Author: RR

Zolbetuximab Plus Chemotherapy Improves Survival in CLDN18.2 Positive Metastatic Gastric and Gastroesophageal Junction Cancer

RR

SUMMARY: The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases will be diagnosed in 2023 and about 11,130 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.
Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 6%.

These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6. Patients with HER2-positive disease are usually treated with chemotherapy plus trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor or checkpoint inhibitor alone if the tumors express PD-L1.

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed and accessible to targeted therapies with antibodies as gastric tumors develop. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death. About 30-40% of patients with gastric cancer have CLDN18.2 expression.

SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. In this study, 565 enrolled patients were randomly assigned 1:1 to receive the combination of Zolbetuximab and mFOLFOX6 (N=283) or placebo and mFOLFOX6 (N=282). Zolbetuximab was given at 800 mg/m2 IV on day 1 of cycle 1 followed by 600 mg/m2 on day 22 of cycle 1, and days 1 and 22 of subsequent cycles, every 3 weeks. mFOLFOX6 (Oxaliplatin, 5-Fluorouracil and Leucovorin) was given IV every 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and beyond, Zolbetuximab was given at the same dosing schedule in combination with 5-Fluorouracil and Leucovorin IV every 2 weeks. Those in the placebo arm were given placebo at the every 3-week schedule and chemotherapy was administered at the same dosing schedule. Treatment was continued until disease progression or discontinuation criteria were met. Enrolled patients had moderate-to-strong CLDN18 staining intensity in at least 75% of tumor cells based on a validated ImmunoHistoChemistry assay, had HER2-negative disease, and an ECOG performance status of 0 or 1. Patients were stratified by region (Asian versus non-Asian), number of organs with metastases (0-2 versus 3 or more), and prior gastrectomy. The median age was 61 years and 31.4% of patients were from Asia. Majority of patients had 0-2 organs with metastases, 30% had prior gastrectomy. Approximately 13% of patients had tumors with a PD-L1 CPS of at least 5. The primary disease site was stomach in 76% of patients and was GastroEsophageal Junction in 24%. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), and Safety.

This study met the Primary endpoint and the median PFS was 10.61 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The OS was also significantly improved (18.23 versus 15.54 months, HR=0.750; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population. The most common Adverse Events with Zolbetuximab plus mFOLFOX6 were nausea, vomiting and decreased appetite. The incidences of serious Adverse Events were similar between the two treatment groups.

The authors concluded that Zolbetuximab plus mFOLFOX6 is a new potential Standard-of-Care treatment for a biomarker-based subgroup of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic Gastric/GE Junction adenocarcinoma. It is unclear if this regimen is superior to chemotherapy plus a checkpoint inhibitor in patients with PD-L1–positive and CLDN18.2-positive disease.

Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. Shitara K, Lordick F, Bang Y-J, et al. J Clin Oncol. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292

Avoiding Radiotherapy in Bulky Early Stage Classical Hodgkin Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2023, about 8830 new cases of Hodgkin Lymphoma will be diagnosed and about 900 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin Lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

Patients with Stage I/II classical Hodgkin Lymphoma (cHL) with bulky disease (mass more than 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray), are typically treated with chemotherapy followed by radiation. However radiotherapy to the chest can result in late complications which include risk of secondary malignancies, particularly breast cancer in women treated under the age of 30 years, cardiovascular disease, as well as the possibility of radiation-associated pneumonitis and fibrosis. Given the prognostic impact of interim PET scans after two cycles of chemotherapy (PET2) on Progression Free Survival, several trials evaluated response-adapted therapy, with de-escalation of treatment in patients with negative PET2, and intensifying therapy in patients with PET2-positive findings.

CALGB 50801 is a single-arm, Phase II trial with response-adapted therapy on the basis of centrally reviewed interim PET, and is the first study focusing exclusively on patients with bulky Stage I and II disease. The researchers hypothesized that a PET-adapted strategy would be effective and limit the use of mediastinal radiotherapy and prevent late complications in this high-risk group of patients. This study included 94 eligible and evaluable patients with bulky disease, for the safety and efficacy analyses. Patients were treated with two cycles of full-dose ABVD (Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine) without delay, regardless of neutrophil count, followed by interim FDG PET (PET2). Patients with a negative PET2 defined as 1-3 on the Deauville 5 point scale received four additional cycles of ABVD. Patients with a positive interim PET2 defined as 4 and 5 on the Deauville 5 point scale were treated with escalated BEACOPP (Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone) for four cycles, followed by 30 Gy involved-field radiotherapy. Median age of patients was 30 years, 22% were PET2 positive and 78% were PET2 negative after two cycles of ABVD.

The Primary objectives of this study were to use a PET-adapted approach to maintain Progression Free Survival (PFS) in patients with negative PET2 without the use of radiotherapy, and to improve outcomes in PET2 positive patients by intensifying therapy. The researchers assessed whether PFS for PET2 positive patients receiving escalated BEACOPP was not inferior to that of PET2 negative patients receiving ABVD, compared with historical differences in PFS between PET2 positive patients and PET2 negative patients receiving ABVD.

This PET-adapted study met the primary objective of maintaining ongoing remissions in PET2 negative patients treated with chemotherapy only, without the addition of radiation therapy. The Primary end point of 3-year Progression Free Survival was 93.1% in PET2 negative patients and 89.7% in PET2 positive patients. The 3 year Overall Survival was 98.6% and 94.4%, respectively. Outcomes were similar with intensified chemotherapy followed by radiation for the 22% of PET2 positive patients. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia. The majority of PET2 positive patients remained disease free without the need for high-dose chemotherapy with Autologous Stem Cell Transplant. The researchers pointed out that this study was initiated before the publication of RATHL study, and consistent with current practice, recommended eliminating Bleomycin from cycles 3-6 in PET2 negative patients.

It was concluded from this study that PET-adapted therapy in bulky Stage I/II classical Hodgkin Lymphoma met its primary goal and was associated with an excellent 3-year Progression Free Survival in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

Positron Emission Tomography–Adapted Therapy in Bulky Stage I/II Classic Hodgkin Lymphoma: CALGB 50801 (Alliance). LaCasce AS, Dockter T, Ruppert AS, et al. J Clin Oncol 2023; 41:1023-1034.

Capivasertib Plus Fulvestrant Improves Progression Free Survival in Advanced Hormone Receptor Positive Breast Cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. 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. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor-positive (HR-positive), HER2-negative breast cancer is the most frequently diagnosed molecular subtype. The most common subtype of metastatic breast cancer is HR-positive, HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of HR+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression due to resistance to endocrine therapy. Therapies overcoming this resistance is an area of active research in the breast cancer space.

Capivasertib is a novel pyrrolopyrimidine derivative, and is first-in-class orally available inhibitor of the serine/threonine protein kinase AKT (protein kinase B), with potential antineoplastic activity. It is a potent, selective ATP-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Inhibition of AKT prevents the phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR/PTEN signaling due to mutations in the genes involved. By targeting AKT, the key node in the PIK3/AKT signaling network, Capivasertib potentially may be used as monotherapy or combination therapy for a variety of human cancers. The researchers conducted the CAPItello-291 trial to determine whether the addition of Capivasertib to Fulvestrant would improve outcomes in patients with HR-positive breast cancer whose tumors had developed resistance to an Aromatase Inhibitor.

CAPItello-291 is a randomized, double-blind Phase III trial in which 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer, whose disease has recurred or progressed during or after Aromatase Inhibitor therapy, with or without a CDK4/6 inhibitor, were enrolled. Patients were randomly assigned 1:1 to receive either the Capivasertib plus Fulvestrant (N=355) arm or the placebo plus Fulvestrant arm (N=353). Patients in the study group received Capivasertib 400 mg orally twice daily for 4 days on and 3 days off along with Fulvestrant 500 mg IM on days 1 and 15 during cycle 1, then every 4 weeks thereafter. The present dosing of Capivasertib was chosen based on tolerability and the degree of target inhibition in early phase trials. The control group received matched placebo along with Fulvestrant. In this trial, patients could have received up to one line of chemotherapy for advanced disease and approximately 40% of tumors had PI3K/AKT/PTEN alterations. Both treatment groups were well balanced. Stratification factors included liver metastases and prior CDK 4/6 inhibitor. The dual Primary endpoints were Progression Free Survival (PFS) in the overall patient population and in a subgroup of patients whose tumors have qualifying alterations in the PIK3CA, AKT1 or PTEN genes. Secondary endpoints included Overall Survival (OS) and Objective Response Rate (ORR).

The trial met both Primary endpoints, improving PFS in the overall patient population and in a prespecified biomarker subgroup of patients whose tumors had qualifying alterations in the AKT pathway genes. In the overall trial population, patients treated with Capivasertib plus Fulvestrant had a median PFS of 7.2 months, compared to 3.6 months in patients treated with placebo plus Fulvestrant (HR=0.60; P<0.001). This amounted to a 40% lower risk of disease progression among patients who received Capivasertib plus Fulvestrant.

Among patients with AKT pathway mutations treated with Capivasertib plus Fulvestrant, the median PFS was 7.3 months versus 3.1 months in the placebo group (HR=0.50; P<0.001), reducing the risk of disease progression or death by 50%, versus placebo plus Fulvestrant. In the group without qualifying alterations in the AKT pathway genes, the PFS was 7.2 months in the Capivasertib group versus 3.7 months in the placebo group (HR=0.70). The benefit from Capivasertib was consistent across key clinically relevant subgroups, including patients previously treated with CDK4/6 inhibitor and patients with liver metastases.

The Objective Response Rate in the overall trial population was 22.9% among patients treated with Capivasertib plus Fulvestrant compared with 12.2% for patients treated with placebo plus Fulvestrant and was 28.8% and 9.7% respectively in the biomarker altered population. Although the Overall Survival data were immature at the time of the analysis, early data are encouraging and follow up is ongoing.

The most frequent Grade 3 or higher toxicities occurring in 5% or more of patients were diarrhea (9.3%) and rash (12.1%). Treatment discontinuation due to adverse events was 13% among patients who received Capivasertib plus Fulvestrant versus 2.3% among patients who received placebo plus Fulvestrant.

It was concluded that a combination of Capivasertib plus Fulvestrant is a new treatment option with significantly improved Progression Free Survival, in patients who have Hormone Receptor–positive/HER2-negative advanced breast cancer, who had progressed on, or become resistant to, endocrine therapies and CDK4/6 inhibitors.

Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Turner N, Oliveria M, Howell SJ, et al. Presented at the 2022 San Antonio Breast Cancer Symposium: December 6-10, 2022; San Antonio, TX. Abstract GS3-04.

BRUKINSA® Superior to IMBRUVICA® in Relapsed/Refractory CLL/SLL

RR

SUMMARY: The American Cancer Society estimates that for 2022, about 20,160 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4410 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® demonstrated survival benefits, when compared to chemoimmunotherapy, both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to IMBRUVICA® discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.

Zanubrutinib (BRUKINSA®) is an irreversible, potent, next-generation, small molecule inhibitor of Bruton’s Tyrosine Kinase, designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity, while minimizing off-target inhibition of TEC- and EGFR-family kinases. It has been hypothesized that the increased selectivity of BRUKINSA® may minimize toxicities, (such as those often associated with IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.

ALPINE study is a randomized, global, Phase III trial in which BRUKINSA® was compared with IMBRUVICA® in previously treated patients with relapsed or refractory CLL or SLL. In this trial, a total of 652 patients were randomly assigned 1:1 to receive either BRUKINSA® 160 mg orally twice daily or IMBRUVICA® 420 mg orally once daily, until disease progression or unacceptable toxicity. Enrolled patients had at least one prior systemic therapy and were required to have measurable lymphadenopathy by CT scan or MRI. Exclusion criteria included current or past Richter’s transformation and prior treatment with BTK inhibitors. The median age was 67 years, 45% of the patients had bulky disease with a tumor that was 5 cm or more in the greatest dimension, 73% had unmutated IGHV status, and 23% had a chromosome 17p deletion, TP53 mutation, or both and fewer than 15% of patients were on anticoagulants. The median number of previous lines of therapy was 1 and a total of 80% of the patients in the BRUKINSA® group and 76% of those in the IMBRUVICA® group had previously received chemoimmunotherapy. The Primary end point of the trial was Overall Response Rate (ORR) assessed by investigator and Independent Review Committee (IRC), and Secondary end points included Progression Free Survival (PFS), event rate of Atrial Fibrillation or Flutter, Duration of Response, Time to Treatment Failure, Overall Survival (OS), Patient-Reported Outcomes, and Safety.

A prespecified interim analysis showed that BRUKINSA® was superior to IMBRUVICA®, with respect to Overall Response Rate. The authors in this final analysis reported the clinical outcomes of Progression Free Survival, a key Secondary endpoint. Progression Free Survival was assessed with the use of a hierarchical testing strategy to determine whether BRUKINSA® was noninferior to IMBRUVICA®. If noninferiority was established, the superiority of BRUKINSA® was assessed and claimed if the two-sided P value was less than 0.05.

At a median follow up of 29.6 months, BRUKINSA® was found to be superior to IMBRUVICA® with respect to Progression Free Survival, as assessed by the investigators and Independent Review Committee (HR=0.65; P=0.002). The PFS at 24 months was 78.4% in the BRUKINSA® group and 65.9% in the IMBRUVICA® group. Median PFS was not reached in the BRUKINSA® group and was 34.2 months in the IMBRUVICA® group.

Among patients with a 17p deletion, a TP53 mutation, or both, those who received BRUKINSA® had longer PFS than those who received IMBRUVICA® (HR=0.53). The percentage of patients who were alive without disease progression at 24 months in this high-risk population was 72.6% in the BRUKINSA® group, and 54.6% in the IMBRUVICA® group. The PFS benefit was in favor of BRUKINSA® across major prespecified subgroups, including age, previous lines of therapy, disease stage, and IGHV mutational status.

Consistent with the findings at the interim analysis, the Overall Response Rate was higher in the BRUKINSA® group than in the IMBRUVICA® group, and were 86.2% and 75.7%, respectively, as assessed by the Independent Review Committee.

BRUKINSA® had a more favorable safety profile, with a lower incidence of cardiac disorders (21.3%), than in the IMBRUVICA® group (29.6%). Cardiac events leading to treatment discontinuation occurred in 0.3% of patients in the BRUKINSA® group and in 4.3% of patients in the IMBRUVICA® group. The incidence of Atrial fibrillation or flutter of any grade, a key Secondary endpoint, was lower in the BRUKINSA® group than in the IMBRUVICA® group (5.2% versus 13.3%).

It was concluded that in patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma, treatment with BRUKINSA® resulted in a significantly longer Progression Free Survival, compared to those patients who received IMBRUVICA®, and BRUKINSA® was associated with fewer cardiac adverse events.

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Brown JR, Eichhorst B, Hillmen P, et al. N Engl J Med 2023; 388:319-332.

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.

Biomarkers May Predict Response to Enfortumab Vedotin in Advanced Urothelial Cancer

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SUMMARY: The American Cancer Society estimates that in 2023, approximately 82,290 new cases of Bladder Cancer will be diagnosed and 16,710 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. 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%. 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. However there are limited data available on biomarkers predictive of outcomes when treated with Enfortumab vedotin.

The researchers in this study investigated potential biomarkers of response to Enfortumab vedotin by analyzing data from the UNITE (Urothelial Cancer Network to Investigate Therapeutic Experiences) database. This analysis include 170 patients from 16 different sites, with available Next Generation Sequencing using institutional or commercial platforms, treated with Enfortumab vedotin alone, outside of a clinical trial setting, for whom outcomes were available. The median age was 70 years, 78% were men, 65% had pure urothelial histology, 69% had primary bladder tumor, and 68% had 2 or more lines of therapy before Enfortumab vedotin.

The following molecular biomarkers were assessed: Tumor Mutation Burden (TMB), PD-L1 status, presence of 1 or more DNA damage response mutations such as BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, BARD1, PPP2R2A, or RAD51B, and somatic alterations such as TERTp, TP53, ARID1A, CDKN2A, CDKN2B, FGFR3, ERBB2, CCND1, KDM6A, MTAP, PIK3CA, RB1, TSC1, in 10% or more of patients. Investigators determined observed response to Enfortumab vedotin in patients with scans after one or more doses of the therapy.

For all patients included in this analysis, the Observed Response Rate was 47%, median Progression Free Survival was 6 months and median Overall Survival was 12 months. The Observed Response Rates were higher in patients with ERBB2 and TSC1 alterations versus wild-type (67% versus 44%; P=0.05 and 68% versus 25%; P=0.04, respectively). Shorter median Progression Free Survival was noted in patients with CDKN2A, CDKN2B, and MTAP alterations, whereas patients with high Tumor Mutation Burden (10 or more Mut/Mb) had longer median Overall Survival.

It was concluded that analysis of this large, multicenter, retrospective cohort of patients with advanced urothelial carcinoma, identified several potential biomarkers associated with differential outcomes to Enfortumab vedotin, and these findings may help inform clinical decision making and potential therapy sequencing.

Biomarkers of response to enfortumab vedotin (EV) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of the UNITE study. Jindal T, Kilari D, Alhalabi O, et al.DOI: 10.1200/JCO.2023.41.6_suppl.450 Journal of Clinical Oncology.

FDA Expands Adjuvant VERZENIO® Indication in High-Risk Early Breast Cancer

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SUMMARY: The FDA on March 3, 2023, approved VERZENIO® (Abemaciclib) with endocrine therapy (Tamoxifen or an Aromatase Inhibitor) for the adjuvant treatment of adult patients with Hormone Receptor (HR)-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence. Patients defined as high risk included those having either four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes and either tumor grade 3 or a tumor size 5 cm or more. VERZENIO® was previously approved for the above high-risk population with the additional requirement of having a Ki-67 score of 20% or more. The present approval removed the Ki-67 testing requirement.

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. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and HR-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. About 90% of all breast cancers are detected at an early stage, and these patients 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. Factors associated with high risk of recurrence in HR-positive, HER2-negative early breast cancer include positive nodal status, the number of positive nodes, large tumor size (5 cm or more), and high tumor grade (Grade 3).

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, by binding to D-cyclins in the ER-positive breast cancer cell, 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 monarchE trial is an international, open-label, two-cohort, randomized, Phase III study, conducted 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. This study 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 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, histologic Grade 3, or centrally tested high proliferation rate (Ki-67 of 20% or more). To be enrolled in Cohort 1 (N=5,120), which is the FDA-approved population, patients had to have 4 or more positive nodes or 1-3 positive nodes and either tumor grade 3 or a tumor size 5 cm or more. To be enrolled in Cohort 2 (N=517), patients could not be eligible for Cohort 1 and must have had 1-3 positive nodes and tumor Ki-67 score of 20% or more. 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 physicians 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), and Secondary end points included Distant Relapse Free Survival (DRFS), Overall Survival (OS), and Safety.

The FDA label expansion is supported by four-year data from the monarchE trial. There was significantly more Invasive Disease Free Survival (IDFS) benefit beyond the two-year treatment course with adjuvant VERZENIO® and the absolute difference in IDFS between the two treatment groups increased over time. The IDFS at 48 months was 85.5% for VERZENIO® plus standard endocrine therapy and 78.6% for standard endocrine therapy alone, with an absolute difference in IDFS of 6.9%. At two years and at three years, the absolute differences between treatment groups were 3.1% and 5.0%, respectively. The addition of VERZENIO® to standard endocrine therapy reduced the risk of recurrence by 35% compared to endocrine therapy alone (HR=0.653). This benefit was primarily among patients in Cohort 1 and there were no new safety findings. However, in Cohort 2, more deaths were observed with VERZENIO® plus standard endocrine therapy compared to standard endocrine therapy alone and the FDA label therefore is restricted to Cohort 1. The Overall Survival (OS) data was immature across the entire study, but there was an OS trend in favor of VERZENIO® in the Cohort 1 population.

It was concluded that the use of adjuvant VERZENIO® in patients with high-risk Hormone Receptor-positive, HER2-negative early breast cancer reduced the risk of recurrent disease, and this benefit was sustained beyond the completion of treatment, with an absolute increase noted at 4 years. Overall Survival data was immature at the time of this analysis.

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. Lancet Oncol. 2023;24:77-90.

Five Year Outcomes with KEYTRUDA® Plus Chemotherapy in Metastatic Nonsquamous Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

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, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-189 is a double-blind, Phase III trial in which 616 patients with untreated Stage IV non-squamous NSCLC, without sensitizing EGFR or ALK mutations, were randomly assigned in a 2:1 ratio to receive treatment with four cycles of KEYTRUDA®/Pemetrexed/Carboplatin (N=410) or placebo plus the same chemotherapy (N=206). Patients then received either KEYTRUDA® 200 mg or saline placebo, both administered IV every 3 weeks for up to 35 cycles. All the patients received four cycles of the investigator’s choice of Cisplatin 75 mg/m2 IV or Carboplatin AUC 5 along with Pemetrexed 500 mg/m2, all administered IV every 3 weeks, followed by maintenance Pemetrexed 500 mg/m2 every 3 weeks. Patients in the placebo combination group were allowed to crossover to KEYTRUDA® monotherapy upon disease progression. Patients with symptomatic brain metastasis were excluded and patients were stratified according to PD-L1 expression (Tumor Proportion Score, 1% or more versus less than 1%), choice of platinum-based drug (Cisplatin versus Carboplatin), and smoking history. Both treatment groups were well balanced and about 17% had brain metastasis and one-third were untreated. A PD-L1 Tumor Proportion Score of 1% or more was reported in 63% of the patients, Carboplatin was the preferred platinum-based drug in 72% of the patients, and 88% of the patients were current or former smokers. The co-Primary end points were Overall Survival (OS) and Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR) and Duration of Response (DOR) and Safety. Exploratory end points included PFS2 (time from random assignment to second/subsequent progressive disease on next-line treatment or death from any cause).

In the initial report from the trial, after a median follow-up of 10.5 months, the median PFS was 8.8 months in the KEYTRUDA® combination group and 4.9 months in the placebo combination group (HR=0.52; P<0.001) and the median OS was Not Reached with KEYTRUDA® combination and was 11.3 months in the placebo combination group (HR=0.49; P<0.001).

In this updated analysis, the researchers presented 5-year outcomes from the Phase III KEYNOTE-189 study. The median time from randomization to data cutoff (in March 2022) was 64.6 months. There was continued benefit in the Progression Free Survival and Overall Survival in the KEYTRUDA® group compared to the control group (HR=0.50 versus HR=0.60, respectively). The 5-year Progression Free Survival rates were 7.5% versus 0.6% and 5-year Overall Survival rates were 19.4% versus 11.3% respectively. The Objective Response Rate in the KEYTRUDA® group was 48.3% versus 19.9% in the control group, and the median Duration of Response was 12.7 and 7.1 months, respectively. Similar trends were observed across the PD-L1 subgroups analyzed. Among the 57 patients assigned to KEYTRUDA® combination and completed 35 cycles of KEYTRUDA®, the Objective Response Rate was 86% and the estimated Overall Survival rate 3 years after completion of 35 cycles (approximately 5 years from random assignment) was 71.9%. Sustained improvements in Overall Survival were observed in the KEYTRUDA® combination group, despite a crossover rate of 57% of patients from placebo plus chemotherapy to subsequent anti-PD1 therapy, further supporting the use of KEYTRUDA® plus chemotherapy as first-line treatment.

It was concluded that KEYTRUDA® in combination with Pemetrexed and Platinum chemotherapy continued to demonstrate prolonged survival and durable antitumor activity, compared to chemotherapy alone, regardless of PD-L1 expression. The authors added that these data continue to support the combination of first-line KEYTRUDA® plus a Platinum and Pemetrexed as a standard of care, in patients with previously untreated metastatic nonsquamous NSCLC, without EGFR/ALK alterations.

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. Garassino MC, Gadgeel S, Speranza G, et al. DOI: 10.1200/JCO.22.01989 Journal of Clinical Oncology. Published online February 21, 2023.

STK11 Mutation

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Both STK11 (also called LKB1) and KEAP1 mutation occur in about 17% of Non Small Cell Lung Cancer (adenocarcinomas), respectively, and correlates with poor outcome with immune checkpoint inhibitors or immune checkpoint inhibitors plus chemotherapy. KRAS is frequently comutated with STK11, KEAP1, and TP53 and these subgroups confer different prognostic outcomes. Within the KRAS mutated population, STK11 and/or KEAP1 mutations are associated with inferior Overall Survival and Progression Free Survival across treatments, compared with STK11-wild type and/or KEAP1-wild type. It appears that anti PD-1/anti-PD-L1 immune checkpoint inhibitors in combination with anti-angiogenic agent and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with KRAS mutations co-occurring with STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

RNF43 Mutations

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RNF43 mutations were identified in 29% of BRAF V600E-mutated MicroSatellite-Stable (MSS) metastatic ColoRectal Cancer tumors, and this finding was strongly associated with a clinical response to anti-BRAF/EGFR-based combination therapy. When compared to BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC patients without the RNF43 mutation (RNF43 wild-type), patients with BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC carrying a RNF43 mutation had a Response Rate of 72.7% versus 30.8% (P=0.03), longer median Progression Free Survival (10.1 months versus 4.1 months, HR=0.30; P=0.01) and longer median Overall Survival (13.6 months versus 7 months, HR=0.26; P=0.008). Conversely, the predictive value of RNF43 mutations seen in MicroSatellite-Stable tumors was not observed in MicroSatellite Instability (MSI)-High tumors.