Tag: Lung Cancer: Non-Small Cell

Immunotherapy Benefits All Patient Groups with Advanced Cancer

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SUMMARY: The American Cancer Society estimates that in 2020, there will be an estimated 1.8 million new cancer cases diagnosed and 606,520 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Biomarkers predicting responses to ICI’s include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

Immune Checkpoint Inhibitors enhance antitumor immunity by unleashing the T cells. However, this benefit may vary among patients and tumor types. Sex is a biological variable that affects immune responses. Women tend to mount stronger innate as well as adaptive immune responses, than men. (Innate immunity is inherently present in the body, whereas Adaptive immunity occurs in response to exposure to a foreign substance). This can translate into greater efficacy with vaccines and more rapid clearance of pathogens. Aging alters immune responses and adaptive immunity becomes less functional. Altered ECOG Performance Status has also been associated with poor immune response. Several other studies have been published looking at these variables, with conflicting results.

To address these discordant results, the authors performed a meta-analysis to examine the potential association of sex, age, and ECOG PS with immunotherapy survival benefit in patients with advanced cancer. This study was limited to randomized clinical trials that compared Overall Survival (OS) in patients with advanced cancer treated with ICI immunotherapy versus non-ICI control therapy. Data sources such as PubMed, Web of Science, Embase, and Scopus were searched and a total of 37 Phase II or III randomized clinical trials involving 23,760 patients were included in the analysis. Of these, 13 trials evaluated ICIs as first-line therapy. The most common cancer types studied were Non-Small Cell Lung Cancer (N= 14). The most common immune checkpoint inhibitors used were PD-1/PD-L1 inhibitors (N=25). The main Outcomes and Measures were the difference in survival benefit of ICIs between sex, age (less than 65 versus 65 years or more), ECOG PS (0 versus 1 or more), as well as the outcomes stratified by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy (ICI alone or ICI combined with non-ICI) in the intervention arm.

The authors noted that Overall Survival benefit with ICI immunotherapy treatment was found for both men (HR=0.75) and women (HR=0.79), for both younger and less than 65 years (HR=0.77) and 65 years or older (HR=0.78) patients, and for both, patients with ECOG Performance Status 0 (HR=0.81) and PS greater than or equal to 1 (HR=0.79). There was no significant difference of relative benefit from immunotherapy over control therapy in patients of different sex (P=0 .25), age (P=0.94), or ECOG PS (P=0.74). Further, there was no significant difference found in subgroup analyses by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm.

It was concluded that the results of this meta-analysis suggest that immunotherapy with ICIs may confer a survival benefit in the treatment of advanced cancer, regardless of patient sex, age, and performance status, and should not be restricted based on these characteristics.

Association of Sex, Age, and Eastern Cooperative Oncology Group Performance Status With Survival Benefit of Cancer Immunotherapy in Randomized Clinical Trials. A Systematic Review and Meta-analysis. Yang F, Markovic SN, Molina JR, et al. JAMA Netw Open. 2020;3(8):e2012534. doi:10.1001/jamanetworkopen.2020.12534

Next-Generation Sequencing Superior to Single Gene Testing in Advanced NSCLC

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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.
In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, NTRK, MET, HER2 are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors. Patients with nonsquamous NSCLC should therefore be tested for Actionable Driver Oncogenes, as highly effective treatments may be available for these patients. Nonetheless, Single Gene Testing for EGFR and ALK is more common in the US rather than broad multigene panel testing with Next-Generation Sequencing.Overview-of-Next-Generation-Sequencing

Next-Generation Sequencing (NGS) platforms or second-generation sequencing, unlike the first-generation sequencing, known as Sanger sequencing, perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. With this high-throughput sequencing, the entire genome can be sequenced in less than 24 hours. There are a number of different NGS platforms using different sequencing technologies and NGS can be used to sequence and systematically study the cancer genomes in their entirety or specific areas of interest in the genome or small numbers of individual genes. Recently reported genomic profiling studies, performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors.

The authors in this study used a decision analytic model they had developed, and compared the value of broad NGS-based testing, to Single Gene Testing (SGT), in patients with nonsquamous NSCLC, and discussed their implications for the US population. The authors noted that Single Gene Testing for EGFR and ALK is relatively common (>80%) in the US, whereas testing for less common Actionable Driver Oncogenes is rare. The broader NGS Actionable Driver Oncogene panel includes EGFR, ALK, ROS1, BRAF, RET, MET, NTRK. The authors took into consideration reimbursement by CMS for broad NGS-based testing ($627.50), reimbursement for Single Gene testing (EGFR+ALK $732.30), and the cost of treatment for 2 years at $10K/year ($20,000). The expected prevalence of Actionable Driver Oncogenes among non squamous NSCLC patients, as well as survival outcomes of patients, in the presence versus absence of an Actionable Driver Oncogenes treatment strategy, was calculated based on current literature. The number of eligible patients with nonsquamous NSCLC, for testing in the US, were 89,000 (N=89,000). The estimated number of patients with Actionable Driver Oncogenes (EGFR, ALK, ROS1, BRAF, RET, MET, NTRK) was 26,300 (N=26,300). The goal of this study was to measure the cost and value differences when one chose to run a Single Gene Testing (narrow genomics panel), which included interrogation for either EGFR or ALK, versus a broader NGS panel. The potential value of each testing approach was measured based on Life Years Gained (LYG) and the cost per LYG. (Life Years gained is a modified mortality measure where remaining life expectancy is taken into account).

It was noted that a broad NGS approach to test for genetic alterations resulted in additional Life Year Gains with cost savings, compared to Single Gene Testing for EGFR or ALK. This analytical model suggested that at the current 80% testing rate, replacing Single Gene Testing with NGS would result in an additional 21,019 Life Year Gained, with reduced cost per LYG of $599. Increasing testing from 80% to 100% of eligible patients would further increase the Life Year Gained by 15,017. If 100% of eligible patients were tested with NGS and every identified patient received treatment, the cost per Life Year Gained with this strategy would be $16,641.57.

According to this decision model, the estimated median survival and 5-year survival for a patient who was tested with NGS, followed by a highly effective therapy selected on the basis of that alteration, would be 39 months and 25%, respectively. For a patient who had an Actionable Driver Oncogene that was not identified by Single Gene Testing, the estimated median survival would be 14 months and 5-year survival would be 5%. This analysis suggested that not running broad multigene NGS panel routinely for eligible patients, and only using Single Gene Testing could be a missed opportunity, as actionable mutations would be missed and patients may not get the most effective therapy for their disease.

The authors concluded that based on their decision analytic model, when highly effective therapy is available to all identified patients with Actionable Driver Oncogenes, broad NGS testing, compared to Single Gene Testing for EGFR or ALK, leads to large gains in Life Years, at reduced cost per Life Year Gained, compared to Single Gene Testing. This model supports universal NGS testing of all patients with advanced nonsquamous NSCLC.

A model comparing the value of broad next-gen sequencing (NGS)-based testing to single gene testing (SGT) in patients with nonsquamous non-small cell lung cancer (NSCLC) in the United States. Pennell NA, Zhou J, Hobbs B. J Clin Oncol 38: 2020 (suppl; abstr 9529)

First Line CYRAMZA® Plus ERLOTINIB® for EGFR-Mutated Non Small Cell Lung Cancer

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SUMMARY: The FDA on May 29, 2020 approved CYRAMZA® (Ramucirumab) in combination with TARCEVA® (Erlotinib) for first line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.

Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Previously published data from the Phase III FLAURA study showed that first-line treatment with TAGRISSO® was superior to first-line treatment with other first and second generation TKI’s, in patients with EGFR-mutated NSCLC, with improved median Overall Survival. Patients with the exon 21 L858R substitution mutation however are less sensitive to TKIs and their PFS therefore has been lower, than those with exon 19 deletions. In the FLAURA study the PFS in the exon 21 mutation group was 14.4 months compared with 21.4 months for patients with an exon 19 deletion, when treated with first line TAGRISSO®. Furthermore, widespread use of TAGRISSO® has led to acquired resistance. Evolving data has shown limited responses to immune checkpoint inhibitors after disease progression on TKIs. There is therefore a critical need to develop new TKI-based therapies, and novel treatment approaches, combining TKI’s with other targeted therapies. RELAY trial was designed to address this unmet need.

CYRAMZA® is a recombinant human monoclonal IgG1 antibody that binds to the human Vascular Endothelial Growth Factor Receptor- 2 (VEGFR-2), preventing the interaction of VEGFR-2 with its ligands. CYRAMZA® was previously approved for use in combination with TAXOTERE® (Docetaxel) for the treatment of patients with metastatic NSCLC who progressed while on or following treatment with platinum-based chemotherapy. Several preclinical studies have shown that dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic NSCLC is synergistic, with higher antitumor activity, when compared with inhibition of the EGFR pathway alone. This has been attributed to upregulation of VEGF in the tumor microenvironment, when tumor cells harbor EGFR mutations.

RELAY trial is global, multicenter, randomized, double-blind, placebo-controlled, Phase III study in which 449 patients with previously untreated metastatic NSCLC, who harbored either an EGFR exon 19 deletion or exon 21 L858R substitution mutation, were enrolled. Patients were randomized 1:1 to receive TARCEVA® 150 mg orally daily in combination with either CYRAMZA® 10 mg/kg IV (N=224) or placebo (N=225), every 2 weeks. Treatment was continued until disease progression or unacceptable toxicity. Both treatment groups were well balanced. Patients had an ECOG performance status of 0-1, median age was 64 years, and about 60% of patients were never smokers. Those with a known EGFR T790M mutation, received prior treatment with an EGFR TKI or chemotherapy, or had brain metastases, were ineligible for study enrollment. Patients were stratified by sex, EGFR mutation type, and EGFR testing methodology. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), Overall Response Rate (ORR) and Duration of Response (DOR).

At a median follow up of 20.7 months, the median PFS was 19.4 months in the CYRAMZA® plus TARCEVA® group compared with 12.4 months in the placebo plus TARCEVA® group (HR= 0.59; P<0.0001). This PFS benefit was observed across several patient subgroups, and was consistent across Exon 19 and Exon 21 subgroups. Unlike in the FLAURA trial, in the RELAY trial, the PFS in patients with exon 21 mutation was comparable to patients with exon 19 deletions. The PFS for these patients with exon 21 mutation was 19.4 months. Further, the addition of CYRAMZA® to TARCEVA® did not increase the incidence of EGFR T790M mutation. The ORR was 76% in the CYRAMZA® plus TARCEVA® group and 75% in the placebo plus TARCEVA® group, with median DoR of 18.0 months and 11.1 months, respectively. At the time of the final analysis of PFS, the OS data were not mature. The most common adverse reactions in the CYRAMZA® plus TARCEVA® group were infections, hypertension, stomatitis, proteinuria, alopecia, epistaxis, and peripheral edema. The most common laboratory abnormalities were increased ALT and AST as well as cytopenias.

It was concluded that CYRAMZA® plus TARCEVA® demonstrated superior PFS, compared with placebo plus TARCEVA®, in treatment naïve patients with EGFR-mutated metastatic NSCLC. Inhibiting the VEGFR and EGFR pathways together, is an important milestone in the treatment of EGFR-mutated NSCLC, with outcomes comparable to that with third generation TKIs, and furthermore, providing these patients an additional treatment option with TAGRISSO® upon progression.

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

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).

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: Adjuvant Therapy with TAGRISSO® Improves Survival in Early Stage EGFR-Mutated 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.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.EGFR-Tyrosine-Kinase-Inhibitors

TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Further, TAGRISSO® has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases. Among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with TAGRISSO® significantly improved median Overall Survival, compared with TARCEVA® and IRESSA®, and should therefore be considered the preferred regimen.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with Cisplatin-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

ADAURA is a global, double-blind, randomized Phase III study, which assessed the efficacy and safety of TAGRISSO® versus placebo in patients with Stage IB–IIIA EGFR mutated NSCLC, after complete tumor resection and adjuvant chemotherapy, when indicated. In this study, 682 patients with completely resected Stage IB, II, IIIA NSCLC, with or without postoperative adjuvant chemotherapy, were randomly assigned 1:1 to receive either TAGRISSO® 80 mg orally once daily (N=339) or placebo (N=343) once daily, for up to 3 years. Eligible patients had an ECOG Performance Status of 0 or 1, with confirmed EGFR mutations (Exon 19del or L858R). Treatment groups were well balanced and patients were stratified by Stage (IB/II/IIIA), mutation type (Exon 19del/L858R), and race (Asian/non-Asian). The Primary endpoint was Disease Free Survival (DFS) in Stage II–IIIA patients. Secondary endpoints included Overall Survival (OS) and safety. Following Independent Data Monitoring Committee recommendation, the trial was unblinded early, due to efficacy. The authors reported the results from the unplanned interim analysis.

It was noted that in the patients with Stage II/IIIA disease, the DFS had not been reached with TAGRISSO® versus 20.4 months with placebo (HR=0.17; P<0.0001). The 2-year DFS rate in this patient group with TAGRISSO® was 90% versus 44% with placebo. In the overall population, the DFS was still not reached with TAGRISSO® versus 28.1 months with placebo (HR=0.21; P<0.0001). The 2-year DFS rate in the overall population was 89% with TAGRISSO® versus 53% with placebo. The OS data are still early and immature, and the median OS has not yet been reached in either treatment groups. The safety profile was consistent with the known safety profile of TAGRISSO®.

The authors concluded that adjuvant TAGRISSO® is the first targeted agent in a global randomized trial, to show a statistically significant and clinically meaningful improvement in Disease Free Survival, among patients with Stage IB/II/IIIA EGFR mutation-positive NSCLC, and provides an effective new treatment strategy for this patient group.

Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. Herbst RS, Tsuboi M, John T, et al. J Clin Oncol 38: 2020 (suppl; abstr LBA5)

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

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SUMMARY: The FDA on May 8, 2020, granted accelerated approval to RETEVMO® (Selpercatinib) for patients with metastatic RET fusion-positive Non-Small Cell Lung Cancer (NSCLC), patients with advanced or metastatic RET-mutant Medullary Thyroid Cancer (MTC) who require systemic therapy and those with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are RadioActive Iodine (RAI)-refractory. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers.

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

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

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

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

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

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

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

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

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

FDA Approves CYRAMZA® Plus TARCEVA® for EGFR Mutated NSCLC

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SUMMARY: The FDA on May 29, 2020 approved CYRAMZA® (Ramucirumab) in combination with TARCEVA® (Erlotinib) for first-line treatment of metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) Exon 19 deletions or Exon 21 (L858R) mutations. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

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

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

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

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

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

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