Author: RR

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

RR

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

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

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

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

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

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

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

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

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

RR

SUMMARY: The American Cancer Society’s estimates that for 2022, about 99,780 new cases of melanoma of the skin will be diagnosed in the United States and 7,650 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. The current standard of care for patients following resection of high-risk Stage II disease is observation, even though patients with Stage IIB and IIC disease presenting with high-risk features (depth of invasion, T-category, ulceration) have 5 and 10 year melanoma-specific survival similar to that of patients with Stage IIIA and IIIB disease.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. The FDA in 2019, approved KEYTRUDA® for the adjuvant treatment of patients with melanoma, with involvement of lymph node(s), following complete resection (Stage III). The present study was conducted to evaluate the role of adjuvant immunotherapy in patients with high risk Stage II melanoma.

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

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

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

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

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

BREYANZI® (Lisocabtagene maraleucel)

RR

The FDA on June 24, 2022, approved BREYANZI® (Lisocabtagene maraleucel) for adult patients with Large B-Cell Lymphoma (LBCL) who have refractory disease to first-line chemoimmunotherapy, or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for Hematopoietic Stem Cell Transplantation (HSCT) due to comorbidities or age. It is not indicated for the treatment of patients with primary Central Nervous System lymphoma. BREYANZI® is a product of Juno Therapeutics, Inc.

TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib)

RR

The FDA on June 22, 2022, granted accelerated approval to TAFINLAR® (Dabrafenib) in combination with MEKINIST® (Trametinib) for the treatment of adult and pediatric patients 6 years of age or older with unresectable or metastatic solid tumors with BRAF V600E mutation, who have progressed following prior treatment, and have no satisfactory alternative treatment options. TAFINLAR® and MEKINIST® are products of Novartis Pharmaceuticals Corporation.

 

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

RR

SUMMARY: It is estimated that in the United States, approximately 19,880 women will be diagnosed with ovarian cancer in 2022 and 12,810 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

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

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

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

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

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

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

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

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

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

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

Late Breaking Abstract – ASCO 2022: Nimotuzumab Significantly Improves Overall Survival in K-Ras Wild-Type Advanced Pancreatic Cancer

RR

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. In patients with pancreatic ductal adenocarcinoma, the main driver is the KRAS oncogene, which is mutationally activated in over 90% of cases, and is more common in older (50 years or more) and female patients. However approximately 8-12% of patients with pancreatic ductal adenocarcinoma do not harbor KRAS mutations.

Nimotuzumab is a humanized anti-EGFR monoclonal antibody, that binds to EGFR (Epidermal Growth Factor Receptor) and disrupts the interaction of the EGFR with its ligand, specifically blocking the EGFR signaling pathway, and mediating Antibody-Dependent Cellular Cytotoxicity (ADCC) and other immune effects, and inducing EGFR endocytosis and degradation. Nimotuzumab as a single agent showed activity in high grade brain tumors, and resulted in high rates of antitumor response in patients with locally advanced squamous cell carcinomas of the head and neck, when combined with radiation therapy. Nimotuzumab is approved in different countries for the treatment of Squamous Cell Carcinoma of Head and Neck (SCCHN), Glioma and Nasopharyngeal carcinoma.

NOTABLE is a prospective, double-blind, Phase III trial in which the efficacy and safety of Nimotuzumab in combination with Gemcitabine was compared with Gemcitabine alone, in patients with KRAS wild-type, locally advanced or metastatic pancreatic cancer. In this study, 92 patients with locally advanced or metastatic pancreatic cancer were randomly assigned to receive either Nimotuzumab 400 mg IV every week followed by Gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 of every 28-day cycle or placebo plus Gemcitabine. Treatment was continued until disease progression or unacceptable toxicity. The treatment groups were well balanced. The median age was 56 years and approximately 56% had prior surgical management or treatment of biliary duct obstruction. The Primary endpoint was Overall Survival (OS), and Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), and Safety. The researchers envisioned that patients who did not need surgical management or treatment of biliary duct obstruction, typically would have better liver function without jaundice, and therefore would better tolerate chemotherapy. A subgroup analyses was therefore conducted based on whether the patients needed surgical management or treatment of bile duct obstructions prior to receiving chemotherapy.

The median Overall Survival was significantly longer in the Nimotuzumab/Gemcitabine group compared to those who received placebo plus Gemcitabine (10.9 months versus 8.5 months; HR=0.50; P=0.025). The one-year survival rate was 43.6% in the Nimotuzumab/Gemcitabine group versus 26.8% in the placebo-Gemcitabine group and the 3-year survival rate was 13.9% and 2.7%, respectively. The median Progression Free Survival was 4.2 months in the Nimotuzumab/Gemcitabine group compared to 3.6 months in the placebo plus Gemcitabine group (HR=0.56; P=0.013).

Among those patients who did not need surgical management or treatment of biliary duct obstruction, subgroup analyses showed significantly more survival benefit in patients without treatment of biliary obstruction (11.9 months versus. 8.5 months; HR=0.54; P=0.037) and among those with no surgical history (15.8 months versus 6.0 months; HR=0.40). Patients without treatment of biliary obstruction also had a significantly longer PFS (5.5 months versus 3.4 months; P=0.008) respectively. There was no statistical difference in the Objective Response Rates between the two treatment groups (P>0.05). Grade 3 adverse events in the Nimotuzumab/Gemcitabine group were neutropenia (11%), leukopenia (9%) and thrombocytopenia (7%). No Grade 4 adverse events were noted.

It was concluded that Nimotuzumab in combination with Gemcitabine, significantly increased Overall Survival and Progression Free Survival, in patients with K-Ras wild-type locally advanced or metastatic pancreatic cancer. This benefit was even more in patients who did not need surgical management or treatment of biliary duct obstruction.

Nimotuzumab combined with gemcitabine versus gemcitabine in K-RAS wild-type locally advanced or metastatic pancreatic cancer: A prospective, randomized-controlled, double-blinded, multicenter, and phase III clinical trial. Qin S, Bai Y, Wang Z, et al. J Clin Oncol. 2022;40(suppl 17):LBA4011. doi:10.1200/JCO.2022.40.17_suppl.LBA4011.