Author: RR

KEYTRUDA® Superior to ADCETRIS® in Relapsed or Refractory Classical Hodgkin Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2020, about 8,480 new cases of Hodgkin Lymphoma will be diagnosed and about 970 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).The HRS cells in turn recruit an abundance of ineffective inflammatory cells and infiltrates of immune cells.WHO-Classification-of-Hodgkin-Lymphoma

Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-L. Classical Hodgkin Lymphoma is an excellent example of how the tumor microenvironment influences cancer cells to proliferate and survive. The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2, with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin lymphomas. It would therefore seem logical to block or inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. 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. 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.

Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL) are often treated with salvage chemotherapy and Autologous Stem Cell Transplant (ASCT). There are however no standard interventions for patients ineligible for ASCT due to chemo-refractory disease, comorbidity, or advanced stage. PD-1 inhibitor such as KEYTRUDA® as well as ADCETRIS® has shown antitumor activity in R/R cHL.

KEYNOTE-204 is a randomized, international, open-label, Phase III study in which KEYTRUDA® was compared with ADCETRIS® among patients with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL). In this study, 304 patients were randomized 1:1, and 300 patients were treated and assigned to receive KEYTRUDA® 200 mg IV every 3 weeks (N=148) or ADCETRIS® 1.8 mg/kg IV every 3 weeks (N=152). Enrolled patients were post-Autologous Stem Cell Transplant (ASCT) or ineligible for ASCT, had measurable disease and had an ECOG Performance Status of 0 or 1. Both ADCETRIS®-naive and ADCETRIS®-exposed patients were eligible. Patients were stratified by prior ASCT and status after first-line therapy (primary refractory versus relapsed less than 12 months versus relapsed 12 months or more after end of first-line therapy). The Primary endpoints were Progression Free Survival (PFS) per Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary endpoints included PFS per investigator review, Objective Response Rate (ORR), and Safety. Median follow up was 24.7 months.

The median PFS was 13.2 months in the KEYTRUDA® group compared with 8.3 months in the ADCETRIS® group (HR=0.65, P=0.00271), suggesting an increase in PFS of 4.9 months with KEYTRUDA®. This benefit with KEYTRUDA® was observed in all subgroups tested, including those ineligible for ASCT (HR=0.61), those with primary refractory disease (HR=0.52), those who were ADCETRIS® naïve (HR=0.67), as well as those who received prior treatment with ADCETRIS® (HR=0.34). The ORR was 65.6% versus 54.2%, and the median Duration of Response was 20.7 months versus 13.8 months, in the KEYTRUDA® and ADCETRIS® groups respectively. Treatment Related Adverse Events were similar in both treatment groups and Grade 3-5 toxicities occurred in 19.6% of patients treated with KEYTRUDA® and 25% of patients treated with ADCETRIS®.

It was concluded that among patients with Relapsed/Refractory Classical Hodgkin Lymphoma, KEYTRUDA® was superior to ADCETRIS®, with a statistically significant and clinically meaningful improvement in PFS across all subgroups tested, and with safety consistent with previous reports. The authors added that KEYTRUDA® should be considered the preferred treatment option and the new standard of care in this patient population.

KEYNOTE-204: Randomized, open-label, phase III study of pembrolizumab (pembro) versus brentuximab vedotin (BV) in relapsed or refractory classic Hodgkin lymphoma (R/R cHL). Kuruvilla J, Ramchandren R, Santoro A, et al. Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. J Clin Oncol 38: 2020 (suppl; abstr 8005).

TAZVERIK® (Tazemetostat)

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The FDA on June 18, 2020 granted accelerated approval to TAZVERIK®, an EZH2 inhibitor, for adult patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL) whose tumors are positive for an EZH2 mutation, as detected by an FDA-approved test, and who have received at least 2 prior systemic therapies, and for adult patients with R/R FL who have no satisfactory alternative treatment options. TAZVERIK® is a product of Epizyme, Inc.

KEYTRUDA® (Pembrolizumab)

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The FDA on June 16, 2020 granted accelerated approval to KEYTRUDA® for the treatment of adult and pediatric patients with unresectable or metastatic Tumor Mutational Burden-High (TMB-H) [10 or more mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. KEYTRUDA® is a product of Merck & Co., Inc.

OPDIVO® (Nivolumab)

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The FDA on June 10, 2020 approved OPDIVO® for patients with unresectable, advanced, recurrent or metastatic Esophageal Squamous Cell Carcinoma (ESCC), after prior Fluoropyrimidine- and Platinum-based chemotherapy. OPDIVO® is a product of Bristol-Myers Squibb Co.

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

RR

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

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

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The FDA in 2017 granted accelerated approval to KEYTRUDA® for patients with advanced MSI-High or dMMR solid tumors, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors.

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

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

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

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

FDA Approves RETEVMO® for RET Altered Non Small Cell Lung Cancer and Thyroid Cancers

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SUMMARY: The FDA on May 8, 2020, granted accelerated approval to RETEVMO® (Selpercatinib) for patients with metastatic RET fusion-positive Non-Small Cell Lung Cancer (NSCLC), patients with advanced or metastatic RET-mutant Medullary Thyroid Cancer (MTC) who require systemic therapy and those with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are RadioActive Iodine (RAI)-refractory. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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.

In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, NTRK, are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors.MOA-of-RETEVMO

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene results in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, breast, and several hematologic malignancies.

RETEVMO® (Selpercatinib) is a highly selective and potent, oral anti-RET Tyrosine Kinase Inhibitor (TKI) designed to inhibit native RET signaling, as well as anticipated acquired resistance mechanisms. RETEVMO® selectively targets wild-type RET as well as various RET mutants and RET-containing fusion products. Additionally, RETEVMO® inhibits Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), VEGFR3, Fibroblast Growth Factor Receptor 1 (FGFR1), FGFR2, and FGFR3. This results in inhibition of cell growth of tumors that exhibit increased RET activity.

The LIBRETTO-001 is the largest open-label, multicenter, Phase I/II trial in patients with advanced solid tumors, including RET fusion-positive solid tumors, RET-mutant Medullary Thyroid Cancers, and other tumors with RET activation, treated with a RET inhibitor. To investigate the efficacy of RETEVMO®, the trial was conducted in 2 parts: Phase 1 (dose escalation) and Phase II (dose expansion). Patients with advanced cancer were eligible, if they have progressed on or were intolerant to available standard therapies, or no standard or available curative therapy existed, or in the opinion of the Investigator, they would be unlikely to tolerate or derive significant clinical benefit from appropriate standard of care therapy, or they declined standard therapy. A dose of 160 mg BID was the recommended Phase II dose. Up to about 850 patients with advanced solid tumors harboring a RET gene alteration in tumor and/or blood were enrolled in 6 different Phase II cohorts, based on tumor type, RET alteration and prior therapy. Identification of RET gene alterations was prospectively determined in local laboratories using either Next Generation Sequencing, Polymerase Chain Reaction, or Fluorescence In Situ Hybridization. The Phase II portion of the trial had a Primary endpoint of Objective Response Rate (ORR) and Secondary endpoints of Duration of Response, Progression Free Survival (PFS) and safety.

The NSCLC cohort included 105 enrolled patients with RET fusion-positive NSCLC who had received prior platinum-based chemotherapy. Patients had received a median of three prior systemic regimens, 55% had previous treatment with an anti-PD-1/PD-L1 antibody and 48% had previous treatment with at least one multikinase inhibitor. The ORR with RETEVMO&reg was 64%, and 81% of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 39 treatment-naïve patients. The ORR for these patients with RETEVMO&reg was 85%, and 58% of responding patients had responses lasting 6 months or longer. It is estimated that up to 50% of RET fusion-positive NSCLC patients can have brain metastases, and in the subset of patients with brain metastases in this registrational trial, treatment with RETEVMO&reg demonstrated a CNS Objective Response Rate of 91%. Median DOR and PFS were not reached at the time of data-cut-off.

In the cohort of advanced or metastatic RET-mutant MTC (N=143), the ORR in patients previously treated with COMETRIQ® (Cabozantinib), CAPRELSA® (Vandetanib), or both (N=55) was 69%, and 76% of responding patients had responses lasting 6 months or longer. Among those patients who had no prior therapy with an approved agent for MTC (N=88), the ORR was 73%, and 61% of responding patients had responses lasting 6 months or longer.

In the cohort of RET fusion-positive thyroid cancer who were RAI-refractory and had received another prior systemic treatment (N=19), the ORR was 79%, and 87% of responders had a response lasting 6 months or longer. Among the patients with RET fusion-positive thyroid cancer who were RAI-refractory and had not received any additional therapy (N=8), the ORR was 100% and 75% of responders had a response lasting 6 months or longer.The most common toxicities included rash, cytopenias, liver function abnormalities, hyperglycemia, hyponatremia, hypocalcemia, increased creatinine and hypertension.

LIBRETTO-001 is the largest trial ever reported in RET-altered cancer patients, and the present FDA approval of RETEVMO® for patients with RET fusions and mutations, across multiple tumor types, represents an important milestone in the Precision Medicine arena.

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions

Oral Relugolix Superior to Leuprolide in Advanced 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 191,930 new cases of prostate cancer will be diagnosed in 2020 and 33,330 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, anti-androgen agents, which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide).

Androgen Deprivation Therapies such as GnRH analogs/Luteinizing Hormone Releasing Hormone (LHRH) agonists are standard treatment for patients with advanced prostate cancer. These agents when first administered cause an initial surge in Luteinizing Hormone, Follicle Stimulating Hormone (FSH), and testosterone levels. With continuous administration, LHRH agonists desensitize the pituitary receptor and suppress the production of Luteinizing Hormone and testosterone, thus blocking the pulsatile secretion of GnRH by the hypothalamus. LHRH agonists however do not fully suppress FSH which is a potential mitogenic growth factor for prostate cancer cells. The initial testosterone surge may result in flaring up of symptoms such as bone pain, obstructive urinary symptoms, and rarely spinal cord compression. For this reason, anti-androgen agents are recommended for the first few weeks after initiation of an LHRH agonist. LHRH agonists have been shown to increase the near-term risk of major adverse cardiovascular events, by promoting plaque destabilization and rupture.

Degarelix (FIRMAGON®) is a GnRH antagonist, and the depot injection was approved by the FDA in December 2018. Degarelix suppresses both Luteinizing Hormone and FSH, resulting in rapid testosterone suppression, without an initial testosterone surge. This agent however has to be administered monthly and approximately 40% of patients experience reactions at the injection site.MOA-of-GnRH-Agonists-and-Antagonists

Relugolix is a highly selective, GnRH antagonist that can be given orally once daily, and has a half-life of 25 hours. In multiple Phase I and Phase II studies, Relugolix has been shown to lower testosterone levels by rapidly inhibiting the pituitary release of Luteinizing Hormone and FSH. The HERO trial is a multinational, randomized, open-label, Phase III study, which evaluated the efficacy and safety of Relugolix, an oral GnRH antagonist, as compared with those of Leuprolide (LUPRON®) (GnRH agonist), in men with advanced prostate cancer. In this study, a total of 930 patients were randomly assigned in a 2:1 ratio to receive either Relugolix 120 mg orally once daily, after a single oral loading dose of 360 mg (N=622) or Leuprolide acetate 22.5 mg IM every 3 months (N=308), for 48 weeks.
Eligible patients had one of three clinical disease presentations: 1) Evidence of biochemical (PSA) or clinical relapse after local primary intervention with curative intent 2) Newly diagnosed hormone-sensitive metastatic disease, or 3) Advanced localized disease unlikely to be cured by local primary intervention with curative intent. Patients with major adverse cardiovascular events within 6 months before trial initiation were excluded. Patients were stratified according to the presence or absence of metastatic disease, and age (75 yrs or less and over 75 years). Approximately 32% of patients had metastatic disease and 50% had biochemical recurrence after definitive treatment.
The Primary endpoint was sustained testosterone suppression to castrate levels (less than 50 ng/dL) through 48 weeks. Secondary end points included noninferiority of Relugolix to Leuprolide with respect to sustained castration rate, castrate levels of testosterone on day 4, and profound castrate levels (less than 20 ng/dL) on day 15. Testosterone recovery after discontinuation of the trial drug was to be evaluated in a subgroup of patients. The median follow up time in both groups, including the 30-day safety follow-up period for adverse events, was 52 weeks.

Relugolix was associated with a significantly higher rate of maintained castrate levels of testosterone, when compared to Leuprolide. Castrate levels of testosterone were maintained through 48 weeks in 96.7% of patients in the Relugolix group compared to 88.8% of patients in the Leuprolide group. The difference of 7.9 percentage points showed noninferiority as well as superiority of Relugolix (P<0.001 for superiority) over Leuprolide. All other key Secondary end points showed superiority of Relugolix over Leuprolide (P<0.001). These endpoints included the percentage of patients with castrate levels of testosterone on day 4 (56% versus 0%) and on day 15 (98.7% versus 12%), testosterone suppression to less than 20ng/dL on day 15 (78.4% versus 1%) and confirmed PSA response of more than 50% decrease at day 15 (79.4% versus 19.8%; P<0.001). In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng/dL in the Relugolix group and 58.6 ng/dL in the Leuprolide group. The incidence of major adverse cardiovascular events among all the patients was 2.9% in the Relugolix group and 6.2% in the Leuprolide group (HR=0.46).

The authors concluded that in this trial involving men with advanced prostate cancer, Relugolix achieved rapid and sustained suppression of testosterone levels, that was superior to that with Leuprolide, with a 54% lower risk of major adverse cardiovascular events.

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. Shore ND, Saad F, Cookson MS, et al. for the HERO Study Investigators. N Engl J Med 2020; 382:2187-2196.

FDA Approves CYRAMZA® Plus TARCEVA® for EGFR Mutated NSCLC

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SUMMARY: The FDA on May 29, 2020 approved CYRAMZA® (Ramucirumab) in combination with TARCEVA® (Erlotinib) for first-line treatment of metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) Exon 19 deletions or Exon 21 (L858R) mutations. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA®, IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients. Previously published data from the Phase III FLAURA study showed that first-line treatment with third generation TKI, TAGRISSO® (Osimertinib), was superior to first-line treatment with other first and second generation TKI’s, in patients with EGFR-mutated NSCLC. However, widespread use of TAGRISSO® has led to acquired resistance. Novel treatment approaches combining TKI’s with other targeted therapies are therefore needed.

CYRAMZA® is a recombinant human monoclonal IgG1 antibody that binds to the human Vascular Endothelial Growth Factor Receptor- 2 (VEGFR-2), preventing the interaction of VEGFR-2 with its ligands. TARCEVA® is a first generation EGFR TKI. Preclinical and clinical data strongly support dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic NSCLC.

RELAY is an International, double-blind, Phase III trial, which included 449 eligible patients who had Stage IV NSCLC, with an EGFR Exon 19 deletion (ex19del) or Exon 21 substitution (L858R) mutation, and with no CNS metastases. Enrolled patients were randomly assigned in a 1:1 ratio to receive TARCEVA® 150 mg orally daily plus CYRAMZA® 10 mg/kg IV once every 2 weeks (N=224) or TARCEVA® plus a matching placebo (N=225). Patients were stratified by sex, EGFR mutation type, and EGFR testing methodology. The Primary endpoint was Progression Free Survival (PFS) and key Secondary endpoints included Safety, Overall Response Rate (ORR), Duration of Response, and Overall Survival (OS).

At a median follow up of 20.7 months, PFS was significantly longer in the TARCEVA® plus CYRAMZA® group compared to TARCEVA® plus placebo group (19.4 months versus 12.4 months respectively; HR=0.59; P<0.0001). This benefit was observed regardless of tumor type, and was consistent across Exon 19 and Exon 21 subgroups. The ORR was similar between the CYRAMZA® and placebo groups (76% versus 75%), but the median Duration of Response was longer in the CYRAMZA® group, compared with the placebo group (18 months versus 11 months). The OS data were not mature at the time of final PFS analysis and the median time to the second disease progression (PFS2) was not yet reached. However, interim results indicated that PFS2 was longer in the CYRAMZA® group compared to the placebo group (HR = 0.69) suggesting that PFS benefits with CYRAMZA® were preserved beyond first progression, indicating that possibility of OS benefit. Upon progression, T790M resistance mutations were detected in 43% of patients who received CYRAMZA®, and in 47% of patients who received placebo. The most common adverse events in the TARCEVA® plus CYRAMZA® combination included infections, stomatitis, hypertension, proteinuria, alopecia, epistaxis and peripheral edema.

It was concluded that TARCEVA® plus CYRAMZA® demonstrated superior PFS compared with TARCEVA® plus placebo, in treatment naïve patients with EGFR-mutated metastatic NSCLC. The combination of TARCEVA® plus CYRAMZA® will be a new additional treatment option for this patient group.

Ramucirumab plus Erlotinib in Patients with Untreated, EGFR-mutated, Advanced Non-Small-Cell Lung Cancer (RELAY): A Randomised, Double-blind, Placebo-Controlled, Phase 3 trial. Nakagawa K, Garon EB, Seto T, et al. Lancet Oncol. 2019;20:1655-1669.

FDA Approves TECENTRIQ® in Combination with AVASTIN® for Hepatocellular Carcinoma

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SUMMARY: The FDA on May 29, 2020, approved TECENTRIQ® (Atezolizumab) in combination with AVASTIN® (Bevacizumab) for patients with unresectable or metastatic HepatoCellular Carcinoma (HCC), who have not received prior systemic therapy. The American Cancer Society estimates that for 2020, about 42,810 new cases of primary liver cancer will be diagnosed in the US and 30,160 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the increasing trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide, and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.Synergistic-Effect-of-PD-L1-and-VEGF-Inhibition

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells. AVASTIN® (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds VEGF (Vascular Endothelial Growth Factor) and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells, thereby preventing endothelial cell proliferation and new blood vessel formation. AVASTIN® in addition to its established anti-angiogenic properties can further enhance TECENTRIQ®’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens. The use of TECENTRIQ® in combination with AVASTIN® therefore has a strong scientific rationale, as this combination can potentially enhance the immune system to combat a broad range of malignancies.

IMbrave150 is a global, open-label, multicenter, randomized, Phase III study in which a combination of TECENTRIQ® and AVASTIN® was compared with standard-of-care NEXAVAR®, in patients with previously untreated locally advanced or metastatic HCC. Patients were randomized 2:1 to receive TECENTRIQ® 1200 mg IV on day 1 along with AVASTIN® 15 mg/kg on day 1 of each 21-day cycle (N=336) or NEXAVAR® 400 mg orally twice daily, each day of the 21-day cycle (N=165). Treatment was continued until disease progression or unacceptable toxicity. The treatment groups were well balanced and enrolled patients had an ECOG performance status of 0 or 1, Child-Pugh Class A disease, and adequate hematologic and end-organ function. The two co-Primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS). The key Secondary endpoints included Overall Response Rate (ORR), Time To Progression (TTP) and Duration of Response (DOR), as well as Patient-Reported Outcomes (PROs), Safety and Pharmacokinetics.

With a median follow up of 8.6 months, the OS was not yet reached in the TECENTRIQ® and AVASTIN® combination group compared with 13.2 months in the NEXAVAR® group (HR=0.58; P=0.0006). The median PFS was 6.8 months versus 4.3 months respectively (HR=0.59; P<0.0001). The ORR was 27% versus 12% (P<0.0001) based on the Independent Review Facility RECIST 1.1 criteria, in favor of the combination regimen. This benefit was seen across clinical subgroups and the combination regimen delayed deterioration of Quality of Life, compared with NEXAVAR®. Grade 3 and 4 Adverse Events were similar and occurred in 57% and 55% of the combination and control arms, respectively.

It was concluded that a combination of TECENTRIQ® and AVASTIN® demonstrated statistically significant and clinically meaningful improvement in both Overall Survival and Progression Free Survival, compared with NEXAVAR®, in treatment naïve patients with unresectable Hepatocelluar Carcinoma. The authors added that this is the first study in 11 years to show an improvement in Overall Survival with a new first line treatment option, compared to NEXAVAR®, and has the potential to be a practice changing treatment in Hepatocellular Carcinoma.

IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Cheng A-L, Qin S, Ikeda M, et al. Annals of Oncology, Volume 30, 2019 Supplement 9. LBA3.