Tag: Lung Cancer: Non-Small Cell

FDA Approves Frontline TECENTRIQ® with Carboplatin and nab-Paclitaxel for Metastatic Non-Squamous NSCLC

RR

SUMMARY: The FDA on December 3, 2019 approved TECENTRIQ® (Atezolizumab) in combination with nab-Paclitaxel and Carboplatin for the first-line treatment of adult patients with metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC), with no EGFR or 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 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. 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 T cells of the immune system. Immuno-Oncology (IO) therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation and a therapeutic response. 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 NSCLC. It is now standard therapy for patients with lung cancer. TECENTRIQ® 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. Unleashing-T-Cell-Function-with-Anti-PD-1-and-Anti-PD-L1-Antibodies

IMpower 130 is an international, multicentre, open-label, randomized, Phase III study, evaluating the efficacy and safety of TECENTRIQ® in combination with Carboplatin and nab-Paclitaxel versus chemotherapy (Carboplatin and nab-Paclitaxel) alone, for chemotherapy-naïve patients with Stage IV non-squamous NSCLC. This study enrolled 724 patients who were randomly assigned 2:1 to receive TECENTRIQ® 1200 mg IV on Day 1, along with Carboplatin AUC 6 on Day 1 and nab-Paclitaxel 100 mg/m2 IV, on days 1, 8 and 15 of each 21-day cycle, for 4 or 6 cycles followed by maintenance TECENTRIQ®, or Carboplatin and nab-Paclitaxel alone (control group), followed by Best Supportive Care during the maintenance treatment phase or Switch maintenance to Pemetrexed every 3 weeks. Stratification factors included gender, baseline liver metastases, and PD-L1 expression. The co-Primary endpoints were investigator-assessed Progression Free Survival and Overall Survival in the intention-to-treat EGFR and ALK wild-type population. The median follow up in the population studied was 19 months.

There was a significant improvement in median Overall Survival in the TECENTRIQ® plus chemotherapy group at 18.6 months compared to 13.9 months in the chemotherapy alone group (HR=0.79; P=0.033), as well as improvement in the median Progression Free Survival (7 months versus 5.5 months, respectively, HR=0.64; P<0.0001). The most common adverse reactions reported in 20% or more of patients in the TECENTRIQ® and chemotherapy group were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite.

It was concluded that first-line TECENTRIQ® in combination with chemotherapy significantly improved Overall Survival and Progression Free Survival, compared to chemotherapy alone, in patients with advanced non-squamous NSCLC without ALK or EGFR mutations. This IO-chemotherapy combination is the second FDA approval for this patient population. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. West H, McCleod M, Hussein M, et al. Lancet Oncol. 2019;20:924-937

Late Breaking Abstract – ESMO 2019 First-Line Treatment with TAGRISSO® Improves Overall Survival in EGFR-Positive NSCLC

RR

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 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. 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.

FLAURA, which is a randomized, double blind, Phase III clinical trial, was conducted to compare the efficacy and safety of first line TAGRISSO® to TARCEVA® or IRESSA® (the latter two are considered standard first line therapies), in NSCLC patients with sensitizing EGFR mutations. This study randomized 556 advanced NSCLC treatment naïve patients, with EGFR Exon 19 Deletions or Exon 21 (L858R) substitution mutations, in a 1:1 ratio, to TAGRISSO® 80 mg orally once daily (N=279) or Standard of Care EGFR-TKI, IRESSA® 250 mg or TARCEVA® 150 mg, orally once daily (N=277). Patients were stratified by mutation status (Exon 19 vs 21 mutations) and race (Asian vs non-Asian). Patients with CNS metastases who were neurologically stable, were allowed in this study. The Primary endpoint was Progression Free Survival (PFS) and Overall Survival (OS) was a Secondary endpoint.

The median PFS was 18.9 months with TAGRISSO®, compared to 10.2 months for the standard therapy (HR=0.46; P<0.001), suggesting a 54% reduction in the risk of disease progression, compared with Standard of Care. TAGRISSO® extended the median Time To Progression by about 9 months. This PFS benefit was consistent across all subgroups of patients, including those with and without CNS metastases at study entry. The Objective Response Rate (ORR) with TAGRISSO® was 80% compared with 76% for TARCEVA® and IRESSA®. The median Duration of Response with TAGRISSO® was 17.2 months versus 8.5 months in the comparator arm.

The authors now reported the Overall Survival (OS) results from the Phase III FLAURA trial. Approximately, 25% of patients in the comparator group had crossed over to the TAGRISSO® group upon disease progression. Despite this crossover, the OS was significantly prolonged with TAGRISSO® with a median OS of 38.6 months compared with 31.8 months for the comparator arm (HR=0.799; P=0.046), representing a 20% reduction in the risk of death with TAGRISSO®. At the time of final data cutoff for the study, about 54% of patients remained alive at 3 years in the TAGRISSO® group compared with 44% in the comparator group, and 28% of patients enrolled in the trial were still receiving TAGRISSO® at three years versus 9% on either TARCEVA® or IRESSA®. Treatment with TAGRISSO® also resulted in a statistically significant and clinically meaningful 52% reduction in the risk of CNS disease progression or death, compared to the comparator arm (HR=0.48; P=0.014). Fewer patients in the TAGRISSO® group experienced Grade 3 or more Adverse Events compared to the comparator arm. Approximately 30% of patients in both treatment groups did not receive subsequent therapy after progression.

It was concluded that 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. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Ramalingam SS, Gray JE, Ohe Y, et al. Presented at 2019 ESMO Congress, Barcelona, Spain, September 28 to October 1, 2019. Abstract LBA5_PR.

Late breaking Abstract – ESMO 2019 Chemotherapy-Free First Line Immunotherapy Combination Improves Overall Survival in Advanced NSCLC

RR

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 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. 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 T cells of the immune system.

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® (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, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® is presently approved for treatment of patients with metastatic NSCLC and progression on or after Platinum-based chemotherapy. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4).

CheckMate-227 is an open-label, multi-part, global, Phase III trial in which OPDIVO® based regimens were compared with Platinum-doublet chemotherapy in patients with first line advanced NSCLC, across non-squamous and squamous tumor histologies. In Part 1 of this trial, there were 2 cohorts- Part 1a in which OPDIVO® plus low dose YERVOY® (N=396) or OPDIVO® monotherapy (N=396) was compared with chemotherapy alone (N=397), in patients whose tumors expressed PD-L1 expression of 1% or more and Part 1b in which OPDIVO® plus low dose YERVOY® (N=187) or OPDIVO® plus chemotherapy (N=177) was compared with chemotherapy alone (N=186), in patients whose tumors did not express PD-L1 (less than 1%). (In Part 2 of this trial, OPDIVO® plus chemotherapy was compared with chemotherapy alone, regardless of PD-L1 expression. Part 2 did not meet its Primary endpoint for Overall Survival for OPDIVO® plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC, and is published elsewhere). It should be noted that when this trial was launched, chemotherapy along with immunotherapy or immunotherapy alone was not approved for the front-line treatment of NSCLC. Therefore, dual immunotherapy combination was not compared with current standards of care such as chemotherapy plus immunotherapy.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

OPDIVO® was administered at 3 mg/kg every 2 weeks, and in the combination arm, YERVOY® was administered at 1 mg/kg every 6 weeks. When administered with chemotherapy, OPDIVO® was administered at 360 mg every 3 weeks. Patients were stratified by histology, and treatment was administered until disease progression, unacceptable toxicity, or for 2 years, for immunotherapy. There were two Co-primary endpoints in Part 1 for OPDIVO® plus YERVOY® versus chemotherapy: Overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and Progression Free Survival (PFS) in patients with TMB of 10 mut/Mb or more, across the PD-L1 spectrum (assessed in patients enrolled across Parts 1a and 1b). The minimum follow up for the Primary endpoint was 29 months.

Both Part 1a and Part 1b groups met their Primary endpoints. In the Part 1a cohort with PD-L1 expression of 1% or more, the Overall Survival was significantly longer with OPDIVO® plus YERVOY®, compared to chemotherapy. The median Overall Survival was 17.1 months in the Immunotherapy combination group compared to 14.9 months in the chemotherapy group (HR=0.79; P=0.007). Progression Free Survival, Objective Response Rates and Duration of Response were all greater with OPDIVO® plus YERVOY® combination, compared to chemotherapy. In the Part 1b cohort with PD-L1 expression of less than 1%, Overall Survival benefit was again observed with the OPDIVO® plus YERVOY® combination, compared with chemotherapy. Grade 3 and 4 treatment-related Adverse Events across all patients was 33% in those treated with OPDIVO® plus YERVOY® combination, 19% with single agent OPDIVO® and 36% with chemotherapy.

It was concluded that first-line treatment of patients with advanced NSCLC with a combination of two immunotherapy drugs improves Overall Survival, compared to chemotherapy, and offers a chemotherapy-free first line treatment option for a subset of NSCLC patients, leaving chemotherapy for later lines of therapy. Nivolumab + low-dose ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non–small cell lung cancer: CheckMate-227 part 1 final analysis. Peters S, Ramalingam SS, Paz-Ares L, et al. Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA4.

Updated Analysis KEYTRUDA® Doubles Overall Survival Compared with Chemotherapy in Advanced NSCLC

RR

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 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 Non Small Cell Lung Cancer (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®.

KEYNOTE-024 is an open-label, randomized phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for up to 2 years or the investigator’s choice of platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. Patients in the chemotherapy group who experienced disease progression were allowed to cross over to the KEYTRUDA® group. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Objective Response Rate (ORR) and Safety.

It was previously reported that at a median follow up of 11.2 months, the median PFS was 10.3 months in the KEYTRUDA® group versus 6 months in the chemotherapy group (HR=0.50; P<0.001). However, median OS had not been reached in the KEYTRUDA® group at the time of that analysis. The Independent Data and Safety Monitoring Committee (IDMC) based on these results recommended stopping the trial early, to allow for use of KEYTRUDA® in patients randomly assigned to chemotherapy. Eighty two patients (N=82) assigned to chemotherapy, met criteria to cross over to the KEYTRUDA® group, upon progression.

This publication is an updated analysis of the KEYNOTE-024 study, after a median follow-up of 25.2 months. The median OS was 30 months in the KEYTRUDA® group and 14.2 months in the chemotherapy group (HR=0.63; P=0.002). When adjusted for crossover, the OS benefit was maintained and the Hazard Ratio for OS among KEYTRUDA® group versus chemotherapy group was 0.49. Further, more patients in the KEYTRUDA® group achieved 12-month OS (70.3% versus 54.8%), and an ORR response (45.5% versus 29.8%), compared to the chemotherapy group respectively. The ORR among those who crossed over to KEYTRUDA®, was 20.7%. The median Duration of Response has not yet been reached for patients assigned to KEYTRUDA® and also for those who crossed over to KEYTRUDA®. For those assigned chemotherapy, the median Duration of Response was 7.1 months. Patients in the KEYTRUDA® group had lower rates of Grade 3-5 adverse events, compared to those in the chemotherapy group (31.2% versus 53.3%), as well as a lower rate of any-grade adverse events (76.6% versus 90%).

It was concluded that in this updated analysis of KEYNOTE-024, KEYTRUDA® continued to provide improved Overall Survival benefit, inspite of the high rate of crossover, with lower rates of Adverse Events, when compared to chemotherapy, among patients with metastatic NSCLC and high PD-L1 expression. The authors added that these updated long term results support KEYTRUDA® monotherapy as a standard-of-care regimen for first line treatment of advanced NSCLC with PD-L1 expression of 50% or greater and without EGFR/ALK alterations. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Reck M , Rodríguez–Abreu D, Robinson AG, et al. J Clin Oncol 2019;37:537-546

SBRT Superior to Standard Radiotherapy in Stage I Non-Small Cell Lung Cancer

RR

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 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. Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the implementation of Lung Cancer screening programs. Patients with early stage disease unless medically unfit, undergo surgical resection with a curative intent. Those who are not surgical candidates are often treated with conventional Radiation Therapy, over a period of 4 to 6 weeks.

Stereotactic Body Radiation Therapy (SBRT) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional Radiation Therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SBRT include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized Hydrogen or Protons, Linear Accelerator (LINAC) and CYBER KNIFE® which use Photons, to target the tumor tissue. Because SBRT is fractionated and delivered over 1-5 days, the short-and long-term side effects of radiation therapy are decreased and may allow higher total dosage to be given. Previously published single-arm trials have shown high local control with SBRT, with no significant difference in Overall Survival, compared with conventional Radiotherapy. This Phase III trial was conducted to prospectively assess the effect of SBRT on local control, Overall Survival, toxicity and Quality of Life.SBRT-Treatment

In this multicentre, randomized, Phase III trial, 101 eligible patients with biopsy proven Stage I (T1-T2aN0M0) NSCLC, diagnosed on the basis of FDG PET, who were medically inoperable or had refused surgery, were enrolled. Patients were randomly assigned in a 2:1 ratio to SBRT (54 Gy in three 18 Gy fractions, or 48 Gy in four 12 Gy fractions if the tumor was less than 2 cm from the chest wall)-(N=66) or standard Radiotherapy (66 Gy in 33 daily 2 Gy fractions or 50 Gy in 20 daily 2.5 Gy fractions (N=35), based on institutional preference. The tumor had to be non-central and peripherally located, at least 1 cm in the mediastinum and 2 cm from the bifurcation of the lobar bronchi. Patients were stratified by T stage and operability (medically operable but refused surgery versus inoperable). The Primary endpoint was time to local treatment failure and Secondary endpoints included Overall Survival, treatment related toxicity and Quality of Life. The median follow up for local treatment failure was 2.1 years for standard Radiotherapy group and 2.6 years for those patients assigned to SBRT.

Local treatment failure was noted in 14% of patients in the SBRT group whereas 31% of patients in the standard Radiotherapy group progressed locally. Freedom from local treatment failure was significantly improved the SBRT group compared with a standard radiotherapy group (HR=0.32, P=0.0077). Median time to local treatment failure was not reached in either group. Median Overall Survival was 5 years in the SBRT group and 3 years in the standard Radiotherapy group (HR=0.53; P=0.027). Overall Survival at 2 years was 77% for those receiving SBRT and 59% for those in the standard Radiotherapy group. Treatment related toxicities were low in both groups and there were no significant differences in Quality of Life between the treatment groups.

It was concluded that in patients with inoperable peripherally located Stage 1 NSCLC, compared with standard Radiotherapy, SBRT resulted in superior local control of the primary disease without an increase in major toxicity, and improvement in Overall Survival. The authors added that these findings suggest that SBRT should be the treatment of choice for this patient group. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Ball D, Tao Mai G, Vinod S, et al. Lancet Oncol 2019;20:494-503

FDA Approves ROZLYTREK® for NTRK Positive tumors and ROS1 Positive Non Small Cell Lung Cancer

RR

SUMMARY: The FDA on August 15, 2019, granted accelerated approval to ROZLYTREK® (Entrectinib) for adults and pediatric patients 12 years of age and older with solid tumors that have a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy. The FDA on the same day approved ROZLYTREK® for adults with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors are ROS1-positive.

Next-Generation Sequencing (NGS) has enabled the detection of Neurotrophic Tropomyosin Receptor Kinase (NTRK) gene fusions, which was first discovered in Colon cancer in 1982. The three TRK family of Tropomyosin Receptor Kinase (TRK) transmembrane proteins TRK A, TRK B, and TRK C are encoded by Neurotrophic Tropomyosin Receptor Kinase genes NTRK1, NTRK2, and NTRK3, respectively. These Receptor Tyrosine Kinases are expressed in human neuronal tissue and are involved in a variety of signaling events such as cell differentiation, cell survival and apoptosis of peripheral and central neurons. They therefore play an essential role in the physiology of development and function of the nervous system. There are over 50 different partner genes that fuse with NTRK genes. Chromosomal fusion involving NTRK genes arise early in cancer development and remain so as tumors grow and metastasize. Gene fusions involving NTRK genes lead to transcription of chimeric TRK proteins which can confer oncogenic potential by increasing cell proliferation and survival. Early clinical evidence suggests that these gene fusions lead to oncogene addiction regardless of tissue of origin. (Oncogene addiction is the dependency of some cancers on one or a few genes for the maintenance of the malignant phenotype). It is estimated that gene fusions involving NTRK genes occurs in about 0.5% to 1% of many common malignancies and have been identified in a broad range of solid tumor types including Non-Small Cell Lung Cancer (NSCLC), Cholangiocarcinoma, Colorectal, Gynecological, Neuroendocrine, Pancreatic tumors and in more than 90% of certain rare tumor types, such as Salivary gland tumors, a type of juvenile Breast cancer, and infantile Fibrosarcoma.

Approximately 1-2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small Cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years), who are relatively young (average age of 50 years) and thus share similar characteristics with ALK-positive patients. ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing.

ROZLYTREK® is a pan-TRK, ROS1 and ALK Tyrosine Kinase Inhibitor (TKI), designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of malignancies. ROZLYTREK® has potent anti-neoplastic activity in various neoplastic conditions, particularly NSCLC, by blocking ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions.

The FDA approvals were based on results from the integrated analysis of the pivotal Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the Phase I/II STARTRK-NG study in pediatric patients. ROZLYTREK®, was studied in several solid tumor types, including NSCLC, Breast cancer, Mammary analogue secretory carcinoma, Cholangiocarcinoma, Colorectal, Gynecological, Neuroendocrine, Salivary gland, Pancreatic, Thyroid cancers and Sarcoma. Patients were enrolled across 15 countries and more than 150 sites, and safety was assessed from an integrated analysis of 355 patients across these four trials. The Primary endpoints included Overall Response Rate (ORR), Duration of Response (DoR) and Secondary endpoints include Progression Free Survival (PFS), Overall Survival (OS) in patients with and without baseline CNS disease, and Safety.

The efficacy of ROZLYTREK® in NTRK gene fusion-positive, locally advanced or metastatic solid tumors was evaluated in 54 adult patients, who received ROZLYTREK® at various doses and schedules in one of three multicenter, single-arm, clinical trials. About 94% of patients received ROZLYTREK® 600 mg orally once daily. The median age was 58 years, about 60% of the patients were women and more than 40% of the patients had received 2 or more prior lines of therapy. Positive NTRK gene fusion status was determined in local laboratories or a central laboratory using nucleic acid-based tests prior to enrollment. The Overall Response Rate as determined by independent review was 57%, and the Duration of Response (DoR) was 6 months or longer for 68% of patients and 12 months or longer for 45% of patients. Objective responses to ROZLYTREK® were seen in people, with CNS metastases at baseline.

The efficacy of ROZLYTREK® in ROS1-positive metastatic NSCLC was evaluated in 51 adult patients who received ROZLYTREK® at various doses and schedules in the same three trials and 90% of patients received ROZLYTREK® 600 mg orally once daily. The Overall Response Rate was 78% and the Duration of Response (DoR) was 12 months or longer for 55% of patients. The most common adverse reactions (20% or more) with ROZLYTREK® were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, arthralgia and vision disorders.

It was concluded that based on this multicenter, pooled analysis of global clinical trials, ROZLYTREK® was well tolerated and induced clinically meaningful, durable systemic responses in patients with NTRK-fusion positive solid tumors, with or without CNS disease. This is the third tissue agnostic cancer therapy (cancer treatment based on a common biomarker across different tumor types rather than the location in the body where the tumor originated) approved by the FDA. The previous tissue agnostic cancer therapies approved by the FDA were KEYTRUDA® (Pembrolizumab) for tumors with MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) tumors in 2017 and VITRAKVI® (Larotrectinib) for NTRK gene fusion tumors in 2018. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Demetri GD, Paz-Ares L, Farago AF, et al. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA17.

Survival Benefit with KEYTRUDA® After Locally Ablative Therapy (LAT) for Oligometastatic NSCLC

RR

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 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.

It is estimated that approximately 7% of patients with NSCLC present with a limited number of metastatic foci (oligometastatic). Several retrospective studies have shown that the use of Locally Ablative Therapy (LAT) to all sites of disease in oligometastatic NSCLC is associated with a significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), when compared with historical data. Preclinical evidence had suggested that chemotherapy and radiotherapy may upregulate PD-L1 expression in tumor cells. Therefore, incorporating immunotherapy along with LAT has been an area of active research. In the PACIFIC trial, consolidation therapy with PD-L1 inhibitor IMFINZI® (Durvalumab), following chemoradiation, significantly improved PFS and OS among patients with locally advanced NSCLC suggesting that there is a strong biological rationale for the use of immunotherapy in patients with minimal residual disease state.

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 primary objective of this study was to evaluate whether the addition of KEYTRUDA® after Locally Ablative Therapy (LAT) improves outcomes among patients with oligometastatic NSCLC, compared with historical data.

The authors conducted a single arm Phase II trial at an academic referral cancer center, and 51 eligible patients with oligometastatic NSCLC (no more than 4 metastatic sites) were enrolled. Enrolled patients had oligometastatic disease at diagnosis (synchronous disease) or who developed oligometastatic disease after initial definitive therapy (metachronous disease). There was no limit on the number of prior therapies, although patients could not have received prior therapy with a Programmed Death 1 (PD-L1) inhibitor. Any form of Locally Ablative Therapy (LAT) was acceptable and LATs included Surgery, Chemoradiotherapy, Stereotactic radiotherapy, and/or Interventional ablation. Forty five of the 51 patients enrolled received KEYTRUDA® within 4 to 12 weeks of completing LAT. Patients received KEYTRUDA® 200 mg IV every 21 days, for 8 cycles and were allowed to continue therapy for a total of 16 cycles in the absence of progressive disease or untoward toxicities. The median age was 64 years and patients were eligible regardless of their PD-L1 or molecular target status. Thirty-two patients had adequate tissue for assessment of PD-L1 status, and 29 patients had adequate tissue for assessment of CD8 T-cell infiltration. In patients undergoing testing, 34% had results positive for PD-L1 (1% or more) and 52% had CD8 T-cell infiltration of greater than 2.5%. Patients received a median of 11 cycles of KEYTRUDA®.

The two Primary efficacy end points were Progression Free Survival (PFS) from the start of Locally Ablative Therapy (PFS-L) and PFS from the start of KEYTRUDA® therapy (PFS-P). This study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included Overall Survival, Safety, and Quality of Life, as measured by the Functional Assessment of Cancer Therapy–Lung (FACT-L) instrument.

After a median follow-up of 23.2 months for surviving patients, the median PFS from the start of Locally Ablative Therapy (PFS-L) was 19.1 months, which was a statistically significant improvement from the historical median of 6.6 months (P=0.005). The median PFS from the start of KEYTRUDA® therapy (PFS-P) was 18.7 months. The mean Overall Survival rate at 12 months was 90.9% and at 24 months was 77.5%. The Progression Free Survival from the start of Locally Ablative Therapy (PFS-L) was not influenced by PD-L1 expression or CD8 T-cell tumor infiltration. Quality of Life as measured by the FACT-L scores at cycles 8 and 16 were not significantly different from FACT-L scores at baseline.

The authors concluded that KEYTRUDA® after Locally Ablative Therapy for oligometastatic NSCLC was associated with a clinically and statistically significant improvement in Progression Free Survival, compared with historical data, without a decrement in Quality of Life. They added that the Overall Survival data is encouraging but will require further follow up. Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non–Small Cell Lung Cancer: A Phase 2 Trial. Bauml JM, Mick R, Ciunci C, et al. JAMA Oncol. Published online July 11, 2019. doi:10.1001/jamaoncol.2019.1449

Low Provider Knowledge Associated with Less Lung Cancer Screening

RR

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 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. In the National Lung Screening Trial (NLST) with Low Dose CT (LDCT) screening for lung cancer, there was a 20% reduction in mortality. Following the publication of the results of NLST and NCCN issued guideline in 2011, the United States Preventive Services Task Force (USPSTF) recommended Lung Cancer screening with Low Dose CT scan in high risk patients. CMS in 2015 determined that there was sufficient evidence to reimburse for this preventive service.

Despite the evidence and recommendation along with supportive public policies, screening with LDCT has not been adequately implemented in the US healthcare system. (A low-dose CT scan will typically deliver 1-4 millisieverts of radiation exposure, whereas a conventional CT scan typically delivers between 5-20 millisieverts).Health Care Providers play a key role because LDCT is currently the only cancer screening modality required by CMS to have a shared decision-making conversation with the patient for reimbursement, making it crucial for providers to have knowledge of the screening recommendations, CMS coverage criteria, and evidence for screening. Low Health Care Provider knowledge of the Lung Cancer Screening (LCS) guidelines represents a potential barrier to implementation.

The authors in this study tested the hypothesis that low provider knowledge of Lung Cancer Screening guidelines is associated with less provider-reported screening with LDCT. The researchers from February thru May 2017 surveyed/invited 625 providers who routinely perform health screenings or care for patients at high risk of lung cancer, out of whom responses from 378 providers were analyzed. Health Care Providers were emailed internet-based questionnaire and participating providers included those who practiced general Internal Medicine/Family Medicine, Pulmonology, Hematology/Oncology, and Gynecology, within an academic medical center (Vanderbilt University Medical Center [VUMC]) and its affiliated Veterans Health Administration (VHA), including hospital-based and community-based practices. A medicine Grand Rounds at VUMC focused on Lung Cancer Screening (LCS) prior to this survey. Eligible providers included Attending physicians, Physicians in training, Physician Assistants, and Nurse Practitioners, who reported providing healthcare services to patients aged more than 50 in the year before the study. The questionnaire was terminated if respondents did not meet these criteria. Approximately 47% were Attending physicians, 43% were Physicians in training and 10% were Nurse Practitioners/Physician Assistants. Questionnaire Content included six multiple-choice items based on the USPSTF and CMS coverage criteria for Lung Cancer Screening. They included the following:

1) Initial age of screening eligibility (correct answer: 55 years)

2) Upper age limit at which a patient is no longer eligible for screening (correct answer: either 77 or 80 years)

3) Minimum smoking exposure (correct answer: 30 pack-years)

4) Smoking status (correct answer: current and former smokers)

5) Screening frequency (correct answer: yearly)

6) Screening for patients who were not surgical candidates (correct answer: no)

High LCS knowledge was defined as correctly identifying 3 major criteria to identify screening candidates: initial age of screening eligibility, minimum smoking exposure, and smoking status. Low LCS knowledge was defined as not correctly identifying these 3 criteria. The Primary outcome was self-reported order/referral of LDCT within the past year. Secondary outcomes were self-reported ordering of non-recommended LCS tests such as chest X Ray and sputum cytology.

On analysis it was noted that 59% of the providers reported ordering/referring for LDCT within the past year. Overall 62% of the provider’s demonstrated low LCS knowledge and the odds of ordering/referring for LDCT were 76% lower for providers with low LCS knowledge than for those with high LCS knowledge. Providers with low LCS knowledge had a 2.7 higher odds of ordering a screening chest radiograph, than providers with high LCS knowledge. The ordering/referring rates for LDCT were highest among general Internal Medicine/Primary Care Providers (75.9%), followed by Pulmonologists (74.4%), Hematologists/Oncologists (39.7%), and Gynecologists (2.1%). After adjusting for other variables, all provider types were less likely than general Internists/Primary Care Providers to order/refer for LDCT.

It was concluded that results of this study suggests that the referring provider knowledge of LCS guidelines is low and providers with low guideline knowledge were less likely to order LDCT lung screening. The authors recommended that strategies to advance effective evidence-based LCS should incorporate provider education and healthcare system interventions, to facilitate the appropriate identification of candidates for Lung Cancer Screening. Low Provider Knowledge Is Associated With Less Evidence-Based Lung Cancer Screening. Lewis JA, Chen H, Weaver KE, et al. J Natl Compr Canc Netw 2019;17:339-346

Late Breaking Abstract – ASCO 2019 Five-Year Survival Data for KEYTRUDA® in Advanced NSCLC

RR

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 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®.Unleashing-T-Cell-Function-with-PD-1-and-PDL1-Antibodies

The FDA approved KEYTRUDA® 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 whose tumors express PD-L1 (Tumor Proportion Score-TPS of 1% or more), as determined by an FDA-approved test. KEYTRUDA® is also approved 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.

The authors in this publication presented the 5-year Overall Survival (OS) for patients enrolled in the Phase 1b KEYNOTE-001 study, which was the first trial evaluating KEYTRUDA® in advanced NSCLC. In this trial, 550 patients were enrolled of whom 101 patients were treatment-naïve (N=101) and 449 patients were previously treated (N=449). Patients received KEYTRUDA® 2 mg/kg IV every 3 weeks or KEYTRUDA® 10 mg/kg IV every 2 or 3 weeks. The protocol in the recent years was changed to a straight dose of KEYTRUDA® 200 mg IV every 3 weeks, which is the typical regimen used in clinical practice. The Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Progression Free Survival (PFS), Overall Survival (OS) and Duration of Response (DOR). The median follow up was 60.6 months and 18% of participants (N=100) were still alive at that point.

The 5-year OS in the treatment-naïve patients (N=101) was 23.2% and 15.5% in previously treated patients (N=449). In treatment-naive patients, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 29.6%, compared with 15.7% with PD-L1 expression levels below 50%. In patients who had received previous treatment, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 25% compared with 12.6% with PD-L1 expression levels between 1% and 49%. Only 3.5% of people with PD-L1 expression levels below 1% were alive after 5 years. The investigator-reported ORR was 41.6% in treatment-naïve patients and 22.9% in previously treated patients. Median Duration of Response was 16.8 months and 38.9 months respectively. Immune-mediated adverse events were reported in 17% of patients at 5 years. Hypothyroidism was the most commonly reported immune-mediated adverse event, followed by pneumonitis, hyperthyroidism and skin toxicities.

It was concluded that the 5-year data from the KEYNOTE-001 trial showed that treatment with KEYTRUDA® was safe and effective and substantially increased Overall Survival in patients with advanced NSCLC. These data provide the longest efficacy and safety follow-up for NSCLC patients treated with KEYTRUDA®. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001. Garon EB, Hellmann MD, Costa EC, et al. J Clin Oncol. 2019;37(suppl; abstract LBA9015).