Category: Meeting Updates

NALIRIFOX Improves Overall Survival in Patients with Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2022, about 62,210 people will be diagnosed with pancreatic cancer and 49,830 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 10%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States. Majority of patients with pancreatic cancer (80% of cases) are diagnosed at an advanced stage, and are not amenable to curative surgical resection, at the time of diagnosis. The current treatment regimens for advanced disease have proved ineffective, conferring a median Overall Survival (OS) of 6-8 months.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

In the NAPOLI-1 open-label Phase III study, a combination of ONIVYDE®, 5-FU and Leucovorin improved Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate following Gemcitabine-based therapy, in patients with metastatic Pancreatic adenocarcinoma. ONIVYDE® in combination with Fluorouracil (5-FU) and Leucovorin was approved for this indication in 2015. In a Phase I/II study, ONIVYDE® in combination with 5-FU, Leucovorin and Oxaliplatin (NALIRIFOX) demonstrated promising anti-tumor activity in patients with metastatic pancreatic ductal adenocarcinoma.

NAPOLI 3 is a global, randomized, open-label Phase III trial which tested the safety and efficacy of NALIRIFOX regimen in treatment naïve patients with metastatic pancreatic ductal adenocarcinoma. In this study, 770 patients with histopathologically/cytologically confirmed untreated metastatic pancreatic ductal adenocarcinoma were randomized in a 1:1 ratio to receive NALIRIFOX (N=383) or Gemcitabine plus nab-Paclitaxel (N=387). The NALIRIFOX regimen consisted of ONIVYDE® 50 mg/m2 IV, given along with 5-FU 2400 mg/m2 IV, Leucovorin 400 mg/m2 IV and Oxaliplatin 60 mg/m2 IV on days 1 and 15 of a 28-day cycle. Patients in the Gemcitabine/nab-Paclitaxel group received Gemcitabine 1000 mg/m2 IV along with nab-Paclitaxel 125 mg/m2 IV, on days 1, 8 and 15 of a 28-day cycle. Both treatment groups were well balanced with similar baseline characteristics, including median age of 64.5 years and number of metastatic sites (three or greater in 37% of patients). Patients were stratified by ECOG performance status, geographic region, and presence or absence of liver metastases. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included were Progression Free Survival (PFS), Overall Response Rate (ORR) and Safety.

At a median follow-up of 16.1 months, the median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gemcitabine plus nab-Paclitaxel arm (HR=0.84; P=0.04). There was also a significant improvement in the PFS at 7.4 months versus 5.6 months respectively (HR=0.70; P=0.0001). This OS and PFS benefit was observed across subgroups. The NALIRIFOX group also had a higher Objective Response Rate at 41.8% versus 36.2% for patients treated with Gemcitabine and nab-Paclitaxel group, and a lower percentage of patients who received NALIRIFOX went on to receive subsequent anticancer therapy (50.5% versus 54.4%). Treatment related toxicities associated with NALIRIFOX regimen were manageable and consistent with the drug profiles in this regimen.

It was concluded that first line treatment with NALIRIFOX regimen demonstrated clinically meaningful and statistically significant improvement in Overall Survival and Progression Free Survival, compared with Gemcitabine and nab-Paclitaxel, in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma.

NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Wainberg ZA, Melisi D, Macarulla T, et al. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 19-21, 2023; San Francisco. Abstract LBA661.

Long Term Overall Survival Benefit with VIDAZA® plus VENCLEXTA® in Elderly AML Patients

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SUMMARY: The American Cancer Society estimates that in 2023, 20,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,310 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard 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.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® (Venetoclax) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. 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. The combination of VIDAZA® and VENCLEXTA® in a previously published Phase Ib study was highly efficacious, with significant responses, duration of response and Overall Survival benefit.

VIALE-A is a Phase III, multicenter, randomized, double-blind, placebo-controlled confirmatory trial, conducted to evaluate the efficacy and safety of a combination of VIDAZA® and VENCLEXTA®, as compared with VIDAZA® plus placebo (the control regimen), in previously untreated patients with AML, who were ineligible for intensive induction therapy. In this study, 431 patients (N=431) with previously untreated AML were randomly assigned in a 2:1 ratio to receive either VIDAZA® plus VENCLEXTA® (N=286), or VIDAZA® plus placebo (N=145). Enrolled patients were ineligible for standard induction chemotherapy because of coexisting conditions, 75 years of age or older, or both. All patients received VIDAZA® 75 mg/m2 subcutaneously or IV on days 1 through 7 of every 28-day cycle. Patients in the study group also received VENCLEXTA® 100 mg orally on day 1 and 200 mg on day 2 and target dose of 400 mg on day 3, and continued daily until day 28 during cycle 1, to mitigate Tumor Lysis Syndrome. The dose of VENCLEXTA® was initiated at 400 mg daily in all subsequent 28-day cycles. In the control group, a matching placebo was administered orally, once daily, in 28-day cycles. The median age was 76 years in both groups, approximately 60% were male and 76% were Caucasian. Molecular abnormalities of interest included FLT-3, observed in 14% of patients receiving VIDAZA® plus VENCLEXTA®, IDH1/2, observed in 25% of patients, TP53, observed in 23.3% of patients and NPM1, observed in 16.6% of patients. Secondary AML was reported in 25% of the patients in the VIDAZA® plus VENCLEXTA® group and in 24% of the patients in the control group. All the patients were hospitalized on or before day 1 of cycle 1 and for at least 24 hours after receiving the final dose of VENCLEXTA®, in order to receive prophylaxis against the Tumor Lysis Syndrome and for monitoring. The Primary endpoint was Overall Survival (OS). The Secondary end points included Complete Remission (CR) rates, composite Complete Remission (Complete Remission or Complete Remission with incomplete hematologic recovery), RBC and platelet transfusion independence, and Quality of Life according to Patient-Reported Outcomes.

At a median follow up of 20.5 months, the median OS was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.66; P<0.001). VIDAZA® plus VENCLEXTA® combination resulted in a CR rate of 36.7% versus 17.9%; P<0.001 and composite CR of 66.4% versus 28.3%; P<0.001, when compared to the control regimen. Most responses were seen after the first 28-day cycle. The median time to first response was 1.3 versus and 2.8 months respectively, duration of CR was 17.5 months versus 13.3 months and median duration of composite CR was 17.5 months in the VIDAZA® plus VENCLEXTA® group and 13.4 months in the control group. RBC transfusion independence occurred in 59.8% of the patients in the VIDAZA® plus VENCLEXTA® group and in 35.2% of those in the control group (P<0.001), and platelet transfusion independence occurred in 68.5% and 49.7% (P<0.001), respectively. The benefits with VIDAZA® plus VENCLEXTA® were noted in almost all molecular subgroups compared to the control regimen. The response rates were highest among patients with FLT3 mutations (72.4% versus 36.4%, P=0.02) and those with IDH1 or IDH2 mutations (75.4 % versus 10.7%, P<0.001), respectively.

The researchers conducted 2 years of additional follow-up to determine the long-term survival benefit of VIDAZA® plus VENCLEXTA® combination and at this meeting reported the analysis of VIALE-A trial, after the occurrence of 100% of the pre-planned survival events. With a median follow-up of 43.2 months, the median Overall Survival (OS) benefit since the interim analysis in the overall population was maintained and was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.58; P<0.001). Among patients with Measurable Residual Disease (MRD) <10-3 who had achieved either Complete Remission (CR) or CR with incomplete hematologic recovery (CRi), the median OS was reached at 34.2 months in the VIDAZA® plus VENCLEXTA® group and 25.0 months in the control group. For patients in the IDH1/2 mutant subgroup, the median OS at final analysis with VIDAZA® plus VENCLEXTA® was 19.9 months and was 6.2 months in the control group (HR=0.31; P<0.001). Overall safety profiles were comparable between the treatment groups.

The 2-year follow up analysis of the VIALE-A trial confirmed the sustained Overall Survival benefit of VIDAZA® plus VENCLEXTA® combination in patients with AML, ineligible for intensive chemotherapy, with no new safety findings noted.

Long-Term Follow-up of the Phase 3 Viale-a Clinical Trial of Venetoclax Plus Azacitidine for Patients with Untreated Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy. Pratz KW, Jonas BA, Pullarkat VA, et al. Presented at the 64th ASH Annual Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana. Abstract # 219

TAILORx Long Term Update for Patients with Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence.

Approximately 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. Patients with early-stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early-stage breast cancer. Chemotherapy recommendations for Hormone Receptor positive, HER negative, early-stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay. Oncotype Dx assay categorizes patients based on Recurrence Scores into Low risk (0-10), Intermediate risk (11-25), and High risk (26-100). It has been unclear whether patients in the Intermediate risk group benefited from the addition of chemotherapy to endocrine therapy. TAILORx was specifically designed to address this question and provide a very definitive answer.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a phase III, randomized, prospective, non-inferiority trial, and is the largest breast cancer treatment trial ever conducted, and the first precision medicine trial ever done, according to the authors. In this study, 10,273 women, 18-75 years of age, with hormone receptor-positive, HER2-negative, T1b-T2N0 early-stage axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score. Women with a Low Recurrence Score of 0-10 received endocrine therapy alone and those with a High Recurrence Score of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy. Patient with Intermediate Recurrence Score of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone (N=3399) or endocrine therapy and adjuvant chemotherapy (N=3312). The Primary endpoint was invasive Disease-Free Survival, defined as recurrence of cancer in the breast, regional lymph nodes, and/or distant organs, a second primary cancer in the opposite breast or another organ, or death from any cause. The researchers conducted an updated analysis, in which patients were followed for an additional 3.5 years, for an average of 11 years. The Primary endpoint in the updated analysis was invasive Disease-Free Survival (DFS) at a median follow-up of 11.0 years in the randomized population and 10.4 years in the overall population.

The previous TAILORx study conclusions remain unchanged. Among patients with a Recurrence Score of 11-25, endocrine therapy alone was non-inferior to chemotherapy plus endocrine therapy. The 5-year invasive DFS with endocrine therapy alone was 92.8% versus 93.1% with chemotherapy plus endocrine (HR=1.08; P=0.26). The 12-year invasive DFS with endocrine therapy alone was 76.8% versus 77.4% with chemotherapy plus endocrine therapy (HR =1.08). Although among those patients with a Recurrence Score of 0-25, less than 10% of patients had disease recurrence by 12 years, late recurrence events beyond 5 years exceeded earlier recurrence, regardless of treatment. There was also a higher risk of early recurrence in Black women.

It was concluded that with longer follow-up, the main TAILORx study findings remain unchanged, and clinicians should continue to use the 21-gene recurrence score results to guide decisions about the use of chemotherapy.

Trial Assigning Individualized Options for Treatment (TAILORx): An update including 12-year event rates. Sparano J, Gray RJ, Makower D, et al. Presented at SABCS 2022. December 6-10, 2022. Abstract GS1-05.

Sequential Conditioning and Allogeneic Hematopoietic Cell Transplantation WITHOUT Prior Remission-Induction Chemotherapy in AML

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SUMMARY: The American Cancer Society estimates that for 2023, about 20,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,310 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior Myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone.

Cytotoxic chemotherapy for AML often consists of induction therapy to achieve remission, followed by consolidation therapy. However, standard induction chemotherapy achieves Complete Remission in only 40-60% of AML patients older than 60 years of age, and majority of these patients will eventually relapse. This had been attributed to clonal evolution and epigenetic reprogramming, leading to aberrant DNA methylation, and persistence of leukemia-initiating cells. Patients with AML who are under age 55 with high-risk cytogenetics in first clinical remission, are considered for allogeneic Hematopoietic Cell Transplantation, as this has shown to offer survival advantage over conventional chemotherapy. Patients receive salvage chemotherapy, targeted therapy for FLT3-mutant and susceptible IDH mutant AML, or treatment with a BCL2 inhibitor and hypomethylating agent, if a donor is not readily available and a prolonged donor search is needed.

ASAP is a randomized Phase III trial, conducted in patients with an unfavorable risk AML who either had a poor response to first induction therapy or had a relapse after first induction therapy. This study enrolled AML patients with poor response after first induction therapy or relapsed AML, who were eligible for intensive chemotherapy and allogeneic Hematopoietic Cell Transplantation with either a matched sibling donor, an HLA-compatible (9 or more/10) unrelated donor, or ongoing donor search with two potential unrelated donors with 90% or more HLA-matching probability. This analysis included 276 patients, of whom 272 patients were treated per protocol. Patients were randomized 1:1 to a Remission Induction arm in which patients received Cytarabine 3 g/m2 IV (1 g/m2 for patients more than 60 years) twice daily on days 1-3 plus Mitoxantrone 10 mg/m2 IV on days 3-5 and subsequent allogeneic Hematopoietic Cell Transplantation (Remission Induction Strategy arm-N=134) or to Disease Control arm (DISC arm-N=138) prior to sequential conditioning and allogeneic Hematopoietic Cell Transplantation. Disease Control Strategy consisted primarily of watchful waiting, but low-dose Cytarabine and single doses of mitoxantrone were permitted for disease-control. The median age was 61 years and at randomization, 39 patients had matched sibling donor, 133 patients had an HLA-compatible unrelated donor with confirmed HLA-typing, and 104 patients had ongoing unrelated donor searches. The Primary endpoint was Disease Free Survival (DFS), defined as Complete Remission at day 56 after allogeneic Hematopoietic Cell Transplantation, although the statistical goal of the study was to show non-inferiority of the Disease Control arm. Major secondary endpoints included Overall Survival (OS) from randomization and Leukemia-Free Survival from Complete Remission at day 56. The median time to allogeneic Hematopoietic Cell Transplantation was 8 weeks in the Remission Induction Strategy arm and 4 weeks in the Disease Control arm. At 24 weeks from randomization 96% and 94% of patients had been transplanted in the Remission Induction Strategy arm and Disease Control arm, respectively.

The Primary endpoint was met with the Disease Control arm, which is the less intensive treatment strategy, meeting the Primary endpoint of DFS/Complete Remission at day 56 after allogeneic Hematopoietic Cell Transplantation. The Disease-Free Survival at day 56 was 81.3% in the Remission Induction Strategy arm and 84.1% in the Disease Control arm (P for noninferiority=0.047). Among patients who met the Primary endpoint, after a median follow-up from randomization of 37 months, there was no significant difference in the Leukemia-Free Survival or Overall Survival from day 56, in the Remission Induction Strategy arm and Disease Control arm. The Disease Control Strategy was also associated with significantly fewer Grade 3 or more adverse events, compared to the Remission Induction Strategy (23% versus 64%, P<0.001), and fewer mean number of days in hospital prior to transplant (19 versus 42 days, P<0.001).

The researchers concluded from this first randomized controlled trial that intensive remission induction chemotherapy prior to allogeneic Hematopoietic Cell Transplantation for patients with Relapsed/Refractory AML DID NOT result in a higher overall success rate and did not confer a survival advantage. It was noted that watchful waiting followed by sequential conditioning and allogeneic Hematopoietic Cell Transplantation resulted in comparable overall Complete Remission rates and survival. The researchers added that the data from this study support sequential conditioning and Hematopoietic Cell Transplantation, without prior remission-induction chemotherapy, whenever a donor is readily available. Further, the results of this study emphasize the importance of allogeneic Hematopoietic Cell Transplantation in patients with Relapsed/Refractory AML and stress the need for starting donor search at diagnosis.

In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial. Stelljes M, Middeke JM, Bug G, et al. 64th ASH Annual Meeting and Exposition December 10th-13,2022. Abstract#4.

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

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years, while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

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

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

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

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

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

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

Elevated White Cell Count and Risk of Thrombotic Events in Polycythemia Vera

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SUMMARY: Polycythemia Vera (P. Vera) is a clonal myeloproliferative neoplasm characterized by isolated erythrocytosis in a majority of the patients, with the remaining demonstrating leukocytosis and/or thrombocytosis along with erythrocytosis. Patients usually present with this disorder in their sixth decade and are often asymptomatic, with the diagnosis made incidentally on routine laboratory evaluation. About 30% of the patients however, may initially present with a thrombotic episode, whereas a small percentage of patients may present with disease related symptoms such as pruritus and fatigue. The conventional risk factors for thrombotic events in MyeloProliferative Neoplasms (MPN) are age more than 60 years and prior thrombosis, and the presence of both these risk factors is associated with a 7-fold increased risk of thrombosis.

Overactivation of the JAK-STAT signal transduction pathway caused by V617F mutation has been implicated in majority of the patients with P. Vera. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STATs (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with P. Vera, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines, associated with this abnormal signaling. JAK2 mutations such as JAK2 V617F are seen in approximately 95% of patients with P. Vera.Molecular-Mechanisms-of-MPNs

Studies have shown that JAK2 mutations that result in the overproduction of erythrocytes, leukocytes, and platelets in P. Vera also promote direct activation of leukocytes and platelets. Activated platelets and leukocytes bind to each other and activate endothelial cells, which may in turn contribute to the prothrombotic state. The prospective CYTO-PV trial published in 2011, established that maintaining hematocrit less than 45% through phlebotomies and/or cytoreductive drugs significantly decreased the risk of thrombotic events in P. Vera patients. Even though several retrospective analyses strongly suggest an association between leukocytosis and thrombosis and leukocytosis particularly at the time of the thrombotic event in P. Vera patients, no prospective trial has been conducted to assess the impact of WBC counts on thrombotic risk in P. Vera.

The REVEAL study is a large, real-world, multicenter, prospective, noninterventional, observational study, in which patients with P. Vera from US community practice and academic centers were enrolled, to evaluate the association between elevated blood counts and occurrence of thrombotic events in patients with P. Vera, using data from the REVEAL study.

This study analyzed the data of 2271 eligible patients for this analysis (78% high risk and 22% low risk). The median patient age was 66 years and 54% were male. The median disease duration was 4.1 years, 20% had a history of thrombotic events and majority of patients (53%) were receiving Hydroxyurea. Patient data was collected at diagnosis, at a 6-month period, and during follow up, 3 years from last patient enrollment, between July 2014 and August 2019 and the researchers analyzed the association between blood counts and thrombotic events. Out of 106 patients who had thrombotic events, 30 had arterial thrombotic events, most commonly, Transient Ischemic Attack and 76 had venous thrombotic events, most commonly, Deep Vein Thrombosis.

It was noted that hematocrit greater than 45% versus 45% or less (P=0.0028), WBC more than 11×109/L versus 11×109/L or less (P<0.0001), and Platelet counts more than 400×109/L versus 400×109/L or less (P=0.0170) were each associated with increased risk of thrombotic events. A WBC count of 11×109/L or more was associated with the highest thrombotic event risk compared with WBC count less than 7×109/L (P<0.0001).  When the HCT was controlled at 45% or less, an elevated WBC count (more than 12 × 109/L) was significantly associated with increased risk of thromboembolism (HR=1.95; P=0.03). In all models analyzed, advanced age and history of thrombotic events, were associated with increased thrombotic event risk.

The authors concluded that in this analysis of the largest real-world cohort of P. Vera patients to date, hematocrit more than 45%, as well as WBC more than 11×109/L and Platelet counts more than 400×109/L, were each associated with increased risk of thrombotic events. WBC more than 12×109/L was significantly associated with increased thrombotic risk, even when the HCT was controlled, suggesting that thrombotic risk may be reduced by controlling both the WBC count and HCT level. The authors added that these data support the incorporation of blood count values into risk stratification and treatment strategies for patients with P. Vera in clinical practice, and to move beyond the conventional risk model.

A Real-World Evaluation of the Association between Elevated Blood Counts and Thrombotic Events in Polycythemia Vera: An Analysis of Data from the REVEAL Study). Gerds AT, Mesa RA, Burke JM, et al. Presented at: 2022 European Hematology Association Congress; June 10, 2022; Vienna, AT. Poster # P1062.

Late Breaking Abstract – ESMO 2022: PADCEV® plus KEYTRUDA® in Previously Untreated Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Cancer

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SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 81,180 new cases of bladder cancer will be diagnosed and approximately 17,100 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic Urothelial Carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin 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. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-103 is a clinical trial conducted to examine the safety and efficacy of Enfortumab vedotin given as monotherapy, and in combination with other anticancer therapies, as first line and second line treatment, for patients with urothelial cancer. This study was conducted in multiple parts for both locally advanced or metastatic urothelial cancer and muscle invasive bladder cancer.

EV-103/KEYNOTE-869 Cohort K is a randomized cohort investigating Enfortumab vedotin alone or in combination with Pembrolizumab as first line treatment in patients with unresectable locally advanced or metastatic urothelial cancer, who are ineligible to receive Cisplatin-based chemotherapy. In this Phase Ib/II randomized study, 149 eligible patients (N=149) were randomly assigned to receive a combination of Enfortumab vedotin 1.25 mg/kg given intravenously on days 1 and 8, and Pembrolizumab 200 mg given intravenously on day 1, every 21 days (N=76) or Enfortumab vedotin monotherapy given on the same schedule (N=73). Ineligibility for Cisplatin-based chemotherapy could be due to at least one of the following: Glomerular filtration rate (GFR) less than 60 mL/min, ECOG Performance Status of 2, Grade 2 or more hearing loss, or New York Heart Association Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease, and adjuvant/neoadjuvant Platinum-based therapy within 12 months prior to randomization, were allowed. The Primary endpoint was confirmed Objective Response Rate (ORR) by BICR (Blinded Independent Central Review). Secondary endpoints included Duration of Response (DOR), Safety, Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 14.2 months, the confirmed Objective Response Rate was 64.5% with the Enfortumab vedotin and Pembrolizumab combination, with 10.5% of patients experiencing a Complete Response and 53.9% of patients experiencing a Partial Response. The median Duration of Response was not reached. The most common Treatment-Related Adverse Events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%).

It was concluded that in Cisplatin-ineligible patients with unresectable locally advanced or metastatic urothelial cancer, treatment with Enfortumab vedotin and Pembrolizumab combination in chemo naïve patients, resulted in high Overall Response Rate, along with a safety profile that was tolerable. The authors added that Antibody-Drug Conjugates have the potential to make a greater impact in treating bladder cancer, especially in combination with checkpoint inhibitors, as shown in this trial and these data support ongoing investigations of first line Enfortumab vedotin and Pembrolizumab in patients with locally advanced or metastatic urothelial cancer.

Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Rosenberg JE, Milowsky M, Ramamurthy C, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA73

Late Breaking Abstract – ESMO 2022: Neoadjuvant KEYTRUDA® with Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma

RR

SUMMARY: The American Cancer Society estimates that in the US for 2022, about 54,000 new cases of oral cavity or oropharyngeal cancer will be diagnosed and about 11,230 patients will die of the disease. Patients with Squamous Cell Carcinoma of the head and neck, frequently present with locoregionally advanced disease.

The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, monoclonal antibody and checkpoint inhibitor, 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. Pembrolizumab has been shown to improve Overall Survival in patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

KEYNOTE-412 is a randomized, double-blind, Phase III trial, conducted to evaluate the efficacy and safety of Pembrolizumab in combination with chemoradiation versus placebo in combination with chemoradiation, in treatment naïve patients with locally advanced Head and Neck Squamous Cell carcinoma. In this study, 804 patients were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV every 3 weeks plus chemoradiation (70Gy in 35 fractions along with Cisplatin 100 mg/m2 IV every 3 weeks) followed by Pembrolizumab (N=402), or placebo every 3 weeks plus chemoradiation, followed by placebo (N=402). Patients received Pembrolizumab /placebo priming dose 1 week before chemoradiation, followed by 2 doses during chemoradiation and 14 doses of maintenance therapy after chemoradiation, for a total of 17 doses. Enrolled patients had newly diagnosed, pathologically proven, treatment naive locally advanced Head and Neck Squamous Cell carcinoma (T3-T4, N0-N3 or any N2a-3, T1-T4 larynx/hypopharynx/oral cavity/p16-negative oropharynx cancers, or T4 or N3 p16-positive oropharynx cancer). Both treatment groups were well balanced. The Primary endpoint was Event Free Survival (EFS). Secondary endpoints included Overall Survival (OS), and Safety.

At the time of data cutoff, with a median follow up of 47.7 months, there was a favorable trend toward improved Event Free Survival (EFS) with the addition of Pembrolizumab vs placebo to chemoradiation (HR 0.83, P=0.04), but the difference did not achieve statistical significance. The 2-year EFS was 63.2% in the Pembrolizumab group and 56.2% in the placebo group. In an exploratory analysis however, the 2-year EFS among patients with high expression of PD-L1 (CPS 20 or higher) was 71% in the Pembrolizumab group and 62% in the placebo group. A favorable of Overall Survival benefit was also observed among these patients, with a 3-year OS of 79% in Pembrolizumab group and 73% in the placebo group.

It was concluded that Pembrolizumab in combination with chemoradiation was associated with a favorable trend toward improved Event Free Survival, compared with placebo plus chemoradiation, in patients with locally advanced Head and Neck Squamous Cell carcinoma, but the difference did not reach statistical significance. The researchers added that perhaps patients with high CPS score on the tumor could benefit with this treatment approach.

Primary results of the phase III KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). Machiels J, Tao Y, Burtness B, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA5

Late Breaking Abstract – ESMO 2022: Abemaciclib plus Transtuzumab versus Chemotherapy in HR-positive, HER2-positive Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is a heterogeneous disease and approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. Human Epidermal growth factor Receptor 2 (HER2) overexpression is reported in about 15%-20% of primary breast carcinomas and is associated with poor prognosis, and nearly half of HER2-positive breast cancers are also HR-positive. Patients with HER2-positive breast cancers are generally treated with HER2-targeted therapy combined with chemotherapy. Patients with HER2-positive and HR-positive breast cancer are additionally treated with long-term hormone therapy.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2 oncogene. FASLODEX® (Fulvestrant) is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer.

monarcHER (NCT02675231) is an International, randomized, multicenter, open-label, three-group, Phase 2 trial, conducted to compare the efficacy of Abemaciclib plus Trastuzumab with or without Fulvestrant, with standard-of-care chemotherapy of physician’s choice plus trastuzumab, in women with advanced breast cancer. In this study, 237 patients were enrolled. Eligible patients had Hormone Receptor (HR)-positive, HER2-positive advanced breast cancer, with unresectable, locally advanced, recurrent, or metastatic disease, and had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to Group A (Abemaciclib, Trastuzumab, and Fulvestrant) N=79, Group B (Abemaciclib and Trastuzumab) N=79, or Group C (standard-of-care chemotherapy and trastuzumab) N=79. Treatment consisted of Abemaciclib 150 mg orally twice daily on days 1-21 of a 21-day cycle, Trastuzumab 8 mg/kg IV on cycle 1, day 1, followed by 6 mg/kg IV on day 1 of each subsequent 21-day cycle, and Fulvestrant 500 mg IM on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Patients were stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. An exploratory biomarker analysis of breast cancer molecular subtypes was conducted by RNA sequencing. The Primary endpoint was investigator-assessed Progression Free Survival (PFS), first testing Group A versus Group C, and if this result was significant, then Group B versus Group C. Secondary end points included Overall Survival (OS), Overall Response Rate, Patient Reported Outcomes, and pharmacokinetics. Safety was assessed in all patients who had received at least one dose of study treatment.

Previous analyses from this trial revealed that after a median follow up of 19.0 months, the Primary endpoint was met, with significantly superior PFS in Group A compared to Group C (8.3 months versus 5.7 months, respectively, HR=0.67; P=0.051), with a reduction in the risk for disease progression or death of 33%. (Lancet Oncol. 2020;21:763–775). The researchers herein reported the results, after a median follow up of 52.9 months.

The median Overall Survival was 31.1 months in Group A, 29.2 months in Group B and 20.7 months in Group C. When Group A was compared with Group C, the triplet regimen with Abemaciclib, Trastuzumab, and Fulvestrant (Group A) induced a statistically significant improvement in Overall Survival, compared with Trastuzumab plus chemotherapy (Group C). There was a numerically improved Overall Survival benefit with Abemaciclib, in combination with HER2-targeted therapy (Trastuzumab) with or without hormonal therapy (Fulvestrant), compared with chemotherapy plus Trastuzumab, and there was a consistent benefit observed with the addition of Abemaciclib across all pre-specified subgroups. Updated Progression Free Survival and safety findings were consistent with the primary analysis. An exploratory biomarker analysis by RNA sequencing suggested that Luminal subtypes were associated with longer Progression Free Survival (8.6 versus 5.4 months, HR=0.54) and Overall Survival (31.7 versus 19.7 months, HR=0.68), compared to non-Luminal subtypes. The most common serious adverse events in Group A were pyrexia, diarrhea, urinary tract infection, and acute kidney injury (3% each); in Group B were diarrhea and pneumonitis (3% each); and in Group C were neutropenia (6%) and pleural effusion (3%).

The authors concluded that based on this final analysis, a triple-agent, chemotherapy-free treatment regimen consisting of Abemaciclib plus Trastuzumab, with or without Fulvestrant, numerically improved Overall Survival in women with Hormone Receptor-positive, HER2-positive, advanced breast cancer, compared to chemotherapy plus Trastuzumab.

Final overall survival (OS) for abemaciclib plus trastuzumab +/- fulvestrant versus trastuzumab plus chemotherapy in patients with HR+, HER2+ advanced breast cancer (monarcHER): A randomized, open-label, phase II trial. Andre F, Nadal JC, Denys H, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA18

Late Breaking Abstract – ESMO 2022: CABOMETYX®, OPDIVO® and YERVOY® in Previously Untreated Advanced Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 79,000 new cases of kidney cancers will be diagnosed in the United States in 2022 and about 13,920 people will die from this disease. Clear Cell Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer in adults. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five-year survival of patients with advanced RCC is about 14% and there is a significant unmet need for improved therapies for this disease.

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, whereas YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. The FDA in 2018, granted approvals to OPDIVO® and YERVOY® in combination, for the treatment of Intermediate or Poor-risk, previously untreated advanced Renal Cell Carcinoma.

CABOMETYX® (Cabozantinib) is an oral, small-molecule Tyrosine Kinase Inhibitor (TKI), which targets Vascular Endothelial Growth Factor Receptors (VEGFR), as well as tyrosine kinases MET and AXL. Both MET and AXL are upregulated in Renal Cell Carcinoma as a consequence of VHL inactivation, and increased expression of MET and AXL is associated with tumor progression and development of resistance to VEGFR inhibitors. Further, CABOMETYX® promotes an immune-permissive environment, which may enhance response to checkpoint inhibitors. CABOMETYX® was approved by the FDA in 2016 for the treatment of advanced Renal Cell Carcinoma.

COSMIC-313 is a global, multicenter, randomized, double-blinded, controlled, ongoing Phase III pivotal trial, conducted to evaluate the triplet combination of Cabozantinib, Nivolumab and Ipilimumab versus the doublet combination of Nivolumab and Ipilimumab, in patients with previously untreated advanced Intermediate or Poor-risk Renal Cell Carcinoma. COSMIC-313 was designed to answer whether adding Cabozantinib to dual checkpoint inhibition can improve outcomes among patients with Intermediate and Poor-risk advanced Renal Cell Carcinoma.

In this trial, 855 treatment naïve, advanced clear cell Renal Cell Carcinoma patients of IMDC (International Metastatic RCC Database Consortium) Intermediate or Poor risk were randomized 1:1 to receive Cabozantinib plus Nivolumab and Ipilimumab (N=428) or placebo plus Nivolumab and Ipilimumab (N=427). Patients in the study group received Cabozantinib 40 mg, orally once daily in combination with Nivolumab 3 mg/kg IV and Ipilimumab 1 mg/kg IV once every 3 weeks for 4 doses total followed by Cabozantinib 40 mg orally once daily and Nivolumab 480 mg/kg flat dose IV, once every 4 weeks for up to 2 years. Patients in the control group received the same regimen, but instead of Cabozantinib, received a matched placebo. Both treatment groups were well balanced. The median patient age was 60 years, 75% were men, 63% had PD-L1 expression of less than 1%, 75% had Intermediate-risk disease, 25% were Poor risk, and 65% had prior nephrectomy. The Primary endpoint was Progression Free Survival (PFS), as assessed by Blinded Independent Radiology Committee (BIRC). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety. The median follow up was 20.2 months.

The study met the Primary endpoint and the median PFS was not reached in the Cabozantinib group and was 11.3 months in the placebo group (HR=0.73; P=0.013). Patients treated with the Cabozantinib three-drug combination had a 27% lower risk of disease progression or death compared to those on the two drug immunotherapy combination. This PFS benefit was predominantly noted in the Intermediate-risk group. The Objective Response Rate was 43% with the Cabozantinib combination versus 36% in the placebo plus dual immunotherapy group, with 3% of patients achieving a Complete Response in both treatment groups. The Disease Control Rate was 86% and 72%, respectively. The median Duration of Response was not reached in either treatment group. Grade 3/4 adverse events occurred in 73% of patients treated with the combination of Cabozantinib, Nivolumab and Ipilimumab, and in 41% of patients treated with the Nivolumab and Ipilimumab combination. Discontinuation of all treatment agents due to adverse events occurred in 12% and 5% of patients, respectively.

The authors concluded that this is the first study to show that a TKI added to dual checkpoint inhibition significantly improved Progression Free Survival, in patients with untreated, Intermediate or Poor risk advanced kidney cancer, compared to doublet immunotherapy. Follow-up for Overall Survival is ongoing.

Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Choueiri TK, Powles TB, Albiges L, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA8