Category: Meeting Updates

Late Breaking Abstract – ASCO 2020: First Line KEYTRUDA® Superior to Chemotherapy in Metastatic MSI-H/dMMR Colorectal Cancer

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SUMMARY: Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 147,950 new cases of CRC will be diagnosed in the United States in 2020 and about 53,200 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have family histories of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes.Testing-for-MicroSatellite-Instability-and-MisMatch-Repair-Deficiency

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors. MSI testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

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, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The FDA in 2017 granted accelerated approval to KEYTRUDA® for patients with advanced MSI-High or dMMR solid tumors, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors.

KEYNOTE-177 is an International, multicenter, randomized open-label, Phase III trial conducted, to evaluate the efficacy and safety of KEYTRUDA® versus Standard-of-Care (SOC) chemotherapy, as first-line therapy for dMMR or MSI-H metastatic ColoRectal Cancer (mCRC). In this study, a total of 307 patients with MSI-H/dMMR mCRC as determined locally, and with ECOG PS of 0 or 1 were randomly assigned 1:1 to first-line treatment with KEYTRUDA® 200 mg IV every 3 weeks for up to 2 years (N=153) or investigator’s choice of mFOLFOX-6 or FOLFIRI every 2 weeks, with or without Bevacizumab or Cetuximab (N=154). Chemotherapy regimens were chosen prior to randomization. Treatment was continued until disease progression, unacceptable toxicity or completion of 35 cycles (for KEYTRUDA® only). The median patient age was 63 years and both treatment groups were well balanced. The co-Primary endpoints of the study were Progression Free Survival (PFS) and Overall Survival (OS). Key Secondary endpoints included Overall Response Rate (ORR) and Safety. Patients with confirmed disease progression on chemotherapy were given the option to crossover, to receive treatment with KEYTRUDA®. The median follow up was 28 months.

It was noted that KEYTRUDA® was superior to chemotherapy with a median PFS of 16.5 months versus 8.2 months for chemotherapy (HR=0.60; P=0.0002). The 12 and 24-months PFS rates were 55.3% and 48.3% with KEYTRUDA® versus 37.3% and 18.6% with chemotherapy, respectively. The confirmed ORR was 43.8% with KEYTRUDA® versus 33.1% with chemotherapy and the median Duration of Response was not reached in the KEYTRUDA® group and was 10.6 months in the chemotherapy group. Following disease progression, 36% of patients assigned to the chemotherapy group crossed over to the KEYTRUDA® group. This study is being continued to evaluate OS. Grade 3-5 treatment related Adverse Event rates were 22% in the KEYTRUDA® arm and 66% in the chemotherapy group.

The authors concluded that when compared to chemotherapy, first-line therapy with KEYTRUDA® provided a clinically meaningful and statistically significant improvement in Progression Free Survival, among patients with MSI-H/dMMR metastatic colorectal cancer, with fewer treatment-related Adverse Events. The authors added that KEYTRUDA® should be the new standard of care for this patient group.

Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. Andre T, Shiu K-K, Kim TW, et al. J Clin Oncol 38: 2020 (suppl; abstr LBA4)

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

Improved Quality of Life and Efficacy with BRAFTOVI®, MEKTOVI® and ERBITUX® Triplet Therapy in Patients with BRAF V600E-Mutant Metastatic Colorectal Cancer

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 147,950 new cases of CRC will be diagnosed in the United States in 2020 and about 53,200 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab), as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC), whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Approximately 5-20% of all metastatic CRC tumors present with BRAF V600E mutations and BRAF V600E is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.BRAF-and-MEK-Inhibition-in-MAPK-Pathway
The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. However, BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than melanoma. BRAFTOVI® (Encorafenib) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as ZELBORAF® (Vemurafenib) and TAFINLAR® (Dabrafenib), with a prolonged target dissociation half-life and higher potency. The combination of BRAFTOVI® along with anti-EGFR monoclonal antibody ERBITUX® (Cetuximab) showed promising activity in early-phase clinical trials. 
The BEACON CRC (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) trial is an international, multicenter, randomized, open-label, Phase III study in which the efficacy and safety of BRAFTOVI® plus ERBITUX® with or without a MEK inhibitor MEKTOVI® (Binimetinib), was compared with the investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan, in patients with BRAF V600E-mutant mCRC, whose disease has progressed after one or two prior regimens. In this trial, 665 patients were randomly assigned in a 1:1:1 ratio to receive either triplet therapy of BRAFTOVI® 300 mg orally daily, MEKTOVI® 45 mg orally twice daily, and ERBITUX® 400 mg/m2 IV as an initial dose, then 250 mg/m2 IV weekly (N=224), doublet-therapy of BRAFTOVI® and ERBITUX® administered in the same doses and on the same schedule as the triplet regimen (N=220) or investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan (N=221). Patients were stratified according to previous Irinotecan use and treatment was administered in 28-day cycles until disease progression. The co-Primary end points were Overall Survival (OS) in the triplet-therapy group as compared with the control group and Secondary end points included OS in the doublet-therapy group as compared with the control group, as well as PFS, Duration of Response, and Safety in all groups. This study was not powered to compare the triplet-therapy group against the doublet-therapy group.
At the time of prespecified interim analysis, with a median duration of follow up for survival at 7.8 months across the three groups, the median OS was 9.0 months in the triplet-therapy group and 5.4 months in the control group (HR for death=0.52; P<0.001). This represented 48% reduction in the risk of death in the triplet-therapy group. The confirmed Response Rate was 26% in the triplet-therapy group and 2% in the control group (P<0.001). The median OS in the doublet-therapy group was 8.4 months (HR for death versus control=0.60; P<0.001).
The authors in this updated analysis focused on the patient-reported Quality of Life (QOL) assessments from this study. QOL assessments using 4 validated QOL measures were secondary endpoints in the trial. They included EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The risk of QOL deterioration was reduced by 45% (HR=0.55) and 44% (HR=0.56), using EORTC QLQ C30 and FACT C assessments respectively, in favor of the triplet regimen over control. Similar findings were observed when the doublet-therapy regimen was compared with the regimen in the control group, and when QOL assessments were made using the other two QOL measures (EuroQol 5D 5L and PGIC). There was however no significant differences in QOL when the triplet and doublet regimen groups were compared.
It was concluded based on this updated analysis of the BEACON CRC trial, that among patients with BRAF V600E-mutant metastatic Colorectal Cancer, a combination of BRAFTOVI® plus ERBITUX® with or without a MEK inhibitor MEKTOVI®, demonstrated longer maintenance of QOL on patient-reported assessments, compared to the current standard of care. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Kopetz S, Grothey A, Van Cutsem E, et al. J Clin Oncol. 2020;38(suppl 4; abstr 8).

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.

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

RR

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 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.

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.