First Line KEYTRUDA® plus Chemotherapy Improves Overall Survival in Advanced Squamous NSCLC

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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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 Non Small Cell Lung Cancer (NSCLC), approximately 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas, and 10% are Large cell carcinomas. Non Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, and less than 15% of patients with advanced Squamous NSCLC survive a year after diagnosis and less than 5% of patients survive for five years or longer.

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. The FDA approved KEYTRUDA® for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), as well as in combination with Pemetrexed and Carboplatin, as first-line treatment of patients with metastatic nonsquamous NSCLC and for previously treated advanced NSCLC with a PD-L1 Tumor Proportion Score of 1% or more. Currently, KEYTRUDA® currently is the only FDA approved immunotherapy for initial treatment of NSCLC as monotherapy (KEYNOTE-024) or in combination with chemotherapy (KEYNOTE-189).Unleashing-T-Cell-Function-with-Combination-Immunotherapy

KEYNOTE-407 is a global, double-blind, placebo-controlled, phase 3 trial which compared KEYTRUDA® plus chemotherapy with placebo plus chemotherapy in patients with squamous NSCLC of any level of PD-L1 expression. In this study, 559 patients with untreated metastatic, squamous NSCLC were randomly assigned, in a 1:1 ratio to receive KEYTRUDA® 200 mg IV along with Carboplatin AUC 6 and either TAXOL® (Paclitaxel) 200 mg/m2 IV or ABRAXANE® (nab-paclitaxel) 100 mg/m2 IV days 1, 8 and 15. every 3 weeks for 4 cycles (N=278) or placebo with the same chemotherapy regimen for 4 cycles (N=281). Patients in the experimental arm following the first 4 cycles continued KEYTRUDA® every 3 weeks, for an additional 31 cycles, whereas the control group received placebo. Patients in the placebo-combination group were eligible to cross over to receive KEYTRUDA® monotherapy and 42.8% of patients assigned to the placebo plus chemotherapy group who discontinued chemotherapy went on to receive subsequent anti PD-1 or anti PD-L1 therapy and 75 patients received KEYTRUDA® monotherapy as part of in-study crossover. Patients were stratified according to the PD-L1 Tumor Proportion Score (1% or less versus more than 1%), choice of Taxane (Paclitaxel versus nab-Paclitaxel), and geographic region of enrollment. Tumor Proportion Score is the percentage of tumor cells with membranous PD-L1 staining, with less than 1% indicating PD-L1 negative score. Both treatment groups were well balanced. The co-Primary end points were Overall Survival and Progression Free Survival and the Secondary end points included Response Rate, Duration of Response and Safety. The effects of PD-L1 expression on Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR) were prespecified exploratory end points.

At the second interim analysis, after a median follow-up of 7.8 months, the median Overall Survival was 15.9 months in the KEYTRUDA® combination group and 11.3 months in the placebo combination group (HR=0.64; P<0.001). This meant that there was a 36% reduction in the risk of death with the addition of KEYTRUDA® to chemotherapy. This OS benefit was consistently seen regardless of the level of PD-L1 expression. The median PFS was 6.4 months in the KEYTRUDA® combination group and 4.8 months in the placebo combination group (HR=0.56; P<0.001) and this suggested that the risk of disease progression or death was 44% lower with the addition of KEYTRUDA® to chemotherapy. The PFS benefit with the addition of KEYTRUDA® to chemotherapy was observed in all prespecified subgroups with incremental improvements noted with increasing PD-L1 Tumor Proportion Score. The Objective Response Rate was also significantly higher in the KEYTRUDA® chemotherapy group compared to the placebo chemotherapy group (59.4% versus 38%; P=0.0004), with a median time to response of 1.4 months and median Duration of Response of 7.7 months versus 4.8 months, respectively. Grade 3 or higher adverse events were similar in both treatment groups. Treatment discontinuation due to adverse events was more frequent in the KEYTRUDA® combination group (13.3% versus 6.4%).

It was concluded that inpatients with previously untreated metastatic, squamous NSCLC, the addition of KEYTRUDA® to chemotherapy resulted in significantly longer Overall Survival and Progression Free Survival than chemotherapy alone, and should become a new standard of care for squamous NSCLC. Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer. Paz-Ares L, Luft A, Vicente D, et al. for the KEYNOTE-407 Investigators. September 25, 2018. DOI: 10.1056/NEJMoa1810865

VIZIMPRO® (Dacomitinib)

The FDA on September 27, 2018 approved VIZIMPRO® for the first-line treatment of patients with metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations, as detected by an FDA-approved test. VIZIMPRO® is aproduct of Pfizer Pharmaceutical Company.

Hyperprogressive Disease after Immunotherapy in Advanced Non-Small Cell Lung Cancer

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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Immunotherapy with PD-1 (Programmed cell Death 1) and PD-L1 (Programmed cell Death Ligand 1) inhibitors have demonstrated a clear survival benefit both as a single agent or in combination, compared with standard chemotherapy, in both treatment-naive and previously treated patients for advanced Non Small Cell Lung Cancer (NSCLC). Immuno-Oncology therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation and a therapeutic response.

Recent reports of an acceleration of tumor growth during immunotherapy, defined as HyperProgressive Disease (HPD), has been observed in 9% of advanced malignancies and in 29% of patients with Head and Neck cancer treated with PD-1/PD-L1 inhibitors. It has been postulated that high level of interferon gamma (IFN-gamma) usually released by PD-1 blockade may have detrimental effects on immunity. Alternatively PD-1/PD-L1 blockade may upregulate Interleukin 6, Interleukin 17, and neutrophil axis, generating a potent aberrant inflammation, responsible for immune escape and accelerated growth.

HyperProgressive Disease should be differentiated from Pseudoprogression. The later  is defined as progressive disease, followed by Complete Response and/or Partial Response or Stable Disease longer than 6 months. The Tumor Growth Rate (TGR) estimates the increase in tumor volume over time based on two Computed Tomography (CT) scan measurements. TGR can be used to quantitatively assess tumor dynamics and kinetics during treatment and can be specifically applied to identify the subset of patients experiencing HPD.

This study was conducted to investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. This multicenter, retrospective study included 406 consecutive eligible patients with confirmed Stage III or IV NSCLC treated with PD-1/PD-L1 inhibitors such as OPDIVO® (Nivolumab), KEYTRUDA® (Pembrolizumab), TECENTRIQ® (Atezolizumab), or IMFINZI® (Durvalumab) as monotherapy in second or later line treatment, at eight French institutions between November 2012 and April 2017. The control cohort included equivalent data collected on 59 eligible patients with advanced NSCLC, who had failed a Platinum-based regimen and received single-agent chemotherapy (Taxanes, Pemetrexed, Vinorelbine , or Gemcitabine) in 4 French institutions from August 2011, to June 2016. The median age was 50 years, over 70% of the patients had nonsquamous histology and approximately 20% of the patients had PD-L1 positive status (1% or more by IHC) confirmed. The median followup was 12.1 months. Measurable disease (defined by Response Evaluation Criteria in Solid Tumors – RECIST version 1.1) on at least two CT scans before treatment and one CT scan during treatment, was required. HyperProgressive Disease (HPD) was defined as disease progression on the first CT scan during treatment with an absolute increase in Tumor Growth Rate exceeding 50%. The Primary end point was assessment of the HyperProgressive Disease rate in patients treated with Immunotherapy or chemotherapy.

Among those treated with PD-1/PD-L1 inhibitors, HyperProgressive Disease was noted in 13.8% of patients. HPD was significantly associated with more than two metastatic sites prior to treatment with PD-1/PD-L1 inhibitors, compared with those without HPD (62.5% versus 42.6%; P=0.006). However, baseline tumor burden and number of previous lines of therapy did not make a significant difference. Patients experiencing HPD within the first 6 weeks of beginning PD-1/PD-L1 inhibitor therapy had significantly lower median Overall Survival compared with those with progressive disease without HyperProgression at the first evaluation (3.4 months versus 6.2 months; HR=2.18; P=0.003). Pseudoprogression was observed in 4.7% patients.

Among patients treated with single-agent chemotherapy, only 5.1% were classified as having HyperProgressive Disease and the median Overall Survival was 4.5 months in those with HPD and 3.9 months in other patients with progressive disease without HyperProgression at the first evaluation (P=0.60).

The authors concluded that HyperProgressive Disease is more common with PD-1/PD-L1 inhibitors compared with chemotherapy, among previously treated patients with advanced NSCLC, and is also associated with high number of metastatic sites at baseline and poor survival. They added that the present study is the largest analysis exploring HPD to date and is the first conducted, in a dedicated NSCLC population, with a control cohort of chemotherapy-treated patients Hyperprogressive Disease in Patients With Advanced Non–Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy. Ferrara R, Mezquita L, Texier M, et al. JAMA Oncol. Published online September 6, 2018. doi:10.1001/jamaoncol.2018.3676

KEYTRUDA® (Pembrolizumab)

The FDA on August 20, 2018 approved KEYTRUDA® in combination with ALIMTA® (Pemetrexed) and Platinum as first-line treatment of patients with metastatic, Non-Squamous Non-Small Cell Lung Cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA® is a product of Merck & Co., Inc.

Tumor Mutation Burden is a Predictive Biomarker for Response to Immune Checkpoint Inhibitors

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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Patients with advanced NSCLC (Non-Small Cell Lung Cancer) often receive either platinum-doublet chemotherapy combination as first line therapy or KEYTRUDA® (Pembrolizumab) if the tumor PD-L1 expression is 50% or more. About 20-25% of patients benefit from immunotherapy. Other biomarkers besides PD-L1 are needed, to select appropriate patients for immunotherapy.

Tumor Mutational Burden (TMB) has recently emerged as a potential biomarker for immunotherapy with anti PD-1 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. In a previously published trial (CheckMate 568), patients most likely to have a response to a combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab), irrespective of tumor PD-L1 expression level in NSCLC, had a TMB of at least 10 mutations per megabase. This was the basis for CheckMate 227, which evaluated the efficacy of OPDIVO® and OPDIVO®-based regimens, as first line treatment in biomarker-selected groups of patients with advanced NSCLC.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

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, whereas YERVOY® 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. The complementary mechanisms of action of OPDIVO® and YERVOY® combination resulted in greater efficacy in phase I trials, compared with OPDIVO® monotherapy.

CheckMate 227 is a three part, open-label, randomized, phase III trial, designed to compare different OPDIVO® -based regimens with chemotherapy in distinct patient populations. This study enrolled 1,739 patients with previously untreated Stage IV or recurrent NSCLC with no known sensitizing EGFR or ALK mutations and patients were randomized in a 1:1:1 ratio and the comparison was between either OPDIVO®, OPDIVO® plus YERVOY® or OPDIVO® plus platinum-doublet chemotherapy and platinum-doublet chemotherapy alone. Patients were stratified according to tumor histology and PD-L1 expression of 1% or more (positive) or less than 1% (negative). The study incorporated Tumor Mutational Burden (TMB) as a biomarker. This was determined by the FoundationOne CDx assay, an FDA approved test for molecular profiling, using the validated cutoff of TMB of 10 or more mutations/megabase as High, and less than 10 mutations/megabase as Low.

The authors in this publication reported data from part 1 of this study, which was a comparison between OPDIVO® plus YERVOY® versus chemotherapy, in patients with previously untreated Stage IV or recurrent NSCLC. In this comparison, 139 TMB-High patients were treated with OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks, whereas 160 TMB-High patients received chemotherapy, based on tumor histology. All treatments were continued until disease progression or unacceptable toxicity. Part 1 of the study had two Coprimary end points. One Coprimary end point was Progression Free Survival (PFS) with OPDIVO® plus YERVOY® versus chemotherapy in a patient population selected on the basis of TMB. The other Coprimary end point was Overall Survival (OS) with OPDIVO® plus YERVOY® versus chemotherapy in a patient population selected on the basis of the PD-L1 expression level.

It was noted that the PFS among patients with High TMB was significantly longer with OPDIVO® plus YERVOY®, compared with chemotherapy. The median PFS with the immunotherapy combination was 7.2 months compared to 5.5 months with chemotherapy (HR=0.58; P<0.001). This represented a 42% reduction in the risk of disease progression or death. The 1 year PFS more than tripled with combination immunotherapy at 42.6% versus 13.2% with chemotherapy. The Objective Response Rate (ORR) was 45.3% with immunotherapy combination and 26.9% with chemotherapy. The improved outcomes with OPDIVO® plus YERVOY® over chemotherapy was broadly consistent within all subgroups and was independent of tumor histology and PD-L1 expression. There was a clear trend toward improved survival with the immunotherapy combination although this data is immature. Grade 3 or 4 treatment related adverse events were 31.2% with immunotherapy combination and 36.1% with chemotherapy.

The authors concluded that this is the first phase III study to evaluate Tumor Mutational Burden as a predictive biomarker for immunotherapy as a coprimary endpoint. They added that these results highlight that Tumor Mutational Burden and PD-L1 are independent biomarkers and TMB is predictive of benefit with OPDIVO® plus YERVOY® irrespective of PD-L1 expression. TMB-High therefore is a new biomarker and represents a distinct subgroup of NSCLC. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. N Engl J Med 2018; 378:2093-2104

First Line TECENTRIQ® plus Chemotherapy in Advanced Squamous NSCLC

Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and 30% are Squamous Cell Carcinomas (SCC). Non Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, and less than 15% of patients with advanced Squamous NSCLC survive a year after diagnosis and less than 5% of patients survive for five years or longer. IMpower131 is a multicenter, open-label, phase III study, in which 1021 chemotherapy-naïve patients with stage IV Squamous NSCLC received TECENTRIQ® ((Atezolizumab)) along with Carboplatin, and Paclitaxel, TECENTRIQ® along with Carboplatin, and ABRAXANE® (nab-paclitaxel) or Carboplatin and ABRAXANE® (control group). The addition of  TECENTRIQ® to chemotherapy significantly improved median Progression Free Survival across all PD-L1 subgroups. This is the first phase III trial of an immunotherapy-based treatment regimen, to demonstrate a significant improvement in Progression Free Survival, in advanced Squamous NSCLC.

Late Breaking Abstract – ASCO 2018 Blood Test Demonstrates High Specificity for Detection of Early Stage Lung Cancer

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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Survival rates however are significantly higher when lung cancer is diagnosed early. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas, and 10% are Large cell carcinomas.

Although the U.S. Preventive Services Task Force (USPSTF) has recommended annual screening for lung cancer with Low-Dose Computed Tomography (LDCT) for individuals with significant smoking history, screening is vastly underutilized, with a screening rate of less than 2% among smokers eligible for screening. Screening for lung cancer using a peripheral blood sample may improve lung cancer screening rates. Analysis of cell-free DNA (cfDNA) from peripheral blood (Liquid Biopsy), is presently approved to select EGFR targeted therapies (cobas EGFR mutation test), in patients with advanced Non Small Cell Lung Cancer. However, the role of cell-free DNA analysis for early detection of lung cancer is not well established.

The Circulating Cell-Free Genome Atlas (CCGA) is a prospective, multi-center, observational study and is the largest study ever initiated, to develop a noninvasive, liquid biopsy assay for early cancer detection, based on cell-free DNA (cfDNA). This study has currently enrolled 10,012 of a planned 15,000 participants, including people with a recent cancer diagnosis and also a control group of individuals with no known malignancy (70% with cancer, 30% without cancer), across 141 sites in the United States and Canada. This report is one of the first pre-planned sub-studies from the CCGA, involving investigation of blood samples from 1,627 participants (878 patients with newly diagnosed untreated cancer including 127 patients with lung cancer and 749 controls – 580 controls and 169 technical assay controls ), across 20 tumor types and all clinical stages.

The cell-free DNA was isolated from the peripheral blood and analyzed using the following three sequencing methods that were designed to detect cancer-defining signals (mutations and other genomic changes), that could be utilized for early cancer detection.

Targeted sequencing to detect somatic (non-inherited) mutations, such as Single Nucleotide Variants and small insertions and/or deletions, in specific sections of the genome.

Whole-Genome Sequencing (WGS) to detect somatic gene copy number changes across the genome.

Whole-Genome Bisulfite Sequencing (WGBS) of cfDNA to detect abnormal patterns of cfDNA methylation (epigenetic changes)

In this initial sub-study, the authors explored the ability of the above three different assays to detect cancer in 127 people with stage I-IV lung cancer. It was noted that biologic signals suggesting lung cancer were detected and comparable across all assays, and the signal increased with cancer stage. At 98% specificity, the Targeted sequencing detected 51% of early-stage (stage I-IIIA) lung cancers and 89% of late-stage (stage IIIB-IV) lung cancers. Whole-Genome Sequencing detected 38% of early-stage cancers and 87% of late-stage cancers. Whole-Genome Bisulfite Sequencing had similar efficacy, detecting 41% of early stage lung cancers and 89% of late-stage cancers. Similar sensitivities were noted across all assays for adenocarcinoma, squamous cell and small cell lung cancer. False positive rates were low. Of the 580 control participants without cancer at study enrollment, less than 1% (five participants) had cancer-like signal across all three assays, of whom two were subsequently diagnosed with cancer. This highlights the potential for these assays to detect early stage cancers. The authors caution that a large proportion of cell-free DNA is derived from White Blood Cells (WBCs) and DNA mutations in the WBC population can also be generated by processes other than cancer such as clonal hematopoiesis during human aging. In this study, signal generated from the WBCs was subtracted resulting in a cleaner signal, only from tumor related variants.

It was concluded that based on the initial results from the CCGA study, it is possible to detect early-stage lung cancer, with a high degree of specificity, from a simple blood test, using genome sequencing. The authors plan to further optimize the assays and validate results in a larger group of people. Genome-wide sequencing for early stage lung cancer detection from plasma cell-free DNA (cfDNA): The Circulating Cancer Genome Atlas (CCGA) study. Oxnard GR, Maddala T, Hubbell E, et al. J Clin Oncol. 2018;36(suppl; abstr LBA8501)

Late Breaking Abstract – ASCO 2018 First Line TECENTRIQ® plus Chemotherapy in Advanced Squamous NSCLC

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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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 Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas, and 10% are Large cell carcinomas. Non Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, and less than 15% of patients with advanced Squamous NSCLC survive a year after diagnosis and less than 5% of patients survive for five years or longer. Immunotherapy is an accepted second line intervention after Platinum-based chemotherapy, in patients with advanced NSCLC, and is an approved first line therapy, for patients with high PD-L1 expressing tumors (50% or more).

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. TECENTRIQ® was approved by the FDA in October 2016 for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose disease progressed during or following Platinum-containing chemotherapy. In this present publication, the authors studied the efficacy of TECENTRIQ® given along with combination chemotherapy, in patients with advanced Squamous NSCLC.Unleashing-T-Cell-Function-with-Anti-PDL1-Antibodies

IMpower131 is a multicenter, open-label, phase III study, in which 1021 chemotherapy-naïve patients with stage IV Squamous NSCLC were randomly assigned in 1:1:1 ratio to receive TECENTRIQ® along with Carboplatin, and Paclitaxel (Group A, N=338), TECENTRIQ® along with Carboplatin, and ABRAXANE® (nab-paclitaxel) (Group B, N=343) and the control arm of Carboplatin and ABRAXANE® (Group C, N=340). Patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and TAXOL® (Paclitaxel) 200 mg/m2 IV, all drugs given on Day 1, every 21 days. Patients in Group B received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 IV on Day 1 and ABRAXANE® 100mg/m2 IV on Days 1, 8, and 15 of each 21-day cycle. Patients in Group C (control group) received Carboplatin AUC 6 IV on Day 1 and ABRAXANE® 100mg/m2 IV on Days 1, 8, and 15 of each 21-day cycle. Patients received 4-6 cycles of this combination treatment and in Groups A and B, TECENTRIQ® alone was continued as long as there was a clinical benefit, without evidence of disease progression. Tumors were tested for PD-L1 expression, but patients were included in the study regardless of PD-L1 expression level. Patients with tumors demonstrating EGFR or ALK gene changes should have received molecularly targeted treatments before enrolling in this study. The co-Primary endpoints for this study were Progression Free Survival (PFS) and Overall Survival (OS). As per the study design, the current analysis compared the outcomes of patients in Group B with Group C. Outcomes data comparing Group A with Group C are not yet available.

At the time of primary analysis, with a median follow up of 17.1 months, the median PFS across all PD-L1 subgroups was 6.3 months with the addition of TECENTRIQ® to chemotherapy (Group B) versus 5.6 months in Group C, with chemotherapy alone (HR=0.71; P=0.0001). This represented a 29% reduction in the risk of disease progression or death, with the addition of TECENTRIQ® to chemotherapy. The 12-month PFS rates in Groups B and C were 24.7% versus 12.0%, respectively, suggesting a doubling of PFS benefit with the addition of TECENTRIQ® to chemotherapy. The PFS benefit was more pronounced in those with higher tumor PD-L1 expression. Overall Survival data are not yet mature. The most common side effects with the addition of TECENTRIQ® to chemotherapy included skin rash, colitis, and hypothyroidism.

The authors concluded that this is the first phase III trial of an immunotherapy-based treatment regimen, to demonstrate a significant improvement in Progression Free Survival, in advanced Squamous NSCLC. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. Jotte RM, Cappuzzo F, Vynnychenko I, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA9000)

Late Breaking Abstract – ASCO 2018 First-Line KEYTRUDA® Superior to Chemotherapy in NSCLC

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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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 Non Small Cell Lung Cancer (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), as well as in combination with Pemetrexed and Carboplatin, as first-line treatment of patients with metastatic nonsquamous NSCLC and for previously treated advanced NSCLC with a PD-L1 Tumor Proportion Score of 1% or more. Currently, KEYTRUDA® is the only FDA approved immunotherapy for initial treatment of NSCLC as monotherapy (KEYNOTE-024) or in combination with chemotherapy. In KEYNOTE-024, KEYTRUDA® significantly improved Progression Free Survival and Overall Survival compared to chemotherapy, as first-line treatment for metastatic NSCLC, without targetable mutations and PD-L1 TPS of 50% or more. KEYNOTE-042 trial evaluated the benefit of KEYTRUDA® in patients whose tumors had a much lower level of PD-L1 expression (TPS of 1% or higher).Unleashing-T-Cell-Function-with-KEYTRUDA-(Pembrolizumab)-for-Advanced-Non-Small-Cell-Lung-Cancer

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 nonsquamous 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=1274). 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, in 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 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 advanced/metastatic NSCLC. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. Lopes G, Wu Y-L, Kudaba I, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA4)

Lung Immune Prognostic Index (LIPI) Identifies Advanced Non Small Cell Lung Cancer Patients Unlikely to Benefit from Treatment with Immune Checkpoint Inhibitors

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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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 Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas.Unleashing-T-Cell-Funtion-with-Combination-Immunotherapy

Immunotherapy with PD-1/PD-L1 (Programmed Death-1/Programmed Death-Ligand 1) inhibitors, also called Immune Checkpoint Inhibitors (ICIs), has changed the treatment paradigm for patients with advanced NSCLC. In previously treated patients with NSCLC, the Overall Response Rates (ORR) with single agent Immune Checkpoint Inhibitors (ICIs) range from 14-20%, with median Overall Survival (OS) of 10 to 12 months. In those with PD-L1 expression of 50% or more by ImmunoHistoChemical (IHC) analysis, the ORR can reach up to 30% with a median OS of 20 months. However, in patients with negative or weak PD-L1 expression (1%-49% positive tumor cells), who account for approximately two thirds of the NSCLC population, the response rates range from 8-19% with a median OS slightly below 10 months. Even among those with tumors expressing PD-L1 expression of 50% or more, not all patients benefit from Immunotherapy with ICIs. Therefore identifying biomarkers for patients likely to respond to ICI therapy, and predicting resistance is important and relevant in selecting the appropriate patients for treatment with ICIs.

There is growing evidence on the role of inflammation in cancer biology and systemic inflammatory response may have prognostic significance in different cancer types. Inflammatory process in various cancers imparts immunoresistance to ICIs, by activating oncogenic signaling pathways, there by promoting cancer growth and dissemination, with resulting poor outcomes. Derived Neutrophil-to-Lymphocyte ratio (dNLR) and serum Lactate DeHydrogenase (LDH) level have been investigated as potential inflammatory biomarkers in patients with cancer. The dNLR is calculated using a formula dNLR= Absolute Neutrophil Count/(White Blood Count – Absolute Neutrophil Count). These ratios are simple and easy to calculate from routine blood tests. Both these biomarkers have been correlated with Immune Checkpoint Inhibitor outcomes, in patients with melanoma. In two large studies involving patients with advanced melanoma treated with Ipilimumab and Pembrolizumab, dNLR of 3 or more and LDH of at least 2.5 times Upper Limit of Normal (ULN), reflected a pro-inflammatory status and resulted in poor outcomes.

Based on this important finding in malignant melanoma, the authors conducted a multicenter, retrospective study to determine whether combining the two factors – pretreatment dNLR and LDH (Lung Immune Prognostic Index-LIPI), was associated with resistance to ICIs in patients with advanced NSCLC. In this study, LIPI was developed on the basis of dNLR (derived Neutrophil-to-Lymphocyte Ratio) of greater than 3 and LDH greater than Upper Limit of Normal (ULN). LIPI was used to stratify patients with NSCLC into 3 groups (Good= 0 factors; Intermediate= 1 of 2 factors, Poor= 2 factors). The pooled cohort treated with ICIs included 466 patients with advanced NSCLC of whom 161 patients were treated at a single institution, to test the potential of the biomarkers score (test cohort) and the hypothesis was then validated in a larger multicentric validation cohort of 305 patients treated at 8 European academic centers. To determine whether the LIPI is specific to Immune Checkpoint Inhibitors (ICIs), a control cohort of 162 patients with advanced NSCLC, treated exclusively with chemotherapy, were also evaluated for LIPI. The median patient age was 62 years, 58% had Adenocarcinoma and 34% had Squamous histology, 74% had PD-L1 expression of at least 1% by IHC analysis and 26% had negative results. Median follow up was 12 months. The Primary end point was Overall Survival (OS) and Secondary end points included Progression Free Survival (PFS) and Disease Control Rate (DCR).

It was noted that in the test cohort, median PFS and OS were 3 and 10 months, respectively which is consistent with prior reports in patients with NSCLC, treated with PD-1 inhibitors in second or later lines. A dNLR greater than 3 and LDH greater than ULN were independently associated with OS. The median OS for Poor, Intermediate, and Good LIPI was 3 months, 10 months and 34 months respectively, and median PFS was 2 months, 3.7 months and 6.3 months respectively (P<0.001). This suggested that the population with a Poor (high) LIPI were more likely to have progressive disease as their best response to immunotherapy and had both shorter PFS and OS, compared to those with an Intermediate or Good (low) LIPI. Disease Control Rate (Complete plus Partial Response plus Stable disease) was also correlated with dNLR greater than 3 and LDH greater than ULN. These results were reproducible in the ICI validation cohort for OS, PFS, and DCR. LIPI however was not associated with outcome in patients treated with chemotherapy only, providing support that it might be a predictor of benefit from Immune Checkpoint Inhibitors (ICIs).

It was concluded that pretreatment LIPI, combining derived Neutrophil-to-Lymphocyte ratio (dNLR) greater than 3 and serum LDH level greater than Upper Limit of Normal, correlated with worse outcomes for Immune Checkpoint Inhibitors (ICIs). The authors suggested that this is the first study to explore LIPI in NSCLC and can serve as a potentially useful tool when selecting patients for treatment with Immune Checkpoint Inhibitors, and LIPI might be useful for identifying patients unlikely to benefit from treatment with an ICI. Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non–Small Cell Lung Cancer. Mezquita L, Auclin E, Ferrara R, et al. JAMA Oncol. 2018;4:351-357