Long GV, Luke JJ, Khattak M, et al. DOI: 10.1200/JCO.2022.40.17_suppl.LBA9500 Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022) LBA9500-LBA9500.

Late Breaking Abstract – ASCO 2022: RUBRACA® Monotherapy as Maintenance Treatment in Newly Diagnosed Ovarian Cancer

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SUMMARY: 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%.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity.

Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers 15% of ovarian cancers, in addition to other cancers such as colon and prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic).

The PARP (Poly ADP Ribose Polymerase) family of enzymes includes PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

RUBRACA® is an oral, small molecule PARP inhibitor, developed for treatment of ovarian cancer associated with Homologous Recombination DNA repair deficiency (HRD). With regards to ovarian cancer, RUBRACA® is presently approved by the FDA for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a Complete or Partial Response to platinum-based chemotherapy.

ATHENA is an international, multicenter, randomized, double-blind, placebo-controlled, Phase III trial, which evaluated first-line maintenance treatment for patients with newly diagnosed advanced ovarian cancer. ATHENA was designed to evaluate RUBRACA® first-line maintenance treatment in a broad group of patients, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of Homologous Recombination Deficiency (HRD), or high-risk clinical characteristics such as residual disease. ATHENA study has two separate and fully independently powered comparisons evaluating RUBRACA® monotherapy (ATHENA–MONO) and RUBRACA® plus Nivolumab (ATHENA–COMBO), as maintenance treatment in this patient population. The authors herein reported the efficacy and safety results from the ATHENA–MONO comparison of RUBRACA® maintenance treatment versus placebo.

In the ATHENA-MONO trial, patients with Stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to 4-8 cycles of first-line platinum-doublet chemotherapy, were randomly assigned 4:1 to receive RUBRACA® 600 mg orally twice daily (N=427) or placebo. Treatment was continued for 24 months or until disease progression or unacceptable toxicity. Patients were stratified by HRD test status, residual disease after chemotherapy, and timing of surgery (primary surgery versus interval debulking). The median age was 61 years, majority of the patients (78%) did not have a BRCA mutation. Patients were stratified by HRD classification (BRCA wild-type/LOH (Loss of Heterozygosity) high-16% or more, BRCA wild-type/LOH low-less than 16%, and BRCA wild-type/LOH indeterminate). The Primary end point of investigator-assessed Progression Free Survival (PFS) was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/LOH high tumor), and then in the Intent-To-Treat (ITT) population. Secondary end points included Overall Survival (OS), investigator-assessed Objective Response Rate (ORR) in patients with measurable disease at baseline and Duration of Response (DOR) for patients with investigator-assessed confirmed radiographic Complete Response (CR) or Partial Response (PR). The median duration of follow was 26 months.

The median PFS in the HRD population was 28.7 months with RUBRACA® maintenance group compared to 11.3 months with placebo (HR=0.47; P=0.0004). In the Intent to Treat (ITT) population, the median PFS was 20.2 months in the RUBRACA® group versus 9.2 months in the placebo group (HR=0.52; P<0.0001). At 24 months, 45% of RUBRACA®-treated patients in the ITT population were progression-free compared with 25.4% with placebo. In the HRD negative population, the median PFS was 12.1 months in the RUBRACA® group versus 9.1 months in the placebo group (HR=0.65). Exploratory subgroup analyses of PFS in the ITT population showed that there was greater clinical benefit with RUBRACA® compared to placebo among all subgroups, including BRCA-mutant, BRCA wild-type/LOH high, and BRCA wild-type/LOH low (HRD-negative).

Among RUBRACA®-treated patients with measurable disease at baseline, the ORR, was 58.8% in the HRD population and 48.8% in the ITT population. Among the placebo-treated patients, the ORR was 20% in the HRD population and 9.1% in the ITT population. The median Duration of Response in the HRD and ITT populations for RUBRACA®-treated responders versus the placebo-treated responders respectively, was 16.7 months versus 5.5 months and 22.1 months versus 5.5 months. The Overall Survival results were immature at the time of the data cutoff. The most common Grade 3 or more adverse events in the RUBRACA® group were anemia (29%) and neutropenia 15%).

The authors concluded that in the ATHENA-MONO trial, RUBRACA® monotherapy is an effective first-line maintenance option that provides clinical benefit to a broad population of patients with newly diagnosed ovarian cancer, regardless of BRCA mutation and HRD status.

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45). Monk BJ, Parkinson C, Lim MC, et al. DOI: 10.1200/JCO.2022.40.17_suppl.LBA5500 Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022) LBA5500-LBA5500. Published online June 08, 2022.