Category: Precision Oncology

KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors

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SUMMARY: The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase, and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on, by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous.
KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS-G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of Colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.Inhibiting-KRAS-G12C

Sotorasib (AMG 510) is a small molecule that specifically and irreversibly inhibits KRAS-G12C and traps KRAS-G12C in the inactive GDP-bound state. Preclinical studies in animal models showed that Sotorasib inhibited nearly all detectable phosphorylation of Extracellular signal-Regulated Kinase (ERK), a key downstream effector of KRAS, leading to durable complete regression of KRAS-G12C tumors.

The authors conducted a multicenter, open label Phase I trial of Sotorasib, in patients with advanced solid tumors harboring the KRAS-G12C mutation. This trial consisted of dose escalation and expansion cohorts and included a total of 129 patients, of whom 59 patients had NSCLC, 42 had Colorectal cancer, and 28 patients had other tumor types (Appendiceal, Endometrial, Pancreatic cancers and Melanoma). Sotorasib was administered orally once daily and each treatment cycle was 21 days. The planned dose levels for the escalation cohorts were 180, 360, 720, and 960 mg. Treatment was continued until disease progression or unacceptable toxicity. The median patient age was 62 years and most of the enrolled patients were heavily pretreated and had received a median of 3 previous lines of anticancer therapy for metastatic disease. Among the NSCLC patient cohort, approximately 90% of patients were current or former smokers and had received anti- Programmed cell Death protein-1 (PD-1) or PD-Ligand 1 (PD-L1) therapies. All patients had received previous platinum-based chemotherapy. The Primary endpoint was safety, including the incidence of dose-limiting toxicities and key Secondary end points were pharmacokinetics and Objective Response Rates. The Sotorasib dose of 960 mg daily was identified as the dose for the expansion cohort. The median follow up was 11.7 months and the median duration of treatment was 3.9 months, with 57% of patients having received treatment for 3 months or more, and 29% of patients, for 6 months or more.

Among those patients with NSCLC, 32.2% of the patients had a confirmed Objective Response (Complete or Partial Response at all dose levels, and 88% had disease control (Objective Response or Stable disease), with a median Progression Free Survival of 6.3 months. Responses were rapid and were seen at week 6, and these responses were durable and ongoing at a median follow up of nearly a year.

Among the colorectal cancer subgroup, at a median follow up of 12.8 months, 7% had a confirmed response, and 74% had disease control, with a median duration of stable disease of 5.4 months and median PFS of 4 months. Responses were also observed in patients with Pancreatic, Endometrial, and Appendiceal cancers and Melanoma. It has been postulated that the inconsistent tumor responses noted between NSCLC and Colorectal cancer suggests either that KRAS-G12C is not the dominant oncogenic driver for colorectal cancer or that other pathways such as Wnt or EGFR pathways may mediate oncogenic signaling beyond KRAS. The authors suggest that a viable option would be to combine Sotorasib with therapies that block additional pathways, as was shown by studies in BRAF V600E-mutant Colorectal cancer. Approximately 57% of patients had treatment-related Adverse Events, of whom, about 12% had Grade 3 or 4 events. These toxicities included abnormal liver function studies, anemia, lymphopenia and diarrhea.

It was concluded Sotorasib showed promising anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS-G12C mutation. Studies evaluating Sotorasib as monotherapy or in combination with various agents in patients with NSCLC or other solid tumors are under way

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. Hong DS, Fakih MG, Strickler JH, et al. N Engl J Med 2020; 383:1207-1217.

Five Year Analysis of Adjuvant TAFINLAR® plus MEKINIST® in Stage III Melanoma

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SUMMARY: It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death, than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas and result in constitutive activation of the MAPK pathway.

TAFINLAR® (Dabrafenib) is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. In patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, a combination of TAFINLAR® and MEKINIST® resulted in a median Overall Survival (OS) of more than 2 years, with approximately 20% of the patients remaining progression free at 3 years. These encouraging results led to the study of this combination in patients with Stage III melanoma, with BRAF V600E or V600K mutations, after complete surgical resection.

COMBI-AD, an international, multi-center, randomized, double-blind, placebo-controlled, Phase III trial, in which 870 patients with completely resected, Stage III melanoma and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. Eligible patients had undergone completion lymphadenectomy, with no clinical or radiographic evidence of residual regional node disease. None of the patients had received previous systemic anticancer treatment or radiotherapy for melanoma. BRAF V600 mutation status was confirmed in primary tumor tissue or lymph node tissue by a central reference laboratory. The median age was 50 years. Both treatment groups were well balanced and 18% had Stage IIIA disease, 41% had Stage IIIB disease, and 40% had Stage IIIC disease. Of the enrolled patients, 91% had a BRAF V600E mutation, and 9% had a BRAF V600K mutation. The Primary end point was Relapse Free Survival (RFS) and Secondary end points included Overall Survival (OS), Distant metastasis-free survival, Freedom from relapse, and Safety.

The authors had previously reported that at a median follow up of 2.8 years, the estimated 3-year RFS rate was 58% in the combination therapy group and 39% in the placebo group (HR=0.47; P<0.001), and this represented a 53% lower risk of relapse. At the time of this analysis, median RFS rate had not been reached in the combination therapy group, and was 16.6 months in the placebo group. The improved RFS benefit with the combination therapy was consistent across patient subgroups, regardless of lymph node involvement or primary tumor ulceration. The risk of distant metastases or death was reduced by 49% with the combination therapy versus placebo (HR=0.51; P<0.001).

The authors in this publication reported the results for RFS and Distant metastasis-free survival at 5 years. Overall survival was not analyzed as the data was not mature. The minimum duration of follow up was 59 months. The RFS at 5 years 52% with TAFINLAR® plus MEKINIST® and 36% with placebo (HR for relapse or death=0.51). The Distant metastasis-free survival at 5 years was 65% with TAFINLAR® plus MEKINIST® and 54% with placebo (HR for distant metastasis or death=0.55). As has been reported in previous studies, majority of relapses occurred, within the first 3 years after surgery. There were no clinically meaningful differences noted in the incidence or severity of serious Adverse Events during the follow up period.

It was concluded that in this 5-year analysis of extended follow up from the COMBI-AD trial, 12 months of adjuvant therapy with a combination of TAFINLAR® and MEKINIST® resulted in longer Relapse Free and Distant metastasis-free Survival, compared to placebo, in patients with resected Stage III melanoma with BRAF V600 mutations.

Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. Dummer R, Hauschild A, Santinami M, et al. N Engl J Med 2020; 383:1139-1148

FDA Approves GAVRETO® for Metastatic RET Fusion-Positive Non Small Cell Lung Cancer

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SUMMARY: The FDA on September 4, 2020, granted accelerated approval to GAVRETO® (Pralsetinib) for adult patients with metastatic RET fusion-positive Non Small Cell Lung Cancer (NSCLC), as detected by an FDA approved test. The FDA also approved the Oncomine Dx Target (ODxT) Test as a companion diagnostic for GAVRETO®. Lung cancer is the second most common cancer in both men and women MOA-of-GAVRETOand 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.

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.

GAVRETO® is an oral, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations, including fusions and mutations, regardless of the tissue of origin. The efficacy of GAVRETO® was investigated in a multicenter, open-label, multi-cohort, Phase I/II basket clinical trial (ARROW), in patients with tumors showing RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either Next Generation Sequencing (NGS), Fluorescence In Situ Hybridization (FISH), or other tests. (In a basket trial, tumors with different histologies and single biomarker are placed in different baskets and receive a single treatment). The main efficacy outcome measures were Overall Response Rate (ORR) and response duration, as determined by a blinded Independent Review Committee, using RECIST criteria.

The efficacy for RET fusion-positive NSCLC was evaluated in 87 patients previously treated with platinum-based chemotherapy. Patients received GAVRETO® 400 mg orally once daily. The ORR was 57%, with a Complete Response (CR) rate of 5.7% and 80% of responding patients had responses lasting 6 months or longer. The median Duration of Response was not reached. Efficacy was also evaluated in 27 patients who never received systemic treatment and the ORR in this patient group was 70% with 11% CR rate and 58% of responding patients had responses lasting 6 months or longer. The most common adverse reactions (25% or more) were fatigue, constipation, musculoskeletal pain and hypertension.

It was concluded that patients treated with GAVRETO® had a rapid, potent, and durable clinical response, in patients with advanced RET fusion positive NSCLC, regardless of RET fusion partner, presence of brain metastases, or prior therapies.

Gainor JF, Curigliano G, Kim D-W, et al. DOI: 10.1200/JCO.2020.38.15_suppl.9515 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 9515-9515.

Precision Medicine in Pancreatic Cancer May Improve Overall Survival

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SUMMARY: The American Cancer Society estimates that for 2020, about 57,600 people will be diagnosed with pancreatic cancer and about 47,050 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 9%.

Patients with metastatic Pancreatic Ductal AdenoCarcinoma (PDAC) are often treated with chemotherapy and treatment regimens include FOLFIRINOX and Gemcitabine with nab-Paclitaxel (ABRAXANE®). However, resistance to current treatment modalities is common, and the median Overall Survival (OS) remains less than 1 year, suggesting that treatment with chemotherapy alone probably may not increase response rates and Overall Survival.

In an attempt to improve outcomes in patients with metastatic PDAC, molecular profiling using Next Generation Sequencing (NGS) and protein IHC panel-based examination of patients’ tumors, has enabled grouping patients into molecular subgroups with therapeutically actionable molecular alterations. It is estimated that approximately 25% of pancreatic cancers harbor actionable molecular alterations, defined as molecular alterations for which there is clinical or strong preclinical evidence of a predictive benefit from a specific therapy. However, less than 5% of patients with pancreatic cancer having actionable molecular alterations receive targeted therapies. This may be because of the aggressive nature of the disease or economic and logistical barriers. The commonly altered pathways include DNA repair (15%), cell cycle (11%), and AKT/mTOR (19%). Molecular targets have included Homologous Recombination Repair genes (14-17%), HER2 amplification genes (2%) and MisMatch Repair gene deficiency (MicroSatellite Instability 2-3%). Mutations in DNA repair genes are the most common “highly actionable” alterations (15%). The most frequently mutated DNA repair genes are ATM (4.5%) and BRCA2 (2.9%). Some examples of available targeted agents for patients with metastatic PDAC include PARP inhibitors for BRCA1 and BRCA2 mutations, TRK inhibitors for NTRK1, NTRK2, or NTRK3 fusions, and Immune Checkpoint Inhibitors for MMR-deficient or MSI-H tumors. Patients with these genetic alterations constitute about 8% of patients, with pancreatic cancer.

Know Your Tumor (KYT) is a precision medicine program, which is a collaboration between Perthera Inc. and the Pancreatic Cancer Action Network (PanCAN), and utilizes Perthera’s precision medicine system for multiomic molecular profiling of a nonselected patient population. Multiomics is data analysis at multiple levels such as genome, epigenome, transcriptome, proteome, and metabolome, to comprehensively understand human health and diseases, by interpreting molecular intricacy and variations. The intent of the KYT program is to match patients with appropriate clinical trials and therapies, based on actionable molecular alterations, treatment history, and geographical locations. The purpose of this study was to determine whether patients with pancreatic cancer whose tumors harbored actionable molecular alterations and who received molecularly matched therapy, had a longer median Overall Survival, than similar patients who did not receive molecularly matched therapy.

In this program, of the 1082 patients who received reports on their tumor genomic profile, outcomes were available for 677 patients, of whom 189 patients had actionable molecular alterations. At a median follow up of 383 days, patients with actionable molecular alterations who received a matched therapy (N=46) had a significantly longer median Overall Survival, compared to those patients who only received unmatched therapies (N=143), and this was statistically significant (2.58 years versus 1.51 years; HR=0.42: P=0.0004). The 46 patients who received a matched therapy also had significantly longer Overall Survival than the 488 patients who did not have an actionable molecular alteration (2.58 years versus 1.32 years; HR=0.34; P<0.0001). The median Overall Survival was not different between the patients who received unmatched therapy and those without an actionable molecular alteration (HR=0.82; P=0.10).

It was concluded from these Real-World outcomes that a matched therapy for patients with actionable molecular alterations can have a substantial effect on survival, in patients with pancreatic cancer. The authors acknowledged that only 2% of patients who were referred to undergo molecular profiling ultimately received a matched therapy and 143 patients with actionable molecular alterations received only unmatched therapies due to a variety of reasons including logistical issues and economic barriers.

Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Pishvaian MJ, Blais EM, Brody JR, et al. Lancet Oncol. 2020 Apr;21(4):508-518.doi: 10.1016/S1470-2045(20)30074-7. Epub 2020 Mar 2.

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)

FDA Approves IO in Combination with Targeted Therapies for BRAF Positive Advanced Melanoma

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SUMMARY: The FDA on July 30, 2020, approved TECENTRIQ® (Atezolizumab), in combination with COTELLIC® (Cobimetinib) and ZELBORAF® (Vemurafenib), for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. Patients with locally advanced or metastatic melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and result in constitutive activation of the MAPK pathway.

ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF, demonstrated significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), compared to Dacarbazine. Squamous cell carcinomas were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. MEK gene is downstream from RAF in the MAPK pathway. The addition of a selective inhibitor of MEK gene such as COTELLIC® (Cobimetinib) to a BRAF inhibitor such as ZELBORAF® has addressed some of these limitations, in previously published studies, with improvement in Objective Response Rates (ORR) and decrease in the incidence of cutaneous secondary cancers. coBRIM is a multicenter, randomized, Phase III study in which the efficacy and safety of COTELLIC® combined with ZELBORAF®, was evaluated in previously untreated patients, with advanced BRAF-mutated melanoma. The final analysis of this trial evaluated the 5-year survival data, and the OS was over 30% in patients who received the combination therapy, with a Complete Response (CR) rate was about 20%.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells. The 5 year OS among patients receiving PD1 targeted immunotherapy is about 34%, with a median OS of 17-20 months. With the approval of multiple therapeutic options for the management of patients with BRAF-mutant melanoma, treatment decisions have become increasingly complex. In patients with limited disease burden, immunotherapy with checkpoint inhibitors is favored by most clinicians, based on the long term data supporting the durability of responses with immunotherapies, but response rates are lower. On the contrary, BRAF-targeted agents are utilized in patients with extensive, symptomatic disease and active brain metastases, as the response rates are higher but are short lived. The optimal sequence of these therapeutic strategies in order to improve long-term patient outcome, has remained unclear.

Preclinical studies suggested that combining these two targeted therapies with a checkpoint inhibitor might overcome the limitations of each class and potentially lead to more durable responses. The safety and efficacy of combining TECENTRIQ® with COTELLIC® (MEK inhibitor) and ZELBORAF® (BRAF inhibitor), in patients with BRAFV600-mutated metastatic melanoma, was evaluated in a Phase I study, with promising results, and a 28-day run-in period with COTELLIC® and ZELBORAF® was associated with an increase in proliferating CD4+ T-helper cells, without increasing the T-regulatory cells (Tregs). Tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response and Tregs remain a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. The aim of IMspire 150 trial was to determine if combining checkpoint inhibitor with two targeted therapies would improve efficacy.

IMspire150 is a pivotal, placebo-controlled, international, multicenter, double-blinded, Phase III trial, in which 514 treatment-naive patients with Stage IIIc and Stage IV, BRAF V600–mutant malignant melanoma were enrolled. Patients were randomly assigned 1:1 to treatment with the doublet combination or the triplet therapy. Doublet therapy given to the control group of patients consisted of ZELBORAF® 960 mg orally twice daily plus COTELLIC® at 60 mg orally, on days 1 to 21 of a 28 day cycle. In the experimental or triplet therapy group, there was a 28-day run-in with ZELBORAF® plus COTELLIC® alone, dosed similar to the control group (cycle 1), following which patients received TECENTRIQ® 840 mg IV on Days 1 and 15 of each 28 day cycle starting cycle 2, in combination with ZELBORAF® at a lower dose of 720 mg orally twice daily and COTELLIC® 60 mg orally once daily. Treatment was continued until disease progression, or unacceptable toxicity. Both treatment groups were well balanced, median patient age was 54 years, 58% were male and 94% of patients had Stage IV disease. The Primary endpoint was investigator-assessed Progression Free Survival (PFS). Secondary end points included Objective Response Rates (ORR), Duration of Response (DOR), and Overall Survival (OS).

The combination of immunotherapy with targeted therapies was significantly superior to targeted therapies alone. At a median follow up of 18.9 months, the median PFS with the triplet combination was 15.1 months versus 10.6 months with the doublet therapy (HR=0.78; P=0.025). This represented a 22% reduction in the risk of disease progression. This benefit was observed across all subgroups including age, disease burden, LDH level, and extent of tumor involvement by organ site. Although Objective Response Rates were similar in both treatment groups, the median Duration of Response was 21.0 months with triplet combination versus 12.6 months for the doublet therapy. The OS data were not mature at the time of this analysis, but interim analysis however showed a median OS of 28.8 months with the triplet combination versus 25.1 months with doublet therapy. Both treatment groups had comparable toxicities. Among those patients receiving triplet combination, the most common toxicities were rash, fever, fatigue, nausea, pruritus, stomatitis, musculoskeletal pain, hepatotoxicity, edema, hypothyroidism, and photosensitivity.

It was concluded that in treatment-naive patients with advanced BRAF V600-mutant malignant melanoma, TECENTRIQ® in combination with ZELBORAF® and COTELLIC® significantly and clinically improved Progression Free Survival, when compared to placebo in combination with ZELBORAF® and COTELLIC®.

Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. McArthur GA, Stroyakovskiy D, Gogas H, et al. Presented at: the 2020 AACR Annual Virtual Meeting I; April 27-28, 2020. Abstract CT012.

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

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

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

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

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

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

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

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

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

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

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

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.