Category: Immuno Oncology

FDA Lowers PD-L1 Expression Threshold for KEYTRUDA® and Expands Indication for Frontline Treatment of NSCLC

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SUMMARY: The FDA on April 11, 2019, approved KEYTRUDA® (Pembrolizumab) for the first-line treatment of patients with Stage III Non-Small Cell Lung Cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, as well as those with metastatic NSCLC. Patients’ tumors must have no EGFR or ALK genomic aberrations and express PD-L1 (Tumor Proportion Score-TPS of 1% or more), as determined by an FDA-approved test. 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 2019 about 228,150 new cases of lung cancer will be diagnosed and 142,670 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.

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. 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®. The FDA approved KEYTRUDA® for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), based on KEYNOTE-024 trial, as well as in combination with Pemetrexed and Carboplatin, as first-line treatment of patients with metastatic non-squamous NSCLC, based on KEYNOTE-021 study. It is also indicated for previously treated advanced NSCLC with a much lower level of PD-L1 expression such as PD-L1 Tumor Proportion Score of 1% or higher, based on KEYNOTE-010 trial.Unleashing-T-Cell-Function-with-PD-1-and-PD-L1-Antibodies

KEYNOTE-042 is a large, international, multicenter, randomized phase III trial in which 1274 patients with untreated locally advanced or metastatic NSCLC were randomly assigned to KEYTRUDA® or chemotherapy with Paclitaxel plus Carboplatin or Pemetrexed plus Carboplatin. In this study, both squamous and non-squamous cancers with PD-L1 Tumor Proportion Score (TPS) of 1% or more were included, but tumors with sensitizing Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) mutations cancers with genetic changes, that could be treated with targeted therapies such as EGFR and ALK inhibitors, were excluded. Eligible patients were randomly assigned in a 1:1 to receive either KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles or investigator’s choice of up to 6 cycles of chemotherapy with Paclitaxel plus Carboplatin or Pemetrexed plus Carboplatin, with optional Pemetrexed maintenance for non-squamous NSCLC. Patients were divided into 3 treatment groups based on their PD-L1 Tumor Proportion Score (TPS): TPS 50% or more (N=599), TPS 20% or more (N=818), and TPS 1% or more (N=637). Each PD-L1 expression group had equal numbers of patients receiving KEYTRUDA® and chemotherapy. The Primary end points were Overall Survival (OS) in patients with TPS 50% or more, 20% or more, and 1% or more.

At a median follow up of 12.8 months, 13.7% of patients were still receiving KEYTRUDA® compared with 4.9% on Pemetrexed maintenance therapy. It was noted that KEYTRUDA® was significantly superior to chemotherapy in all PD-L1 expression subsets. In patients with a PD-L1 TPS 50% or more, the median OS with KEYTRUDA® was 20 months versus 12.2 months for chemotherapy (HR=0.69, P=0.0003), for patients with PD-L1 TPS 20% or more, the median OS was 17.7 months versus 13 months respectively (HR=0.77, P=0.002), and for those with PD-L1 TPS 1% or more, the median OS was 16.7 months versus 12.1 months respectively (HR=0.81, P = 0.0018). The Response Rates (RR) were also higher among patients who received KEYTRUDA®, with RR of 39.5% for KEYTRUDA® versus 32% for chemotherapy in patients with a TPS 50% or more, 33.4% and 28.9% respectively in patients with TPS 20% or more and 27.3% and 26.5%, respectively, among patients with TPS of 1% or more. The duration of response was also superior with KEYTRUDA® in all three PD-L1 subgroups compared to chemotherapy (20.2 months versus 8-11 months). Patients receiving KEYTRUDA® experienced fewer severe Adverse Events, compared with chemotherapy (17.8% versus 41%).

The authors concluded that this is the largest clinical trial of KEYTRUDA® as a stand-alone therapy, and is the first study with a Primary end point of OS to demonstrate superiority of KEYTRUDA® over platinum-based chemotherapy, in patients with previously untreated locally advanced/metastatic NSCLC, without sensitizing EGFR or ALK alterations and a PD-L1 TPS of 1% or more. These data confirmed the benefit of KEYTRUDA® monotherapy as a standard first-line treatment, for PD-L1-expressing locally advanced Stage III as well as metastatic NSCLC. KEYTRUDA® monotherapy is now a new treatment option for more patients with NSCLC, including those for whom combination therapy may not be appropriate. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Mok TS, Wu Y-L, Kudaba I, et al. The Lancet. Published: April 04, 2019. DOI: https://doi.org/10.1016/S0140-6736(18)32409-7

AACR Late-Breaking Research Predicting Response to Anti-PD1/PDL1 Therapy beyond Tumor Mutational Burden

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SUMMARY: Immunotherapy with checkpoint inhibitors such as anti-PD1/PDL1 antibodies, is rapidly moving to the forefront of cancer treatment. These agents include PD1 targeted therapies such as KEYTRUDA® (Pembrolizumab), OPDIVO® (Nivolumab) and LIBTAYO® (Cemiplimab-rwlc) and PDL1 targeted therapies such as TECENTRIQ® (Atezolizumab), IMFINZI® (Durvalumab) and BAVENCIO® (Avelumab). Treatment with checkpoint inhibitors given as a single agent or in combination with chemotherapy has resulted in significant survival benefit in a variety of solid tumors, as well as hematologic malignancies. The efficacy of checkpoint inhibitors however varies considerably across different cancer types. Understanding tumors and their microenvironment and identifying the underlying variables that predict response to anti-PD1/PDL1 antibodies, has been challenging.

Tumor Mutational Burden (TMB) has recently emerged as a potential biomarker for immunotherapy with anti PD-1/PDL1 antibodies. 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. Drawbacks with TMB include sample consumption, higher attrition rate due to sample quality and quantity, and lack of standardization for the different TMB testing assays, with the definition of High TMB varying across studies from 7.4 or more to 20 mutations/megabase.

The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, is a joint effort between the National Cancer Institute and the National Human Genome Research Institute. This program began in 2006 and has molecularly characterized over 20,000 primary cancers and matched normal samples, across 33 different cancer types. After 12 years and contributions from over 11,000 patients, TCGA has deepened our understanding of the molecular basis of cancer, changed the way cancer patients are managed in the clinic, established a rich genomics data resource for the research community and helped advance health and science technologies.

The authors in this study systematically analyzed Whole Exome Sequencing (WES) and RNA sequencing (RNAseq) data of 10,000 patients from the Cancer Genome Atlas, and the Overall Response Rate (ORR) to anti-PD1/PDL1 therapy of 21 different cancer types obtained from previous clinical trials. The researchers took into consideration more than 30 different variables belonging to three distinct classes: a) those associated with tumor neoantigen landscape (Tumor Mutational Burden-TMB) b) tumor microenvironment and inflammation, and c) the checkpoint inhibitor targets (PD1/PDL1). The performance of each of these variables and their combinations was then evaluated in predicting the ORR to anti-PD1/PDL1 therapy.

It was noted that the most important predictor of response to anti-PD1/PDL1 therapy across cancer types was CD8+ T-cell abundance in the tumor microenvironment, followed by the Tumor Mutational Burden, and a high PD1 gene expression in each cancer type in a fraction of samples. These three top predictors encompassed the three distinct classes considered in this analysis, and their combination was highly predictive of the ORR to anti-PD1/PDL1 therapy, and was able to explain more than 80% of the variance observed across different tumor types.

The authors concluded that in this first systemic evaluation of the different variables associated with PD1/PDL1 therapy response across different tumor types, the three top predictors mentioned above can explain most of the observed cross-cancer response variability. Combining tumor mutational burden, CD8+ T-cell abundance and PD1 mRNA expression accurately predicts response to anti-PD1/PDL1 therapy across cancers. Lee JS and Ruppin E. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA.LB-017/9

Immune Checkpoint Inhibitor Combination Efficacious in High-Grade Neuroendocrine Tumors

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SUMMARY: It is estimated that in the United States, more than 12,000 people are diagnosed with a Neuroendocrine tumor each year. NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. The most common type of malignant gastrointestinal NETs originate in the midgut (jejunoileum and the proximal colon) and often metastasize to the mesentery, peritoneum and liver. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis.

OPDIVO® (Nivolumab) 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, whereas YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Immune checkpoint blockade with monoclonal antibodies such as OPDIVO® and YERVOY® has revolutionized the treatment of multiple cancers. Previously published studies have demonstrated successful patient outcomes across various tumor types, when treated with a combination of CTLA-4 and PD-1 inhibitors. However, it has remained unclear whether these agents can benefit those with rare, metastatic solid tumors. The investigators therefore launched the DART trial to fulfill this unmet need.

SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) is the first NCI-funded prospective, open-label, rare tumor immunotherapy basket study. Basket trials involve single treatment and single biomarker, different histologies, placed in multiple groups or baskets. These trials are an efficient way for screening experimental therapeutics across multiple patient populations.

In this phase II trial which included 37 different types of rare tumors, patients received YERVOY® 1 mg/kg IV every 6 weeks along with OPDIVO® 240 mg IV every 2 weeks. The Primary endpoint was Overall Response Rate (ORR) and Secondary endpoints included Progression Free Survival (PFS), Overall Survival (OS), Stable disease more than 6 months, and toxicity. This publication included a cohort of 33 eligible patients with Neuroendocrine tumors. Pancreatic Neuroendocrine tumors are currently being evaluated in a separate cohort within the trial. More than half of the patients (58%) had high-grade disease, and the most common tumor sites were gastrointestinal-non pancreatic (45%) and lung (18%). Enrolled patients had received a median of 2 prior lines of therapy.

The Overall Response Rate was 24% with 3% Complete Responses and 21% Partial Responses. Patients with high-grade Neuroendocrine cancer had a 42% Response Rate, whereas the Response Rate was 0% in low/intermediate grade tumors (P=0.01), independent of primary site. The authors hypothesized that the high response rate among those with high-grade Neuroendocrine carcinomas may be related to a higher Tumor Mutational Burden, which is an indicator of better response to immunotherapy. The 6-month PFS was 30% and the median OS was 11 months (historically, it has been around 10% and 3 months respectively). The most common toxicities were fatigue (30% of patients) and nausea (27%) and the most common grade 3/4 immune-related Adverse Events were ALT elevation in 9% of patients.

It was concluded that YERVOY® plus OPDIVO® combination was well tolerated with a 42% ORR in patients with high-grade Neuroendocrine cancer, regardless of primary site. The authors based on this study pointed out that, clinical trials are feasible even in rare tumors. A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort. Patel SP, Othus M, Chae YK, et al. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA.

FDA Approves TECENTRIQ® and ABRAXANE® Combination for Advanced Triple Negative Breast Cancer

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SUMMARY: The FDA on March 8, 2019 granted accelerated approval to TECENTRIQ® (Atezolizumab) in combination with ABRAXANE® (Paclitaxel protein-bound) for adult patients with unresectable locally advanced or metastatic Triple Negative Breast Cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering 1% or more of the tumor area), as determined by an FDA-approved test. The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for TECENTRIQ®. 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. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. Those who do not achieve a pathological Complete Response tend to have a poor prognosis. It therefore appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that tumor-infiltrating lymphocytes were associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

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, and thus enabling the activation of T cells. Single-agent TECENTRIQ® is presently approved for the treatment of metastatic Urothelial carcinoma and Non Small Cell Lung Cancer (NSCLC). TECENTRIQ® has also been shown to have clinical activity with acceptable safety profile in patients with other solid tumors including Triple Negative Breast Cancer. The premise for combining chemotherapy with immune checkpoint inhibitors is that chemotherapy may enhance release of tumor antigens and antitumor responses to immune checkpoint inhibition. Taxanes in particular may additionally activate toll-like receptor activity and promote dendritic-cell activity. ABRAXANE® (Nanoparticle Albumin-Bound – nab Paclitaxel) was selected as a chemotherapy partner in the present study because at the time that this trial was designed, the glucocorticoid premedication that is required with solvent-based Paclitaxel (TAXOL®), had been hypothesized to affect immunotherapy activity.

IMpassion130 is an international, randomized, double-blind, placebo-controlled phase III trial in which first-line treatment with TECENTRIQ® plus ABRAXANE®, was compared with placebo plus ABRAXANE®, in patients with locally advanced or metastatic Triple Negative Breast Cancer. Patients with untreated metastatic Triple Negative Breast Cancer (N=902) were randomly assigned in a 1:1 ratio and received TECENTRIQ® 840 mg IV or placebo on days 1 and 15 and ABRAXANE® 100 mg/m2 IV on days 1, 8, and 15 of every 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Stratification factors included presence or absence of liver metastases, use or non-use of neoadjuvant or adjuvant taxane treatment, and PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area (less than 1% was considered PD-L1 negative versus1% or more considered PD-L1 positive) according to ImmunoHistochemical testing (IHC). Both treatment groups were well balanced. Approximately 40% of the patients were PD-L1 positive. The two Primary end points were Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 12.9 months, the median PFS in the intent-to-treat population was 7.2 months with TECENTRIQ® plus ABRAXANE®, as compared with 5.5 months with placebo plus ABRAXANE® (HR=0.80; P=0.002). This suggested a 20% improvement in PFS with the TECENTRIQ® combination. At the time of the first interim analysis, the median overall survival was 21.3 months in the TECENTRIQ® plus ABRAXANE® group and 17.6 months in the placebo plus ABRAXANE® group (HR for death=0.84; P=0.08). The Objective Response Rate (ORR) in the intent-to-treat population was 56% in the TECENTRIQ® and ABRAXANE® group versus 45.9% in the placebo plus ABRAXANE® group.

Among patients with PD-L1–positive tumors, the benefit was even more significant. The addition of TECENTRIQ® improved PFS by 38% (HR=0.62; P<0.001) and similar benefit was noted in the OS, with a median OS of 25 months with the TECENTRIQ® combination and 15.5 months with placebo plus ABRAXANE® (HR=0.62). Grade 3 or 4 adverse events were 48.7% in the TECENTRIQ® and ABRAXANE® and 42.2% in the placebo plus ABRAXANE® group.

It was concluded that TECENTRIQ® plus ABRAXANE® significantly prolonged Progression Free Survival among patients with metastatic Triple Negative Breast Cancer in both the intent-to-treat population and the PD-L1 positive subgroup, and could potentially change how we manage patients with Triple Negative Breast Cancer. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. Schmid P, Adams S, Rugo HS, et al. N Engl J Med 2018; 379:2108-2121

FDA Approves KEYTRUDA® for Adjuvant Treatment of Melanoma

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SUMMARY: The FDA on February 15, 2019, approved KEYTRUDA® (Pembrolizumab) for the adjuvant treatment of patients with Melanoma with involvement of lymph node(s) following complete resection. It is estimated that in the US, approximately 96,480 new cases of Melanoma will be diagnosed in 2019 and about 7,230 patients are expected to die of the disease. The incidence of Melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage Melanoma, with a 5-year survival rate of 98% for stage I disease and 90% for stage II disease. Stage III malignant Melanoma however is a heterogeneous disease, and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78% whereas those patients with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively. Several agents are presently approved by the FDA for the adjuvant treatment of high-risk Melanoma and they include YERVOY® (Ipilimumab), OPDIVO® (Nivolumab), TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) for BRAF-mutant Melanoma and Interferon alfa. Unleashing-T-Cell-Function-with-Combination-Immunotherapy

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. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

The present FDA approval was based on the European Organization for Research and Treatment of Cancer (EORTC) 1325/(KEYNOTE-054) trial which is a randomized, double-blind, placebo-controlled Phase III study which involved high-risk patient population of patients with Stage III Melanoma. This study included 1019 patients with completely resected, Stage IIIA (more than 1 mm lymph node metastasis), IIIB or IIIC Melanoma. Patients were randomly assigned 1:1 to receive KEYTRUDA® 200 mg IV every three weeks (N=514) or placebo (N=505), as adjuvant therapy, for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxicity. Enrolled patients required complete resection of Melanoma with negative margins and lymph node dissection. Patients with mucosal or ocular Melanoma were excluded. The Primary end points were Recurrence-Free Survival (RFS) in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-L1, as well as Safety.

At a median follow up of 15 months, KEYTRUDA® was associated with significantly longer Recurrence-Free Survival (RFS) compared to placebo in the overall intent-to-treat population, with a 1-year RFS rate of 75.4% versus 61.0% respectively (HR for recurrence or death=0.57; P<0.001). This suggested that the risk of recurrence or death in the total population was 43% lower in the KEYTRUDA® group than in the placebo group. Patients receiving KEYTRUDA® experienced fewer recurrences/deaths, 26% compared with 43% in the placebo group. The RFS benefit with KEYTRUDA® compared with placebo was observed regardless of tumor PD-L1 expression. In the subgroup of 853 patients with PD-L1-positive tumors, the 1-year RFS rate was 77.1% in the KEYTRUDA® group and 62.6% in the placebo group (HR=0.54; P<0.001). This suggested that the risk was 46% lower in the KEYTRUDA® group than in the placebo group, among patients with PD-L1-positive tumors. KEYTRUDA® was also consistently effective in patients with PD-L1-negative tumors and in those with undetermined tumor PD-L1 expression The Median RFS was 20.4 months in the placebo arm and not reached for those receiving KEYTRUDA®. The most common adverse reactions were rash, asthenia, influenza-like illness, diarrhea, pruritus, nausea, arthralgia and hypothyroidism.

It was concluded that KEYTRUDA® as adjuvant therapy for high-risk Stage III Melanoma, resulted in significantly longer Recurrence-Free Survival than placebo, with no new toxic effects identified. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. Eggermont AM, Blank CU, Mandala M, et al. N Engl J Med 2018;378:1789-1801

Late Breaking Abstract – ESMO 2018 Frontline KEYTRUDA® Improves Overall Survival in Advanced Head and Neck Cancer

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SUMMARY: The American Cancer Society estimates that 65,410 people will be diagnosed with Head and Neck cancer in 2019 and 14,620 patients will die of the disease. Patients with Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck have a poor prognosis with a short median Overall Survival. The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of Immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the Immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, 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.

KEYNOTE-048 is an open-label, three arm, randomized, phase III trial, in which KEYTRUDA® monotherapy and KEYTRUDA® plus chemotherapy was compared to ERBITUX® (Cetuximab) plus chemotherapy, as first-line systemic therapy, among patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. A total 882 patients were randomized in a 1:1:1 ratio to receive either KEYTRUDA® 200 mg IV every 3 weeks for 24 months (N=301), KEYTRUDA® 200 mg IV every 3 weeks for 24 months plus Cisplatin 100 mg/m2 IV or Carboplatin AUC 5 IV (investigator’s choice) on day 1, along with 5-FU 1,000 mg/m2/day IV, days 1-4 of each 3-week cycle, for a maximum of 6 cycles (N=281) or the control arm (EXTREME) consisting of ERBITUX® 400 mg/m2 loading dose followed by 250 mg/m2 weekly, plus Cisplatin 100 mg/m2 or Carboplatin AUC 5 IV on day 1 along with 5-FU 1000 mg/m2/day IV, days 1-4 of each 3-week cycle, for a maximum of 6 cycles (N=300).

Enrolled patients had Recurrent or Metatastic Squamous Cell Carcinoma of the Oral cavity, Oropharynx, Hypopharynx or Larynx, and had not received prior systemic therapy for their recurrent or metastatic disease. Patients were stratified by PD-L1 expression, HPV p16 status, and ECOG Performance Status. PD-L1 expression was measured using the Combined Positive Score (CPS) and Tumor Proportion Score and a CPS of 20 or more indicated high PD-L1 expression, whereas a CPS of 1 or more was the lower threshold of positivity. (CPS measures high PD-L1 expression in the tumor and surrounding immune cells, whereas TPS only captures PD-L1 expression on tumor cells). Approximately 21% of patients were positive for Human Papillomavirus Virus (HPV) p16.

In this analysis, the authors compared the outcomes with KEYTRUDA® alone versus EXTREME (ERBITUX® plus chemo combination) in patients stratified for PD-L1 expression as well as KEYTRUDA® plus chemotherapy versus ERBITUX® plus chemotherapy in all patients with any PD-L1 status. The Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) in patients with a PD-L1 CPS of 20 or more and CPS of 1 or more in all enrolled patients. The Secondary endpoints of the study were PFS at 6 months and 12 months, Objective Response Rate (ORR), and time to deterioration in Quality of Life. The minimum follow up was about 17 months.

It was noted that in patients with PD-L1 CPS of 20 or more (high expressors, N=255), single agent KEYTRUDA® was superior to ERBITUX® combination, with a median OS of 14.9 months in patients who received single agent KEYTRUDA® versus 10.7 months in patients who received ERBITUX® with combination chemotherapy (HR=0.61; P=0.0007). There was however no difference in PFS in this PD-L1 subset between the 2 treatment groups (HR=0.99; P=0.5). Similar benefit was seen for patients with a PD-L1 CPS of 1 or more subset (low expressors, N= 512), in which the median OS for KEYTRUDA® monotherapy versus ERBITUX® plus chemotherapy was 12.3 months versus 10.3 months respectively (HR=0.78; P=0.0086). The OS for KEYTRUDA® monotherapy was noninferior to ERBITUX® plus chemotherapy in the total population of patients (N=601). The ORRs were 23% and 36%, with single agent KEYTRUDA® and ERBITUX® combination respectively, in the high expressor subgroup and 19% and 35%, respectively in the low expressor subgroup. However, the median Duration of Response was almost 5 times longer with KEYTRUDA® monotherapy compared to ERBITUX® combination.

When KEYTRUDA® plus chemotherapy was compared with ERBITUX® plus chemotherapy, KEYTRUDA® combination was non-inferior and in fact was superior to ERBITUX® combination for OS in the total population (N = 559), with a median OS of 13.0 versus 10.7 months respectively (HR=0.77; P=0.0034).

It was concluded that among patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma, KEYTRUDA® monotherapy significantly improved Overall Survival compared to ERBITUX® plus chemotherapy in patients with PD-L1 Combined Positive Score of 1 or more. Additionally, KEYTRUDA® plus chemotherapy significantly improved Overall Survival in the total patient population, compared to ERBITUX® plus chemotherapy. Responses associated with single agent KEYTRUDA® and KEYTRUDA® chemotherapy combination, were durable. These data support KEYTRUDA®, as well as KEYTRUDA® plus platinum and 5-FU as the new first-line standards of care for this patient group. KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Burtness B, Harrington KJ, Greil R, et al. Proceedings from the 2018 ESMO Congress: October 19-23, 2018; Munich, Germany. Abstract LBA8_PR.

Late Breaking Abstract – ESMO 2018 First Line BAVENCIO® plus INLYTA® Highly Effective in Advanced Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 73,820 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2019 and about 14,770 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is significant unmet need for improved therapies for this disease. SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/ smooth vessel cell wall and is capable of specifically binding to tyrosine kinases, inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® is the standard first-line intervention for treatment naïve patients with advanced RCC. In a large, multi-center, randomized, phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.International-Metastatic-RCC-Database-Consortium-(IMDC)

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 receptors 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). INLYTA® (Axitinib) is a kinase inhibitor and inhibits receptor tyrosine kinases including Vascular Endothelial Growth Factor Receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. These receptors have been implicated in pathologic angiogenesis, tumor growth, and cancer progression. INLYTA® is approved by the FDA for the treatment of advanced Renal Cell Carcinoma (RCC) after failure of one prior systemic therapy. The rationale behind combining these two agents was that BAVENCIO® stimulates the immune system while INLYTA® inhibits tumor neoangiogenesis by preventing VEGF activity. Preclinical data suggested that combining these two agents is effective, as their mechanisms of action complement each other. A combination of BAVENCIO® and INLYTA® also showed encouraging antitumor activity among patients with advanced RCC in a phase 1b trial.Unleashing-T-Cell-Function-with-PD-1-and-PD-L1-Antibodies

JAVELIN Renal 101 is a global, randomized phase III trial in which 886 patients with clear cell advanced Renal Cell Carcinoma who had no prior systemic therapy, were randomly assigned in a 1:1 to receive BAVENCIO® 10 mg/kg IV every 2 weeks along with INLYTA® 5 mg orally twice daily, in 6 week cycles (N=442) or SUTENT® 50 mg orally daily, 4 weeks on followed by 2 weeks off (N=444). This study included all MSKCC (Memorial Sloan Kettering Cancer Center) prognostic subgroups (good, intermediate, and poor risk). According to the IMDC (International Metastatic RCC Database Consortium), 21% were in the favorable risk group, 62% were in the Intermediate risk group and 16% were in the poor risk group. Among the enrolled patients, 63.2% (N=560) patients were PD-L1positive (1% or more positive immune cells) of whom 270 patients received the BAVENCIO® and INLYTA® combination whereas 290 patients received SUTENT®. The Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) in the PD-L1 positive group and Secondary endpoints included PFS and OS irrespective of PD-L1 expression, Objective Response Rate (ORR) and Safety.

It was noted that in the patient group with PD-L1 positive tumors, the median PFS was 13.8 months in the combination group compared to 7.2 months in the single agent SUTENT® group (HR=0.61; P<0.0001). The median PFS in patients irrespective of PD-L1 expression was 13.8 months with the combination treatment compared to 8.4 months with SUTENT® (HR=0.69; P=0.0001). The confirmed Objective Response Rate (ORR) among those with PD-L1 positive tumors was 55.2% in the combination group and 25.5% in the SUTENT® group. The benefit with combination treatment was noted in all prognostic risk groups. The OS data were immature at the time of data cutoff. Grade 3 or more treatment related adverse events were similar in both treatment groups and led to discontinuation of drug in 22.8% of patients in the combination group versus 13.4% in the SUTENT® group.

It was concluded that a combination of BAVENCIO® given along with INLYTA® significantly improved Progression Free Survival as well as Objective Response Rate, irrespective of PD-L1 expression, and across all prognostic risk groups. The authors added that these results support this combination as a potential new first line standard of care for patients with advanced Renal Cell Carcinoma. JAVELIN Renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). Motzer RJ, Penkov K, Hannen JBAG, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA6_PR.