Category: Meeting Updates

Neoadjuvant KEYTRUDA® Plus Chemotherapy Improves Pathological Complete Response in Triple Negative Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pCR following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS). Those who do not achieve a pathological Complete Response tend to have a poor prognosis. For all these reasons, pCR is considered a valid endpoint for clinical testing of neoadjuvant therapy in patients with early stage TNBC. It appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. Cytotoxic chemotherapy releases tumor-specific antigens and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Preliminary results from Phase I and II trials have shown that in patients with TNBC, KEYTRUDA® given along with chemotherapy in a neoadjuvant setting resulted in a high rate of pCR.

KEYNOTE-522 is an international, placebo controlled Phase III trial, conducted to evaluate the safety and efficacy of neoadjuvant KEYTRUDA® plus chemotherapy followed by adjuvant KEYTRUDA® or placebo, in patients with early stage TNBC. In this study, 1,174 patients were randomly assigned in a 2:1 ratio to receive neoadjuvant KEYTRUDA® 200 mg IV every 3 weeks (N=784) or placebo (N=390). All patients received 4 cycles of Carboplatin plus Paclitaxel, followed by 4 cycles of Doxorubicin or Epirubicin plus Cyclophosphamide, in the neoadjuvant setting. Following definitive surgery, adjuvant KEYTRUDA® or placebo was continued every 3 weeks for 9 cycles or until disease recurrence or unacceptable toxicity. Enrolled TNBC patients were newly diagnosed, treatment naïve, and included both node-negative and node-positive patients with nonmetastatic disease (Tumor Stage T1c, Nodal Stage N1-N2 or Tumor Stage T2-T4, Nodal Stage N0-N2, per AJCC criteria). Treatment groups were well balanced and patients were stratified according to nodal status, tumor size, and Carboplatin schedule (weekly versus every 3 weeks). The two Primary endpoints were pathological Complete Response (pCR) at the time of definitive surgery and Event Free Survival (EFS). The median follow up was 15.5 months.

At the first interim analysis, the pCR among the first 602 patients who underwent randomization was 64.8% in the KEYTRUDA® plus chemotherapy group, compared with 51.2% in the placebo plus chemotherapy group (P<0.001). This pCR benefit was consistent across subgroups including PD-L1 expresssion subgroups. In the PD-L1-positive population, the pCR was 68.9% in the KEYTRUDA® plus chemotherapy group compared with 54.9% in the placebo plus chemotherapy group. In the PD-L1 negative group, the pCR in the KEYTRUDA® plus chemotherapy group was 45.3% and 30.3% in the placebo plus chemotherapy group. Neoadjuvant KEYTRUDA® plus chemotherapy followed by adjuvant KEYTRUDA® showed a favorable trend for Event Free Survival compared with chemotherapy alone, although these data are still premature. Across all treatment phases, Grade 3 or higher treatment-related toxicities were 78.0% in the KEYTRUDA® plus chemotherapy group and 73.0% in the placebo plus chemotherapy group.

It was concluded that among patients with early stage Triple Negative Breast Cancer, the addition of KEYTRUDA® to neoadjuvant chemotherapy significantly increased the pathological Complete Response rate, compared to those who received placebo plus neoadjuvant chemotherapy, with a favorable trend in Event Free Survival. Pembrolizumab for Early Triple-Negative Breast Cancer. Schmid P, Cortés J, Pusztai L, et al. for the KEYNOTE-522 Investigators. N Engl J Med 2020;382:810-821

Late Breaking Abstract – ASH 2019: DARZALEX®, KYPROLIS® and Dexamethasone Combination Improves PFS in Relapsed or Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32, 270 new cases will be diagnosed in 2020 and 12,830 patients are expected to die of the disease. Multiple Myeloma (MM) in 2020 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). 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 or refractory disease have the worst outcomes. The median survival for patients with Myeloma is over 10 years.

REVLIMID® (Lenalidomide) in combination with VELCADE® (Bortezomib) and Dexamethasone is the preferred regimen according to the NCCN guidelines, for both transplant and non-transplant candidates with newly diagnosed Multiple Myeloma, and when given continuously or with maintenance therapy, has improved survival outcomes. Nonetheless, a significant number of patients progress while on these agents or discontinue therapy due to toxicities. There is therefore a need for effective and tolerable regimens for patients who are exposed or refractory to REVLIMID® or VELCADE®.Mechanism-of-Action-of-Daratumumab

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE®, proteasome inhibition with KYPROLIS® is irreversible. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and direct Apoptosis. Additionally, DARZALEX® may play a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. Both KYPROLIS® and DARZALEX® are approved as single agents, as well as in combination with other drugs, for the treatment of patients with Relapsed/Refractory Multiple Myeloma. In a Phase I study, KYPROLIS® in combination with Dexamethasone and DARZALEX® demonstrated safety and efficacy in patients Relapsed/Refractory Multiple Myeloma.

CANDOR is a multicenter, open-label, Phase III trial, which included Relapsed/Refractory Multiple Myeloma patients with measurable disease who had received 1-3 prior lines of therapy, with Partial Response or better to one or more lines of therapy. A total of 466 patients were randomly assigned 2:1 to receive triplet of KYPROLIS®, Dexamethasone, and DARZALEX® (KdD)- N=312 or KYPROLIS® and Dexamethasone (Kd) alone- N=154. All patients received KYPROLIS® as a 30 minute IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). DARZALEX® 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (cycles 3-6), and every 4 weeks thereafter. All patients received Dexamethasone 40 mg oral or IV weekly (20 mg for patients over 75 years of age). The median age was 64 years, 42% and 90% received prior REVLIMID® and VELCADE® (Bortezomib) containing regimens respectively, and a third of patients were refractory to REVLIMID®. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints including Overall Response Rate (ORR), Minimal Residual Disease (MRD)-negative status, Complete Response (CR) rate at 12 months, Overall Survival (OS), Duration of Response, and Safety.

After a median follow up of 17 months, the study met its Primary endpoint and the median PFS was not reached for the KdD arm and was 15.8 months for the Kd arm (HR=0.63; P=0014). This represented a 37% reduction in the risk of progression or death in the KdD group. The PFS benefit of KdD was maintained across prespecified subgroups, particularly among REVLIMID®-exposed and REVLIMID®-refractory patients. The ORR was 84.3% in the KdD group versus 74.7% in the Kd group (P=0.004), with a CR rate or better of 28.5% versus 10.4% respectively. The median time to first response was one month in both treatment groups. Patients treated with KdD achieved deeper responses which was nearly 10 times higher, with a MRD-negative Complete Response rate at 12 months of 12.5% for KdD versus 1.3% for Kd (P<0.0001). The median treatment duration was longer in the KdD group compared to the Kd group (70.1 versus 40.3 wks). The median OS was not reached in either groups, at a median follow up time of 17 months. Toxicities were generally manageable and the incidence of Adverse Events leading to treatment discontinuation was similar in both treatment groups.

It was concluded that a combination of KYPROLIS® along with Dexamethasone and DARZALEX® resulted in a significant PFS benefit over KYPROLIS® and Dexamethasone alone, with deeper responses, and the PFS benefit of KdD was maintained across prespecified, clinically important subgroups, particularly REVLIMID®-exposed and REVLIMID®-refractory patients. The authors added that KdD regimen should be considered as a novel, efficacious, and tolerable immunomodulatory-free treatment option for Relapsed/Refractory Multiple Myeloma patients. Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688). Usmani SZ, Quach H, Mateos M-V, et al. Presented at the 61st American Society of Hematology Annual Meeting and Exposition; Orlando, Florida; December 7-10, 2019; Abstract LBA-6.

PROSE: Randomized proteomic stratified phase III study of second line erlotinib versus chemotherapy in patients with inoperable non–small cell lung cancer (NSCLC)

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SUMMARY: VeriStrat ® is a clinically validated serum/plasma-based assay, for patients with advanced Non Small Cell Lung Cancer (NSCLC). VeriStrat® is a serum test of prognostic and predictive value that classifies patients as VeriStrat-Good (VS-G) or VeriStrat-Poor (VS-P) based on eight mass spectral peaks or proteomic patterns of the patients serum. Proteomics is the large-scale study of protein structure and functions. VeriStrat® testing is protein based and therefore has no correlation with known genomic biomarkers. It is well established that EGFR-TKIs (Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors) are more effective in NSCLC patients with EGFR activating mutations. PROSE is a multicenter, double blind, randomized, VeriStrat® stratified, phase III study. In this trial, over 90% of the patients had no EGFR mutations (EGFR-Wild Type). Two hundred and eighty five (285) patients with advanced NSCLC who had first line treatment regimen with platinum-based therapy were randomly assigned to receive second line chemotherapy (CT) with single agent ALIMTA® (Pemetrexed) or TAXOTERE® (Docetaxel), at standard doses (N=129) or TARCEVA® (Erlotinib) 150 mg po qd (N=134). Patients and study investigators were blinded to the patients VeriStrat® status. Patients were classified as VeriStrat-Good or VeriStrat-Poor based on the VeriStrat® results. Patients in the treatment groups were stratified by age, gender, tumor histology, ECOG-PS and smoking history. Crossover was permitted upon disease progression. The primary objective of the study was to demonstrate differential treatment benefit between TARCEVA® and CT with regards to Overall Survival (OS). Median overall survival (OS) was 9 months for the patients in the CT group and 7.7 months for TARCEVA® group and this was not statistically significant (P=0.3). However when evaluated by VeriStrat® status, CT was beneficial for the VeriStrat-Poor patients compared to TARCEVA®, with significantly better median OS (6.3 vs 3 months, P=0.02). Age, gender, histology (squamous vs non-squamous) and smoking history had no impact on the overall survival. The authors concluded that patients classified as VeriStrat-Poor have better survival with CT than TARCEVA®, whereas patients classified as VeriStrat-Good have similar survival with TARCEVA® and CT. VeriStrat® testing therefore, can help physicians choose between TARCEVA® and CT, for their patients with advanced NSCLC. This test helps physicians identify patients who are likely to have good or poor outcomes after treatment with EGFR inhibitors and thereby can provide valuable insight into whether CT or targeted therapy with TARCEVA®, a EGFR-TKI, is appropriate for their patients with advanced NSCLC, in the second line setting. This information is especially important for patients without an EGFR mutation or for those, whose EGFR mutation status is unknown. Sorlini C, Barni S, Petrelli F, et al. J Clin Oncol 29: 2011 (suppl; abstr TPS214)

 

IDHIFA® plus VIDAZA® Significantly Improves Complete Remission and Overall Response in Newly Diagnosed IDH2-Mutated AML

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SUMMARY: The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%. 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. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

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% 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.

IDHIFA® (Enasidenib) is a selective, oral, small molecule inhibitor of mutated IDH2 protein that promotes myeloid cell differentiation. IDHIFA® indirectly reduces DNA methylation by suppressing the oncometabolite, 2-HydroxyGlutarate, thereby restoring function to Alpha-Ketoglutarate-dependent TET family enzymes. IDHIFA® was approved in the US in 2017 for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML), with an IDH2 mutation. Further, treatment with single agent IDHIFA® resulted in an Overall Response Rate (ORR) of 31% and a Completer Response (CR) rate of 18% in patients with newly diagnosed AML. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS) when compared to conventional care regimens in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. In vitro studies demonstrated that a combination of IDHIFA® and VIDAZA® enhance cell differentiation and apoptosis.

Based on this preclinical data and early clinical trials, an open label, Phase I/II study was conducted comparing a combination of IDHIFA® and VIDAZA® with single agent VIDAZA® in patients with newly diagnosed IDH2 mutated AML, who are not candidates for intensive chemotherapy. The authors reported the first interim outcomes from the randomized, Phase II portion of this ongoing study. The Phase II portion of the trial enrolled 101 patients with newly diagnosed IDH2-mutant AML who were ineligible to receive intensive chemotherapy. Patients had an ECOG PS score of 2 or less and were randomized in a 2:1 ratio to receive IDHIFA® plus VIDAZA® or VIDAZA® alone in repeated 28-day cycles. All patients received VIDAZA® 75 mg/m2/day SC for the first 7 days of each treatment cycle, whereas patients randomized to IDHIFA® plus VIDAZA® also received IDHIFA® 100 mg orally QD continuously. The median patient age was 75 years, and 78% in the combination group and 90% in the VIDAZA® only group had intermediate-risk cytogenetics respectively, and 18% and 10% had poor-risk cytogenetics. The median number of treatment cycles was 8. The Primary endpoint was Overall Response Rate (ORR), which included Complete Remission (CR), CR with incomplete blood or platelet count recovery (CRi/CRp), Partial Remission (PR), and Morphologic Leukemia-Free State (MLFS), per modified IWG 2003 AML response criteria. Mutant IDH2 Variant Allele Frequencies (VAF) in bone marrow mononuclear cells was assessed by digital PCR.

It was noted that the ORR were significantly higher with combination treatment vs VIDAZA® alone (71% versus 42% respectively, P=0.0064) and the CR rates were 53% versus 12% (P=0.0001). The time to first response was about 2 months in each treatment group and the median Duration of Response was 24.1 months with the combination treatment and 12.1 months with VIDAZA® alone. Responses were observed in patients with RAS pathway co-mutations, which have been usually associated with resistance to IDHIFA® monotherapy. The maximal mutant IDH2 VAF suppression from baseline was significantly greater with the combination treatment versus single agent VIDAZA® (median –69.3% versus –14.1% respectively, P=0.0004). Treatment related Grade 3-4 Adverse Events occurring in 10% or more of patients in the combination group were neutropenia, thrombocytopenia, anemia, febrile neutropenia and IDH differentiation syndrome.

It was concluded that a combination of IDHIFA® plus VIDAZA® was associated with significantly improved Complete Remission and Overall Response Rates, with significant mutant IDH2 Variant Allele Frequencies reductions, compared with VIDAZA® alone, in patients with newly diagnosed IDH2-mutant AML. Further the combination treatment was generally well tolerated, with a safety profile similar to that reported for monotherapy with either of these two agents. Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study. DiNardo CD, Schuh AC, Stein EM, et al. Presented at 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 643.

FDA Approves ENHERTU® for Advanced HER2-Positive Breast Cancer

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SUMMARY: The FDA on December 20, 2019, granted accelerated approval to ENHERTU® (Trastuzumab deruxtecan) for patients with unresectable or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2-based regimens in the metastatic setting. 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 268,600 new cases of invasive breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.Mechanism-of-Action - ENHERTU

ENHERTU® is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA®, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, minimizing systemic exposure. In a Phase 1 dose-finding study involving patients with advanced HER2-positive breast cancer, treatment with ENHERTU® resulted in a confirmed response rate was 59.5%, and the median response duration was 20.7 months. However, the efficacy of ENHERTU® in patients with HER2-positive metastatic breast cancer, previously treated with KADCYLA® remained unclear.

The present FDA approval was based on DESTINY-Breast01 study, which is a multicenter, single-arm, Phase II trial, in which 184 patients with HER2-positive, metastatic breast cancer, who had received two or more prior HER2 targeted therapies including KADCYLA®, were enrolled. Patients received ENHERTU® 5.4 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity. The median age was 55 years, 53% had Hormone Receptor-positive tumors and the median number of previous lines of therapy for metastatic disease was six and included KADCYLA® (100%), Trastuzumab (100%), Pertuzumab (66%), and other anti-HER2 therapies (54%). The Primary end point was Objective Response Rate (ORR) assessed by Independent Central Review and Secondary endpoints included Duration of Response, Progression Free Survival (PFS) and Overall Survival (OS). The median follow up was 11.1 months. The ORR was 60.9%, with 6% Complete Responses and 54.9% Partial Responses. The median time to response was 1.6 months and the median response duration was 14.8 months. The median PFS was 16.4 months the median OS was not reached at the time of this publication. The most Grade 3 or higher adverse events were cytopenias, nausea, diarrhea and Interstitial Lung Disease.

It was concluded that ENHERTU® has a high level of clinical efficacy with a durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi S, Saura C, Yamashita T, et al. for the DESTINY-Breast01 Investigators. N Engl J Med. 2019 Dec 11. doi: 10.1056/NEJMoa1914510. [Epub ahead of print]

FDA Grants Accelerated Approval to PADCEV® for Metastatic Urothelial Cancer

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SUMMARY: The FDA on December 18, 2019, granted accelerated approval to PADCEV® (Enfortumab vedotin-ejfv), for adult patients with locally advanced or metastatic urothelial cancer who have previously received a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand1 (PD-L1) inhibitor, and a Platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. The American Cancer Society estimates that in 2019, approximately 80,470 new cases of Bladder Cancer will be diagnosed and 17,670 patients will die of the disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen and a Check Point Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Treatment options for patients who progress after first and second line therapies are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.

PADCEV® is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Following binding to Nectin-4 on the cell surface, PADCEV® becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, Monomethyl auristatin E, which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. In a Phase I dose-finding study of PADCEV®, the Objective Response Rate (ORR) was 42% among patients with advanced urothelial cancer, who previously received treatment with a PD-1/PD-L1 inhibitor.

This FDA approval was based on the results from the pivotal Phase II EV-201 study, which is an open-label, single-arm, multicenter trial in which 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and Platinum-based chemotherapy were enrolled. Patients received PADCEV® 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle, until disease progression or unacceptable toxicity. The median age was 69 years. The Primary endpoint was ORR as assessed by blinded Independent Central Review. Secondary endpoints included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Safety and Tolerability.

The ORR was 44%, with 12% Complete Responses and 32% Partial Responses. Overall, 84% of evaluable patients showed some degree of tumor shrinkage. The responses were noted at a median of 1.8 months after treatment initiation and the median Duration of Response was 7.6 months. These objective responses were seen in all patient subgroups evaluated, including those with poor prognostic features. The median PFS was 5.8 months, and the median Overall Survival was 11.7 months. The most common adverse reactions were fatigue, alopecia, decreased appetite and peripheral neuropathy. Blood glucose levels should be monitored closely in patients with, or at risk, for diabetes mellitus or hyperglycemia.

It was concluded from this study that treatment with PADCEV® demonstrated clinically meaningful Objective Response Rate, in patients with advanced metastatic urothelial cancer, who received prior treatment with a PD-1 or PD-L1 inhibitor and Platinum-based chemotherapy, thus fulfilling an unmet need. PADCEV® is the first Nectin-4-directed Antibody-Drug Conjugate to receive FDA approval, and a Phase III study is underway comparing PADCEV® against standard single-agent chemotherapy, in patients with advanced, previously treated metastatic urothelial cancer. EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. Petrylak DP, Balar AV, O’Donnell PH, et al. DOI: 10.1200/JCO.2019.37.18_suppl.LBA4505 Journal of Clinical Oncology 37, no. 18_suppl (June 20, 2019) 4505-4505.

DARZALEX® Combination Improves Overall Survival in Transplant-Ineligible Myeloma Patients

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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, 32,110 new cases will be diagnosed in 2019 and 12,960 patients are expected to die of the disease. Multiple Myeloma (MM) in 2019 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). 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 or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

Elderly patients with myeloma in the US are often treated with a combination of REVLIMID® (Lenalidomide) and Dexamethasone, whereas Melphalan, Prednisone, and Thalidomide (MPT) and VELCADE® (Bortezomib), Melphalan and Prednisone (VMP) are the most widely used regimens outside the US. These regimens are associated with a PFS of 18-24 months and an OS of 4-5 years. For patients with newly diagnosed multiple myeloma who are ineligible for ASCT, treatment with VMP regimen has been a standard effective regimen, based on the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial.Mechanism-of-Action-of-Daratumumab

DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) 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.

ALCYONE is a multicenter, randomized, open-label, active-controlled, Phase III trial in which DARZALEX® given along with VELCADE®, Melphalan and Prednisone (D-VMP regimen) was compared with VMP alone (control group), in patients with newly diagnosed multiple myeloma, who were ineligible for Autologous Stem Cell Transplantation (ASCT). Of the 706 enrolled patients, 350 were assigned to the DARZALEX® group and 356 to the control group. The median age was 71 yrs. All the patients received up to nine 6 week cycles of VELCADE® 1.3 mg/m2 SQ, twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), Melphalan 9 mg/m2 orally, once daily on days 1-4 of each cycle, and Prednisone 60 mg/m2 once daily on days 1-4 of each cycle. In the study group, patients received DARZALEX® 16 mg/kg IV administered with Dexamethasone 20 mg oral or IV (to manage infusion reactions), once weekly for a total of 6 doses, every 3 weeks for a total of 16 doses and every 4 weeks thereafter until disease progression or unacceptable toxicity. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Response Rate (ORR), rates of Very Good Partial Response (VGPR), Complete Response (CR) rate, Minimal Residual Disease (MRD) negativity and Overall Survival (OS). The FDA in 2018 approved DARZALEX® in combination with VELCADE® (Bortezomib), a proteasome inhibitor, Melphalan, an alkylating agent and Prednisone VMP regimen), for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for Autologous Stem Cell Transplant (ASCT), based on the Progression Free Survival (PFS) benefit at 16.5 months, noted during the primary analysis of the ALCYONE study. The authors herein presented outcomes after more than 36 months of follow-up from the ALCYONE study, including analysis of Overall Survival (OS) from a prespecified interim analysis.

In this updated analysis, treatment with D-VMP continued to demonstrate a twofold greater median PFS at 36.4 months versus 19.3 months with VMP, after a median follow-up of 41months (HR=0.42; P<0.0001). Patients assigned to D-VMP also had significantly prolonged PFS on subsequent therapy (PFS-2). Median PFS-2 was not reached with D-VMP versus 42.3 months with VMP (HR=0.55; P<0.0001), representing a 45% reduction in the risk for progression or death. The median time to subsequent therapy had yet to be reached in the D-VMP group versus 25.9 months for the VMP group. The Overall Response Rate was 91% in the D-VMP group as compared with 74% in the control group and the rate of Complete Response or better (including stringent CR) was 46%, versus 24.4% in the control group. The MRD-negative rate (at a threshold of 1 tumor cell per 105 white cells) was 28% with D-VMP and 7% with VMP and D-VMP also led to higher rates of sustained MRD negativity. MRD negativity for 12 or more months was associated with improved PFS. The estimated 36 month OS rate was 78% with D-VMP versus 68% with VMP, with a significant benefit for OS observed for D-VMP versus VMP alone (HR=0.60; P=0.0003). This represented a 40% reduction in the risk of death, in favor of D-VMP.

The authors concluded that for the first time, this study demonstrated that the addition of DARZALEX® to VMP significantly prolonged Overall Survival in patients with transplant-ineligible newly diagnosed Multiple Myeloma, with a 40% reduction in the risk of death, when compared with VMP alone. They added that these findings, together with the Phase 3 MAIA study (DARZALEX® plus Lenalidomide and Dexamethasone versus Lenalidomide plus Dexamethasone), continue to support the addition of DARZALEX® to frontline treatment regimens for patients with Multiple Myeloma. Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Overall Survival in Alcyone. Mateos MV, Cavo M, Bladé J, et al. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 859.

Long-Term Breast Cancer Preventive Benefit with ARIMIDEX®

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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 268,600 new cases of invasive breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Some high risk factors for the development of breast cancer include first-degree relative with breast cancer at any age, first-degree relative with bilateral breast cancer who developed the first breast cancer at 50 years of age or less, Lobular Carcinoma In Situ (LCIS), Atypical ductal or lobular hyperplasia in a benign lesion, and Ductal Carcinoma In-Situ (DCIS).

Previously published studies have shown a 38% reduction in all breast cancers and 50% reduction of ER-positive tumors with the use of SERMs (Selective Estrogen Receptor Modulators) such as Tamoxifen and Raloxifene for breast cancer prevention. Further it has been shown that the effects of Tamoxifen continue with a constant 29% annual preventive effect for at least 15 years after completion of treatment. A further improvement in breast cancer incidence short-term was seen in two trials using, two Aromatase Inhibitors, ARIMIDEX® (Anastrozole) in the International Breast Cancer Intervention Study II (IBIS-II) and AROMASIN® (Exemestane) in the MAP.3 trial. However in the MAP.3 study, the study was unblinded after the initial publication and a post-treatment effect, as was seen with Tamoxifen, was not possible.

The International Breast Cancer Intervention Study II (IBIS-II) is an international, randomized, double-blind, placebo-controlled trial, which was initiated in 2003. In this trial, 3864 postmenopausal women aged 40-70 years, at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either ARIMIDEX® 1 mg orally daily (N=1920) or matching placebo (N=1944) daily for 5 years. After treatment completion, women were followed on a yearly basis and data was collected on breast cancer incidence, death, incidence of other cancers, and major adverse events (cardiovascular events and fractures). The median age at study entry was 59 years. The exclusion criteria for this study included premenopausal status, prior breast cancer including Ductal Carcinoma In Situ (DCIS) diagnosed more than 6 months before trial entry, current or previous Tamoxifen, Raloxifene, or other SERM use for more than 6 months, or previous or planned prophylactic mastectomy. Unblinding was only permitted if the participant developed breast cancer, when a clinician considered there to be valid medical or safety reasons. The Primary outcome was the development of histologically confirmed breast cancer, either invasive or non-invasive (DCIS), particularly during the post-5-year time period. Secondary outcomes were ER-positive breast cancer, breast cancer mortality, incidence of other cancers, cardiovascular disease, fractures, and all-cause mortality. The decision to analyze the data was made without looking at the results before hand. The first analysis after a median follow-up of 60 months showed a significant reduction (53%) in incidence for all breast cancer (including DCIS). The authors now report the results on the extended duration of benefit of ARIMIDEX® in preventing breast cancer, for up to 12 years after trial entry.

After a median follow up of 10.9 years for this analysis, women assigned to the ARIMIDEX® group were 49% less likely to develop breast cancer than women assigned to the placebo arm of the study ((HR=0.51, P<0.0001). The reduction in incidence in the first 5 years of follow up was 61% (HR=0.39; P<0.0001), and a smaller but still significant 36% reduction (HR=0.64; P=0•014) was seen in subsequent years, which was still larger than that seen for Tamoxifen in previous trials, and the effects in the two time periods was not significantly different (P=0.08). Invasive ER-positive breast cancer was reduced by 54% with ARIMIDEX® treatment (HR=0.46; P<0.0001), with a continued significant effect observed in the post-treatment follow up period. A 59% reduction in DCIS overall was observed (HR=0.41; P=0.0081), with a very large reduction noted in those cases known to be ER-positive (HR = 0.22; P<0.0001). A significant decrease in non-breast cancers was observed in the ARIMIDEX® group, primarily contributed by non-melanoma skin cancer (P=0.0042), and no excess rates of fractures or cardiovascular disease was observed.

The authors concluded that this updated analysis shows a continuing long-term effect of 5 years of ARIMIDEX® treatment, in preventing breast cancer, in high-risk postmenopausal women. These new results strongly suggest that ARIMIDEX® should be preferred therapy for breast cancer prevention in postmenopausal women at increased risk for the disease, with Tamoxifen used for women who experience severe side effects from ARIMIDEX®. Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial. Cuzick J, Sestak I, Forbes JF, et al. The Lancet. Published:December 12, 2019. DOI:https://doi.org/10.1016/S0140-6736(19)32955-1

Late Breaking Abstract – ASTRO 2019 Detectable HPV Circulating Tumor DNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression

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SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a significant increase in incidence during the past several decades. They represent approximately 70% of all OPSCC in the United States and Canada. HPV is a non-enveloped, double-stranded, DNA virus that infects epithelial cells and majority of the HPV subtypes cause epithelial lesions such as warts or papillomas, which are of low malignant potential. However, there is a subset of high-risk HPV that can cause cancer by integrating its DNA into the host genome, with the resulting expression of two important oncogenes E6 and E7 in the host cell. The E6 oncogene binds and degrades tumor suppressor TP53 via ubiquitin-mediated processes thereby preventing the host cell from engaging in cell cycle checkpoints and enduring an apoptotic response. The E7 oncogene binds to and destabilizes tumor suppressor retinoblastoma (pRb) resulting in transcription of genes involved in proliferation and cell cycle progression. One of the main molecular pathways amplified through E7 is the CDKN2A/p16 gene pathway, which results in the overexpression of p16 protein. E7 also induces cellular proliferation by disrupting the activity of Cyclin Dependent Kinase inhibitors p21 and p27. In essence, HPV infection induces failures in cell cycle checkpoints, resulting in genetic instability and over time, progression of premalignant lesions to invasive Squamous Cell Carcinoma. Unlike tobacco induced HNSCC where TP53 and pRb pathways are nullified due to mutation and epigenetic alterations, in HPV-related HNSCC, wild-type TP53 and pRb are functionally inactivated by the viral oncogenes.

Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV infection. The HPV-positive primary Squamous Cell Carcinoma tends to be smaller in size, with early nodal metastases, and HPV status particularly in OroPharyngeal Squamous Cell Carcinoma is an independent prognostic factor for Overall Survival (OS) and Progression Free Survival (PFS). These patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Further, HPV positive patients demonstrate higher Response Rates to chemoradiation as well as an improved Overall Survival. However, approximately 20% of patients diagnosed with HPV-positive OPSCC experience cancer progression within 5 years.

The role of circulating tumor DNA (ctDNA) as a cancer biomarker in the post-operative surveillance of patients with HPV-associated OPSCC has remained unclear. The authors in this study aimed to investigate ctDNA detectability rates by post-op risk category and association with prognosis in this patient population. The researchers prospectively collected and tested serum samples from 29 patients with HPV-associated OPSCC who had not yet undergone treatment, for assay validation. As a control, 7 HPV negative OPSCC patients were included. A cohort of 46 patients with HPV-associated OPSCC who had undergone surgery for the disease had serum samples collected prior to beginning adjuvant therapy. The serum collected from this total group of 82 patients (N=29+7+46) was analyzed in a blinded fashion for E6/E7 HPV ctDNA using ddPCR multiplex assay (HPV 16, 18, 31, 33), and HPV ctDNA detectability was compared statistically across groups. Associations of patient and tumor characteristics with recurrence were assessed and estimates of Progression Free Survival (PFS) and Overall Survival (OS) were made using the Kaplan-Meier (KM) method.

The researchers found that ctDNA was detectable in 27 of 29 patients who had not yet undergone treatment, for a sensitivity rate of 93%, whereas none of the 7 HPV-negative patients had detectable ctDNA, for a specificity rate of 100%. Post-op serum was collected at a median of 25 days after surgery prior to beginning adjuvant therapy and ctDNA was detectable in 43% of patients including 47% with high-risk features (Extra Nodal Extension or R1-microscopic residual tumor). All detected ctDNA was HPV type 16.

At a median follow up of 20 months for the post-op HPV-OPSCC cohort, 24% of these patients had recurrent disease. Among those who recurred, 64% had detectable ctDNA compared with 35% whose disease did not recur (P=0.1). There was a significant association between detectable ctDNA and 24-month Progression Free Survival (45% versus 84%; P=0.04) and Overall Survival (80% versus 100%; P=0.02). Overall, detectable ctDNA, T4 tumors, and more than 4 positive lymph nodes were positively associated with disease recurrence.

It was concluded that detectable HPV circulating tumor DNA is a highly sensitive and specific means of determining HPV-status and was significantly associated with worsened Progression Free Survival and Overall Survival among post-op patients with Human Papilloma Virus (HPV)-associated OroPharyngeal Squamous Cell Carcinoma. HPV circulating tumor DNA as a cancer biomarker may also assist in risk stratification, treatment assessment, and surveillance. Detectable HPV ctDNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression. Routman DM, Chera BS, Jethwa KR, et al. International Journal of Radiation Oncology • Biology • Physics 2019;105, 682-683. LBA5

Late breaking Abstract – ESMO 2019 OPDIVO® Improves Overall Survival in Advanced Esophageal Cancer Regardless of PD-L1 Expression

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SUMMARY: The American Cancer Society estimates that in 2019, about 17,650 new cases of esophageal cancer will be diagnosed in the US and about 16,080 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in caucasians. About 20% of patients survive at least 5 years following diagnosis. Patients with advanced esophageal cancer following progression on first line chemotherapy have limited treatment options and have a poor prognosis, with a 5-year relative survival rate of 8% or less.

The FDA in July 2019 approved KEYTRUDA® (Pembrolizumab) for patients with recurrent, locally advanced or metastatic Squamous Cell Carcinoma of the Esophagus (ESCC), whose tumors express PD-L1 (Combined Positive Score-CPS of 10 or more). This approval was based on the Phase III KEYNOTE-181 global trial in which KEYTRUDA® significantly improved Overall Survival compared with chemotherapy, as second line therapy for patients with advanced esophageal cancer, with PD-L1 CPS of 10 or higher. The median Overall Survival in the Intent-To-Treat population was however was not statistically significant.

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. OPDIVO® in a Phase II study showed promising antitumor activity and safety profile among patients with advanced refractory Squamous Cell Carcinoma of the Esophagus (ESCC). ATTRACTION-3 is a multicentre, randomized, open-label, Phase III trial in which 419 patients with unresectable advanced or recurrent ESCC refractory or intolerant to one prior Fluoropyrimidine/Platinum-based chemotherapy, regardless of PD-L1 expression, were enrolled. Patients were randomly assigned (1:1) to either OPDIVO® 240 mg IV every 2 weeks (N=210) or investigator’s choice of Paclitaxel 100 mg/m2 IV once per week for 6 weeks then 1 week off or Docetaxel 75 mg/m2 IV every 3 weeks (N=209). Both treatment groups were well balanced and nearly 90% of the patients were male and 96% were Asian. Approximately 85% of patients were current or former smokers, about half of patients had prior surgery and about 70% had prior radiotherapy. Approximately 50% of patients had tumor PD-L1 expression of 1% or more. The Primary endpoint was Overall Survival (OS), in the intent-to-treat population that included all randomized patients.

At a minimum follow-up of 17.6 months, OPDIVO® showed a statistically significant improvement in OS, with a 23% reduction in the risk of death, compared to chemotherapy. The median Overall Survival was 10.9 months in the OPDIVO® group versus 8.4 months in the chemotherapy group (HR for death=0.77, P=0.019). The proportion of patients alive at 18 months was numerically larger with OPDIVO® versus chemotherapy (31% vs 21%). The OS benefit with OPDIVO® over chemotherapy was noted across tumor PD-L1 expression levels (PD-L1 1% or more, HR=0.69; PD-L1 less than 1%, HR=0.84). The Objective Response Rate was similar in both treatment groups (19% vs 22%). However the median duration of response with OPDIVO® was 6.9 months, versus 3.9 months with chemotherapy, suggesting that the responses were substantially more durable with OPDIVO® compared to chemotherapy. There was no significant difference in the Progression Free Survival between the treatment groups. Grade 3 or 4 adverse events occurred in 18% of the OPDIVO® group and 63% of the chemotherapy group.

It was concluded that OPDIVO® was associated with a significant improvement in Overall Survival with a favorable safety profile compared with chemotherapy, in previously treated patients with advanced Esophageal Squamous Cell Carcinoma, regardless of PD-L1 expression, and represents a potential new standard second-line treatment option for this patient group. Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): the phase 3 ATTRACTION-3 study. Cho BC, Kato K, Takahashi M, et al. Presented at ESMO 2019: September 27-October 1, 2019; Barcelona, Spain. Abstract LBA 11.