Author: RR

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.

Folate Receptor Alpha

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Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha, and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue and is considered positive if at least 75% of cells had 2+ staining intensity or greater, based on immunohistochemistry-based scoring. .

ESR1 Gene Mutation

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ESR1 (Estrogen Receptor 1) gene mutation is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers treated with prior Aromatase Inhibitor (AI) therapy in the metastatic setting, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI in advanced breast cancer. Approximately 40% of patients who had received AI therapy for metastatic breast cancer have ESR1 mutations. It is best to test for ESR1 mutations with a liquid biopsy following progression on an AI and CDK 4/6 inhibitor.

Overall Survival Benefit with Pembrolizumab in Advanced Gastric Cancer

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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. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine and, if appropriate, HER2/neu-targeted therapy. This can however be associated with significant toxicities impacting patient’s quality of life. The efficacy of PD-1 inhibitors in combination with chemotherapy has been demonstrated in Gastric and GastroEsophageal cancer.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

KEYNOTE-859 was a double-blind, placebo-controlled, randomized Phase III trial, conducted to evaluate the benefit of adding Pembrolizumab to Fluoropyrimidine and Platinum-containing doublet chemotherapy in patients with advanced HER2-negative Gastric or GastroEsophageal cancer. In this study, 1,579 patients with locally advanced or metastatic HER2-negative Gastric or GastroEsophageal adenocarcinoma, with known a PD-L1 Combined Positive Score (CPS), were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV (N=790) or placebo (N=789), every 3 weeks for 35 cycles or less, given along with investigator’s choice of 5-FU plus Cisplatin or Capecitabine plus Oxaliplatin (CAPOX). Baseline characteristics were balanced between treatment groups and randomization was stratified by region, PD-L1 CPS (less than 1 versus 1 or more), and choice of chemotherapy. At baseline, 78% of patients had PD-L1 CPS 1 or more, while 35% had tumors with CPS 10 or more.

The Primary end point was Overall Survival (OS) by blinded Independent Central Review. Secondary end points included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR) and Safety. The researchers provided the data from the interim analysis, at a median follow up of 31.0 months.

The median Overall Survival was 12.9 months with Pembrolizumab plus chemotherapy versus 11.5 months with chemotherapy alone (HR=0.78, P<0.0001). The median PFS was 6.9 months versus 5.6 months, respectively (HR=0.76, P<0.0001). The benefit with Pembrolizumab was consistent across subgroups, including those by PD-L1 CPS. The risk reduction was especially notable among patients with MicroSatellite Instability (MSI)-High status, who had a 66% relative reduction in the risk of death, and patients with PD-L1 CPS 10 or more, whose risk was reduced by 36%. The Objective Response Rate was 51.3% in the Pembrolizumab group and 42.0% in the control group (P=0.00009), and the median Duration of Response was 8.0 months versus 5.7 months, respectively. Immune-related toxicities, especially hypothyroidism, were more common with Pembrolizumab plus chemotherapy and no new safety signals were seen.

It was concluded that treatment with Pembrolizumab plus chemotherapy resulted in a statistically significant and clinically meaningful improvement in Overall Survival, Progression Free Survival and Objective Response Rate, among patients with locally advanced or metastatic, HER2-negative Gastric or GastroEsophageal adenocarcinoma of any PD-L1 expression level, thus providing a new treatment option for this patient group.

Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction cancer: Phase III KEYNOTE-859 study. Rha SY, Wyrwicz LS, Weber PEY, et al. ESMO Virtual Plenary Session Date: 16-17 February 2023. VP1-2023. Published: February 16, 2023. DOI: https://doi.org/10.1016/j.annonc.2023.01.006.

Rucaparib or Physicians Choice of Therapy in Metastatic Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 288,300 new cases of Prostate cancer will be diagnosed in 2023 and 34,700 men will die of the disease.

The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPI), which include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

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 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination and 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, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Recently published data has shown that deleterious Germline and/or Somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 25% of patients with advanced prostate cancer, including metastatic CRPC. Approximately 12% of men with metastatic CRPC harbor a deleterious BRCA1 or BRCA2 mutation (BRCA1, 2%; BRCA2, 10%). Mutations in BRCA1 and BRCA2 also account for about 20-25% of hereditary breast cancers, about 5-10% of all breast cancers, and 15% of ovarian cancers.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1and 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 trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that 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® (Rucaparib) is an oral, small molecule inhibitor of PARP inhibitor, and in the Phase II TRITON2 study, Rucaparib showed a high level of activity in metastatic Castration Resistant Prostate Cancer (CRPC) associated with a deleterious BRCA alteration, in patients who had received previous treatment with a second-generation Androgen-Receptor Pathway Inhibitor (ARPI) and taxane-based chemotherapy.

TRITON3 is an open-label, controlled, randomized, Phase III trial, conducted to evaluate the benefit of Rucaparib in men with metastatic CRPC at an earlier stage of treatment, and to confirm and expand on data from the TRITON2 study. This study enrolled patients who had metastatic CRPC with a BRCA1, BRCA2, or ATM alteration, who had disease progression after treatment with a second-generation ARPI, and who had not received previous chemotherapy for metastatic CRPC. Patients were randomly assigned in a 2:1 ratio to receive Rucaparib 600 mg orally twice daily or a physician’s choice of therapy (Docetaxel or a second-generation ARPI such as Abiraterone acetate or Enzalutamide). Abiraterone acetate or Enzalutamide could not be selected if the patient had received either drug before trial initiation. Approximately 56% received Docetaxel in the control group. The median age was 70 years and baseline genomic, demographic, and disease characteristics were well balanced in the two groups although men of African descent were underrepresented relative to the general population. Among the patients who had undergone randomization, 302 patients had a BRCA alteration and 103 patients had an ATM alteration. In this study, there were smaller numbers of patients with BRCA1 alterations than with BRCA2 alterations. The Primary end point was the median duration of imaging-based Progression Free Survival (PFS) according to Independent Review. Secondary outcomes included Overall Survival (OS) and Objective Response Rate (ORR), Duration of Response, Time to progression according to Prostate Specific Antigen (PSA) testing and Patient-Reported Outcomes.

At 62 months, the median duration of imaging-based PFS was significantly longer in the Rucaparib group than in the control group, both in the BRCA subgroup (11.2 months and 6.4 months, respectively; HR=0.50) and in the intention-to-treat group (10.2 months and 6.4 months, respectively; HR=0.61; P<0.001 for both comparisons). These findings demonstrating the benefit of Rucaparib compared to the Docetaxel control group are significant, as numerous previous studies either did not include Docetaxel in the control group, or did not show the superiority of PARP inhibition to Docetaxel. These study findings were consistent with the results of previous studies, suggesting that repeated use of second-generation ARPIs appeared to have only modest activity and inferior to PARP inhibition. Among patients with measurable disease at baseline, the confirmed Objective Response in the Rucaparib group and the control group was 45% and 17% respectively in the BRCA subgroup, 35% and 16% respectively, in the intention-to-treat population and no response and 14% respectively in the ATM subgroup. Because there were a smaller number of patients with BRCA1 alterations than with BRCA2 alterations in this study, the treatment benefit was not conclusive in those with BRCA1 alterations.

In an exploratory analysis in the ATM subgroup, the median duration of imaging-based PFS was 8.1 months in the Rucaparib group and 6.8 months in the control group (HR=0.95), suggesting limited efficacy of Rucaparib in the ATM subgroup, similar to the results of previous clinical trials involving PARP inhibitors. The most frequent adverse events with Rucaparib were fatigue and nausea.

It was concluded that in patients with metastatic Castration-Resistant Prostate Cancer in whom treatment with an Androgen Receptor Pathway Inhibitor (ARPI) had failed, the use of Rucaparib resulted in a longer duration of imaging-based Progression Free Survival than a physician’s choice of Docetaxel or a second-generation ARPI.

Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. Fizazi K, Piulats JM, Reaume MN, et al., for the TRITON3 Investigators. N Engl J Med 2023; 388:719-732.