Author: RR

FDA Approves KEYTRUDA® for Tumor Mutational Burden-High Solid Tumors

RR

SUMMARY: The FDA on June 16, 2020 granted accelerated approval to KEYTRUDA® (Pembrolizumab) for the treatment of adult and pediatric patients with unresectable or metastatic Tumor Mutational Burden-High (10 or more mutations/megabase) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. The FDA on the same day also approved the FoundationOne® CDx assay (Foundation Medicine, Inc.) as a companion diagnostic for KEYTRUDA®. 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.

Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor genome and is emerging as a quantitative indicator for predicting response to Immune Checkpoint Inhibitors such as KEYTRUDA®, across a wide range of malignancies. These non-synonymous somatic mutations in the tumor genome generate larger number of neo-antigens which are more immunogenic. Immune Checkpoint Inhibitors are able to unleash the immune system to detect these neoantigens and destroy the tumor. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/Megabase as High, and less than 10 mutations/Megabase, as Low. (A megabase is 1,000,000 DNA basepairs).

KEYNOTE-158 is a multicenter, non-randomized, open-label, Phase II basket trial investigating the antitumor activity and safety of KEYTRUDA® in multiple advanced solid tumors. The accelerated approval was based on data from a prospectively-planned, retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic solid tumors with TMB-H, who were enrolled in KEYNOTE-158 study. Patients received KEYTRUDA® 200 mg IV every 3 weeks until unacceptable toxicity or documented disease progression. In this study, 1,050 patients were included in the efficacy analysis and TMB was analyzed in the subset of 790 patients with sufficient tissue for testing. Of these 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB 10 mutations /Megabase or more. The median age in this study population of 102 patients was 61 years, ECOG PS was 0-1, and 56% of patients had at least 2 prior lines of therapy. TMB status was assessed using the FoundationOne® CDx assay. Tumor response was assessed every 9 weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) in the patients who received at least one dose of KEYTRUDA®. The key Secondary outcome measures included Progression Free Survival (PFS), Overall Survival (OS), and safety.

In the 102 patients whose tumors were TMB-H, KEYTRUDA® demonstrated an ORR of 29%, with a Complete Response rate of 4% and a Partial Response rate of 25%. After a median follow up time of 11.1 months, the median DOR had not been reached. Among the responding patients, 57% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer. The median duration of exposure to KEYTRUDA® was 4.9 months. The most common adverse reactions for KEYTRUDA® were fatigue, decreased appetite, rash, pruritus, fever, nausea, diarrhea, cough, dyspnea, constipation, abdominal pain and musculoskeletal pain.

It was concluded that in patients with advanced solid tumors treated with KEYTRUDA® monotherapy, high TMB was associated with higher Objective Response Rates and median Duration of Response, with the Progression Free Survival favoring patients with high TMB. These data suggest that TMB may be predictive of the efficacy of KEYTRUDA® monotherapy in patients with a wide range of tumor types.

Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Marabelle A, Fakih MG, Lopez J, et al. Annals of Oncology (2019) 30 (suppl_5): v475-v532. 10.1093/annonc/mdz253.

ENHERTU® Demonstrates Promising Clinical Activity in HER2 Positive 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 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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including breast, gastric, lung and colorectal cancers. It is a growth-promoting protein and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types. Other HER2 gene alterations such as HER2 mutations, as distinct molecular targets, have been identified in 2-4% of patients with NSCLC, specifically with adenocarcinoma histology. These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis. There are currently no therapies approved specifically for the treatment HER2 mutant NSCLC, and is therefore an unmet need.Mechanism-of-Action-ENHERTU

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to HERCEPTIN® (Trastuzumab), attached to a potent cytotoxic Topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker. ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), which is also an Antibody-Drug Conjugate, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), the released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, minimizing systemic exposure. ENHERTU® is approved in the US for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2 based regimens, based on the DESTINY-Breast01 trial.

DESTINY-Lung01 is an ongoing, global, multicenter, open-label, two-cohort, Phase II study, evaluating the safety and efficacy of ENHERTU® in 170 patients with HER2 mutant or HER2 overexpressing (defined as ImmunoHistoChemistry-IHC 3+ or IHC 2+), unresectable and metastatic non-squamous NSCLC. Eligible patients could not have received prior HER2-targeted therapy, with the exception of pan-HER TKIs. Patients were enrolled into 2 cohorts. The first cohort enrolled patients with HER2-expressing tumors as defined by IHC 3+ or 2+ (N = 42). The second cohort included patients whose tumors harbored a HER2 mutation as determined by a local laboratory test (N = 42). Enrolled patients had a median of two prior lines of therapy with majority of patients receiving platinum-based chemotherapy (90.5%), anti-PD-1 or PD-L1 treatment (54.8%) and 19% receiving Docetaxel. Patients received ENHERTU® 4.6 mg/kg every 3 weeks by intravenous infusion. The 42 patients included in the second cohort had a median age of 63 years, 64.3% of patients were female, and 45.2% had CNS metastases. For the majority of patients (90.5%), HER2 mutation was located in the kinase domain. The Primary endpoint was confirmed Objective Response Rate (ORR). Additional endpoints included Disease Control Rate (DCR), Duration of Response (DoR), Progression Free Survival (PFS), and safety. The authors reported data for the cohort with HER2 mutations (second cohort), after a median follow up of 8.0 months.

The ORR was 61.9%, with 2.4% Complete Response, 59.5% Partial Response, and stable disease noted in 28.6% of patients. The Disease Control Rate was 90.5%. The median PFS was 14 months. The median Duration of Response and Overall Survival (OS) had not yet been reached at the time of data cut-off. The most common Grade 3 or higher treatment related Adverse Events were neutropenia and anemia. Confirmed treatment-related Interstitial Lung Disease (ILD) and pneumonitis were noted in approximately 12% of patients and were all Grade 2 and there were no deaths. Nonetheless, ILD is an important identified risk for patients treated with ENHERTU® and requires careful monitoring and management.

It was concluded that ENHERTU® demonstrated promising clinical activity in this interim analysis, with a high Objective Response Rate and durable responses, in a heavily pretreated population of patients with HER2-mutated NSCLC.

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): Interim results of DESTINY-Lung01. Smit EF, Nakagawa K, Nagasaka M, et al. J Clin Oncol 38: 2020 (suppl; abstr 9504).

PIQRAY® Effective after Progression on CDK Inhibition in Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. Approximately 6% of newly diagnosed breast cancer patients present with Stage IV disease and about half of patients with primary breast cancer will progress later to the metastatic stage. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Most of these patients with advanced disease in the current era are treated with a combination of CDK4/6 inhibitor and endocrine therapy (often an oral Aromatase Inhibitor), based on survival data. However, resistance to these regimens typically develops in a majority of the patients.

The PhosphoInositide 3-Kinase (PI3K) pathway is an intracellular signaling pathway important in the regulation of cancer cell proliferation and metastasis. PI3K is a lipid kinase and has four distinct isoforms – alpha, beta, gamma and delta, which play a unique role in the survival of different tumor types and establishment of supportive tumor microenvironments. The alpha and beta isoforms are expressed in a wide variety of tissues whereas the gamma and delta isoforms are primarily expressed in hematopoietic cells such as B and T cells. The PI3K alpha isoform is particularly important in breast cancer and plays an important role in tumorigenesis, supporting tumor angiogenesis and stromal interactions, making this a viable target. PIK3CA is an oncogene that codes for the alpha isoform of PI3K, (PI3Kα), more specifically for the alpha isoform of p110. The PI3k pathway is the most frequently altered pathway in human cancers including breast cancer, and has been implicated in disease progression in a significant number of patients with breast cancer. Activation of the PI3K pathway in breast cancer has been associated with resistance to endocrine therapy and disease progression. Approximately 40% of patients with Hormone Receptor positive (HR+), HER2-negative breast cancers, harbor activating mutations in the PIK3CA isoform of PI3K, which is the most common mutation in HR+ breast cancer. Patients with advanced breast cancer harboring PIK3CA mutations typically have a poor prognosis. This provides a strong rationale for targeting the PI3K pathway in breast cancer.Alpelisib-Mechanism-of-Action

PIQRAY® is an oral, alpha-specific PI3K inhibitor that specifically inhibits PIK3 in the PI3K/AKT kinase signaling pathway. Further, it was shown in preclinical studies that cancer cells with PIK3CA mutations are more sensitive to PIQRAY® than those without the mutation, across a broad range of tumor types. In the SOLAR-1 Phase III trial, there was a 35% improvement in Progression Free Survival (PFS) in patients randomized to PIQRAY® plus FASLODEX®, compared to the placebo plus FASLODEX® group, among postmenopausal patients with PIK3CA-mutated, HR+/HER2- negative, advanced breast cancer, who had progressed on or following prior Aromatase Inhibitor (AI) treatment with or without a CDK 4/6 inhibitor. However in this study, only 6% had received prior CDK4/6 inhibitor therapy and there is presently limited data available, to inform treatment decisions in patients who progress on AI and CDK 4/6 inhibitor combination.

BYLieve is an ongoing, prospective, open-label, Phase II, non-comparative trial, which evaluated the benefit of PIQRAY&reg in combination with endocrine therapy in patients with HR+, HER-negative, PIK3CA-mutated, advanced breast cancer, who progressed on or after a prior therapy including CDK inhibitor. This study included 3 patient cohorts– Cohort A included patients who received a CDK4/6 inhibitor plus an AI as immediate prior therapy, Cohort B included patients who received a CDK4/6 inhibitor plus FASLODEX® (Fulvestrant) as immediate prior therapy, and Cohort C included patients who progressed on/after an AI and received chemotherapy or endocrine therapy as immediate prior treatment.

The authors in this publication shared findings from Cohort A group of patients, who had received CDK4/6 inhibitor plus an AI as their immediate prior therapy. Cohort A enrolled 127 patients of whom 121 patients had centrally confirmed PIK3CA mutation. Patients in Cohort A received PIQRAY® 300 mg orally once daily along with FASLODEX® 500 mg IM on Day 1 and 15 of cycle 1 followed by Day 1 treatment, of each 28 day cycle thereafter. The median patient age was 58 years. Seventy percent (70%) of patients had received one prior metastatic regimen, none of the patients had received FASLODEX® as a first-line metastatic agent, and 60% of patients had secondary endocrine resistance. The median follow up was 11.7 months. The Primary endpoint was proportion of patients alive without disease progression at 6 months. Secondary end points included Progression Free Survival (PFS), Overall Response Rate (ORR), Overall Survival (OS), and safety.

The Primary endpoint was met and the proportion of patients with confirmed PIK3CA mutation and without disease progression at 6 months was 50.4%. The median PFS was 7.3 months. Among the 121 patients in Cohort A with a confirmed PIK3CA mutation, the response rate, which was all partial responses was 17.4%, and 45.5% achieved stable disease.

Although the BYLieve trial did not have a control group to allow comparing patients in Cohort A to patients receiving other standard therapies, the authors conducted a weighted/matched analysis between the patients in Cohort A of the BYLieve trial and a Real-World similar group of 95 patients with HR+, HER2-negative, PIK3CA-mutated advanced breast cancer, who were treated with standard therapies. The Real-World patient data was obtained from the de-identified clinic-genomic database of Flatiron Health and Foundation Medicine. These 95 patients had received a wide range of regimens, with the most frequent being XELODA® (Capecitabine) monotherapy, FASLODEX® monotherapy, FASLODEX® plus IBRANCE® (Palbociclib), AFINITOR® (Everolimus) plus AROMASIN® (Exemestane), FASLODEX® plus FEMARA® (Letrozole), and IBRANCE® monotherapy.

Unadjusted results showed a median PFS of 7.3 months in BYLieve Cohort A versus 3.6 months in the Real-World cohort. Similar outcomes were noted when data were weighted by odds, propensity score matching, and exact matching.

It was concluded that the BYLieve trial is continuing to show clinically meaningful efficacy with a combination of PIQRAY® and FASLODEX® in HR+, HER2-negative, PIK3CA-mutated advanced breast cancer, post CDK inhibitor treatment, building further on the findings of SOLAR-1 trial. The matched analysis comparing BYLieve with Real-World Data in the post-CDK4/6 inhibitor setting, further supports use of PIQRAY® plus FASLODEX® for this patient group.

Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. Rugo HS, Lerebours F, Ciruelos E, et al. J Clin Oncol 38: 2020 (suppl; abstr 1006).

Overall Survival Benefit with Frontline OPDIVO® plus YERVOY® and Limited Chemotherapy in NSCLC

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SUMMARY: The FDA on May 26, 2020, approved the combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab) and 2 cycles of Platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent Non-Small Cell Lung Cancer (NSCLC), with no Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. 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.

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 by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

In the CheckMate-227, Part 1, Phase III trial, a combination of OPDIVO® plus YERVOY® significantly improved Overall Survival (OS), Progression Free Survival (PFS), Objective Response Rates (ORR) and Duration of Response, compared to chemotherapy, independent of PD-L1 expression level. The authors in this study hypothesized that a limited course of chemotherapy combined with OPDIVO® plus YERVOY® could provide rapid disease control, while building on the durable Overall Survival benefit seen with dual PD-1 and CTLA-4 inhibition.

CheckMate-9LA is a randomized, open-label, multi-center, Phase III trial which evaluated the benefit of a combination of OPDIVO® plus YERVOY®, and 2 cycles of Platinum-doublet chemotherapy versus Platinum-doublet chemotherapy for 4 cycles followed by optional Pemetrexed maintenance therapy, as a first-line treatment in patients with metastatic or recurrent NSCLC, regardless of PD-L1 status and histology. In this study, 719 adults treatment naïve patients with histologically confirmed Stage IV/recurrent NSCLC, with ECOG Performance Status 0-1, and no known sensitizing EGFR/ALK alterations, were randomly assigned 1:1 to receive OPDIVO® 360 mg every 3 weeks plus YERVOY® 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy (N=361), or 4 cycles of platinum-doublet chemotherapy alone (N=358). Chemotherapy was based on histology. Patients with non-squamous NSCLC in the chemo-only randomized group could receive optional Pemetrexed maintenance treatment. Patients were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 years. Patients were stratified by PD-L1 status (less than 1% versus 1% or more), sex, and histology (squamous versus non-squamous). Demographics in treatment groups were well balanced. The Primary end point was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR) and efficacy by PD-L1 subgroups.

At a preplanned interim analysis after a minimum follow up 8.1 months, this trial demonstrated a statistically significant benefit in OS for patients treated with OPDIVO® plus YERVOY® and limited chemotherapy, compared to those who received chemotherapy alone. The median OS was 14.1 months versus 10.7 months, respectively (HR=0.69; P=0.0006). With longer follow up at 12.7 months, this OS benefit continued to improve in the immunotherapy plus chemotherapy group, with a median OS of 15.6 months versus 10.9 months, respectively (HR=0.66). The 1-year OS rates were 63% versus 47%. This clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology.

The median PFS was 6.8 months in the OPDIVO® plus YERVOY® and chemotherapy group and 5 months in the chemotherapy-only group (HR=0.70; P=0.0001). The ORR was 38% and 25%, respectively (P= .0003). The median response duration was 10 months in the OPDIVO® plus YERVOY® and chemotherapy group, and 5.1 months in the chemotherapy-only group. Grade 3-4 treatment related Adverse Events were reported in 47% of the patients receiving the immunotherapy plus chemotherapy combination versus 38% in the chemotherapy-only group.

It was concluded that CheckMate 9LA met its Primary endpoint of Overall Survival, and OPDIVO® plus YERVOY® with a limited course of chemotherapy should be considered as a new first line treatment option for patients advanced Non Small Cell Lung Cancer.

Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. Reck M, Ciuleanu T-E, Dols MC, et al. J Clin Oncol 38: 2020 (suppl; abstr 9501)

Late Breaking Abstract – ASCO 2020: Local Therapy Does Not Extend Survival in Newly Diagnosed Metastatic Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. Approximately 6% of newly diagnosed breast cancer patients present with Stage IV disease. Breast surgery is often not a consideration for patients with metastatic breast cancer. However, breast surgery can be offered for palliation of symptoms, taking into consideration the risks and benefits of such intervention, in a patient with an ulcerated, bleeding, or a fungating tumor mass, that cannot be controlled with systemic therapy. It has been hypothesized based on retrospective analyses, that the addition of surgical resection of the primary tumor in the breast, to systemic therapy, in patients presenting with Stage IV disease, improved survival. Randomized clinical trials however have provided conflicting results.

E2108 is a randomized, Phase III trial which evaluated the benefit of locoregional treatment for the intact primary breast tumor, following initial systemic therapy, in newly diagnosed breast cancer patients presenting with Stage IV disease. In this study, 256 eligible patients with de novo metastatic disease, who did not progress during a 4-8 months period, while on optimal systemic therapy based on patient and tumor characteristics, were randomized to either continue systemic therapy alone (N=131) or combine it with locoregional therapy such as surgery and radiation for the intact primary breast tumor (N = 125). Of the 125 patients who received early locoregional therapy, 109 patients underwent surgery of whom 87 had free margins and 74 patients received locoregional radiation therapy. The Primary endpoint was Overall Survival (OS), and Secondary endpoint was locoregional disease control.

At a median follow up of 59 months, there was no significant difference in Overall Survival (OS) between the optimal systemic therapy plus locoregional therapy compared with optimal systemic therapy alone (3-year OS rate was 68.4% versus 67.9%; HR=1.09; P=0.63). Further, the addition of locoregional therapy to systemic therapy, also failed to improve 3-year Progression Free Survival (P=0.40). There was however significantly higher locoregional recurrence or progression in the systemic therapy alone group compared with the systemic therapy plus locoregional therapy group (3-year rate 25.6% versus 10.2%, P=0.003). Health-related Quality of Life measures such as depression, anxiety and well-being were significantly worse in patients who underwent systemic therapy plus locoregional therapy, compared with systemic therapy alone.

The authors concluded that for patients with a new diagnosis of breast cancer presenting with Stage IV disease, surgery and radiation for the primary breast tumor should not be offered, with the expectation of a survival benefit.

A randomized phase III trial of systemic therapy plus early local therapy versus systemic therapy alone in women with de novo stage IV breast cancer: a trial of the ECOG-ACRIN Research Group (E2108). Khan SA, Zhao F, Solin LJ, et al. J Clin Oncol 38: 2020 (suppl; abstr LBA2)

Late Breaking Abstract – ASCO 2020: FDA Approves BAVENCIO® for Maintenance Treatment in Advanced Urothelial Carcinoma

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SUMMARY: The FDA on June 30, 2020 approved BAVENCIO® for maintenance treatment of patients with locally advanced or metastatic Urothelial Carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. The American Cancer Society estimates that for 2020, about 81,400 new cases of bladder cancer will be diagnosed in the US and about 17,980 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but is less common in women, and the average age at the time of diagnosis is 73. Patients with advanced Urothelial Carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen. Progression Free Survival (PFS) and Overall Survival (OS) however are generally short because of resistance to chemotherapy. Treatment options for patients who progress after Platinum based chemotherapy are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.

BAVENCIO® (Avelumab) is a human, immunoglobulin G1 lambda, PD-L1 targeted monoclonal antibody that binds to PD-L1 and blocks the interaction between PD-L1 and its receptor PD-1. This in turn negates the inhibitory effects of PD-L1 on the immune response by unleashing the immune system and restoring antitumor immune responses. In addition, BAVENCIO® induces Antibody Dependent Cell-mediated Cytotoxicity (ADCC). BAVENCIO® was previously granted an accelerated approval by the FDA in 2017 for the treatment of patients with locally advanced or metastatic Urothelial Carcinoma who have disease progression during or following Platinum-containing chemotherapy.

JAVELIN Bladder 100 study is an international, multicenter, open-label, parallel-arm, randomized Phase III trial, which evaluated BAVENCIO® as maintenance therapy following response or stable disease with first-line Platinum-based chemotherapy, in patients with advanced Urothelial Carcinoma. This study included 700 patients with unresectable locally advanced or metastatic Urothelial Cancer, whose disease did not progress following 4 to 6 cycles of standard Gemcitabine with either Cisplatin or Carboplatin. These patients were randomly assigned 1:1 to receive maintenance BAVENCIO® 10 mg/kg IV every 2 weeks in 4 week cycles plus Best Supportive Care (N=350) or BSC alone (N=350). Best Supportive Care included symptom control and pain management, supportive nutrition, correction of metabolic disorders and antibiotics if indicated. Patients were stratified by best response to first-line chemotherapy (Complete vs Partial Response vs stable disease), and by visceral vs non-visceral disease, when initiating first-line chemotherapy. Across the study population, 51% of patients had tumors that were PD-L1 positive. The Coprimary end points were Overall Survival (OS) in all randomized patients, and in those with PD-L1 positive tumors. Secondary end points included Progression Free Survival (PFS), Objective Response Rate (ORR), and safety. The median follow up was 19.6 months for the BAVENCIO® cohort and 19.2 months for the BSC-alone cohort.

The combination of BAVENCIO® plus BSC significantly prolonged OS, compared with BSC alone, in all randomized patients (HR=0.69; P=0.0005), suggesting a 31% reduction in the risk of death with the addition of  maintenance BAVENCIO®. The median OS was 21.4 months with BAVENCIO® plus BSC compared with 14.3 months with BSC alone. Significantly prolonged OS with BAVENCIO® plus BSC, compared with BSC alone, was also noted among patients with PD-L1 positive tumors, and the median OS was not reached in the BAVENCIO® group versus 17.1 months in the control group (HR=0.56; P=0.0003). The OS benefit with BAVENCIO® was noted across all prespecified subgroups, including those defined by Cisplatin-based or Carboplatin-based chemotherapy, and regardless of whether response or stable disease was reached after first-line induction chemotherapy. Based on blinded Independent Central Review, the median PFS favored the BAVENCIO® group both in the overall randomized population (3.7 months versus 2 months, HR=0.62; P<0.001) as well as in the PD-L1 positive subgroup (HR=0.56). All-grade Adverse Events occurred in 98% of the BAVENCIO® group versus 77.7% of the control group, and grade 3/4 AEs occurred in 47.4% versus 25.2%, respectively.

It was concluded that this study met its primary objective, demonstrating significantly prolonged Overall Survival with first-line maintenance BAVENCIO® plus BSC compared with BSC alone, in all patients with advanced Urothelial Carcinoma, and should therefore be the new first-line standard of care in this patient group.

Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. Powles T, Park SH, Voog E, et al. J Clin Oncol 38: 2020 (suppl; abstr LBA1)

PHESGO®

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The FDA on June 29, 2020 approved a new fixed dose combination of Pertuzumab, Trastuzumab, and Hyaluronidase–zzxf (PHESGO®) for the following indications:

A) Use in combination with chemotherapy as:
1) Neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer
2) Adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.

B) Use in combination with Docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

PHESGO® is a product of Genentech, Inc.