GAVRETO® (Pralsetinib)

The FDA on December 1, 2020 approved GAVRETO®, for adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant Medullary Thyroid Cancer (MTC) who require systemic therapy, or RET fusion-positive thyroid cancer who require systemic therapy and who are Radioactive Iodine-refractory (if Radioactive Iodine is appropriate). GAVRETO® is a product of Blueprint Medicines Corporation.

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

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

RETEVMO® (Selpercatinib)

The FDA on May 8, 2020, granted accelerated approval to RETEVMO® for the following indications:

1) Adult patients with metastatic RET fusion-positive Non-Small Cell Lung Cancer (NSCLC).

2) Adult and pediatric patients 12 years of age or older with advanced or metastatic RET-mutant Medullary Thyroid Cancer (MTC) who require systemic therapy.

3) Adult and pediatric patients 12 years of age or older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy, and who are Radioactive Iodine-refractory (if Radioactive Iodine is appropriate).

RETEVMO® is a product of Eli Lilly and Company.

Radioactive Iodine Increases Risk of Myeloid Malignancies in Patients with Thyroid Cancer

SUMMARY: The American Cancer Society estimates that about 53,990 new cases of thyroid cancer will be diagnosed in the United States for 2018 and about 2,060 patients will die of the disease. Thyroid cancer is the most prevalent endocrine malignancy and is classified into three histological groups – Well Differentiated Thyroid Cancers (94%) which include Papillary (80%), Follicular (11%) and Hürthle cell (3%) histologies, Medullary Thyroid Carcinoma (MTC) representing 4% and Anaplastic (undifferentiated) Thyroid Carcinoma (ATC) representing about 2%. Patients with WDTC often undergo thyroidectomy followed by adjuvant radioactive iodine (RAI) to ablate residual or unresectable disease. Approximately 20% of the patients with WDTC develop local recurrence and 10% develop metastatic disease at 10 years following surgery, RadioIodine Ablation (RIA) and TSH suppressive therapy. There has been a four-fold increase in the incidence of WDTC over the past 30 years and this has been attributed to improved detection of small, low-risk tumors. Majority of these patients are treated with RAI where patients do not derive therapeutic benefit but are rather exposed to its carcinogenic effects. Although prior studies have shown an increased risk of Secondary Hematologic Malignancies in patients with WDTC treated with RAI, these analyses grouped all types of leukemia under one broad category, which oversimplified risk estimation.

The authors conducted this study to investigate the risk and outcomes of second hematologic malignancies (SHMs) among patients with Well Differentiated Thyroid Cancer (WDTC) treated with RadioActive Iodine (RAI). A total of 183,894 patients with thyroid cancer were identified from 18 registries of the National Cancer Institute SEER (Surveillance, Epidemiology, and End Results) program and 148,215 patients with WDTC were included in this study. Among those included, 53% underwent surgery alone, and 47% underwent surgery and received RAI. Patients were excluded if their thyroid malignancy was not of follicular or papillary histology. Low/Intermediate-risk patients with WDTC were defined per the latest American Thyroid Association guidelines as T1-2, N0 tumors 4 cm or less in size, or T1-3, N1 tumors in patients older than 45 years of age.

The Primary outcome was the development of Second Hematologic Malignancies (SHMs), defined as a non-synchronous Hematologic Malignancies occurring 1 year or more after treatment of WDTC. SHMs included in this study were Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Hodgkin Lymphoma, Non-Hodgkin Lymphoma, and Multiple Myeloma (MM). SHMs occurring less than 1 year after WDTC diagnosis were also excluded. The authors performed a competing risk regression analysis to calculate the risks of SHMs that occurred after WDTC treatment and they assessed the outcomes after SHM diagnosis.

At a median follow up of 6.5 years after WDTC diagnosis, 783 patients developed a Secondary Hematologic Malignancy. In multivariate analysis, when compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing AML (HR=1.79; P=0.01) and CML (HR=3.44; P<0.001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. In those patients with WDTC developing AML, the median Overall Survival was significantly shorter compared with matched controls (8 years versus 31 years; P=0.001). Further, among those developing AML after RAI treatment, median Overall Survival was inferior compared to matched controls with de novo AML (1.2 years versus 2.9 years; P=0.06).

The authors concluded that patients with Well Differentiated Thyroid Cancer (WDTC) treated with RAI are at an increased early risk of developing AML and CML. Patients developing AML following treatment with RAI have a poor prognosis. RAI use in patients with WDTC should therefore be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance. Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer. Molenaar RJ, Sidana S, Radivoyevitch T, et al. J Clin Oncol 2017;36:1831-1839

Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer

SUMMARY: The U. S. Food and Drug Administration on February 13, 2015 approved Lenvatinib (LENVIMA®) for the treatment of patients with locally recurrent or metastatic, progressive, RadioActive Iodine (RAI)-refractory Differentiated Thyroid Cancer (DTC). The American Cancer Society estimates that about 62,450 new cases of thyroid cancer will be diagnosed in the United States for 2015 and about 1,950 patients will die of the disease. Thyroid cancer is the most prevalent endocrine malignancy and is classified into three histological groups – Differentiated Thyroid Cancers (94%) which include Papillary (80%), Follicular (11%) and Hürthle cell (3%) histologies, Medullary Thyroid Carcinoma (MTC) representing 4% and Anaplastic (undifferentiated) Thyroid Carcinoma (ATC) representing about 2%. Approximately 20% of the patients with DTC develop local recurrence and 10% develop metastatic disease at 10 years following surgery, radioiodine ablation and TSH suppressive therapy. These tumors lose avidity for iodine and are considered RadioActive Iodine (RAI) refractory. The discovery of genetic alterations in the MAP Kinase pathway as well as the PI3K (Phosphatidylinositol-3-Kinase)-AKT-mTOR pathway in thyroid tumors, has lead to the development of Tyrosine Kinase Inhibitors (TKI’s), to target these activated pathways. LENVIMA® is an oral multitargeted TKI which targets Vascular Endothelial Growth Factor Receptor (VEGFR)1-3, Fibroblast Growth factor Receptor (FGFR)1-4, Rearranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with antiangiogenesis properties by its ability to inhibit FGFR-1 thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting by FGFR and PDGFR beta. The SELECT trial is a double-blind, multicenter, phase III study in which 392 patients with advanced RAI-refractory Differentiated Thyroid Cancer (DTC) were randomly assigned in a 2:1 ratio to receive LENVIMA® 24 mg PO daily in 28-day cycles (N=261) or placebo (N=131). Both treatment groups were well balanced and pretreatment with one prior Tyrosine Kinase Inhibitor (TKI) was allowed. Patients in the placebo group were allowed to cross over and receive open-label LENVIMA®, at the time of disease progression. The primary end point was Progression Free Survival (PFS) and secondary end points included Response Rate, Overall Survival, and safety. The median Progression Free Survival was 18.3 months in the LENVIMA® group and 3.6 months in the placebo group (HR= 0.21; P<0.001). This benefit in PFS associated with LENVIMA® was observed in all pre-specified subgroup of patients including those who had received one prior treatment with a TKI. The objective response rate with LENVIMA® was 64.8% versus 1.5% with placebo (P<0.001) and the median overall survival was not reached in either group. The most frequently reported grade 3 or more adverse events in the LENVIMA® group included hypertension (42.9%) and proteinuria (10%). Approximately 14% of the patients in the LENVIMA® group discontinued the drug due to adverse effects. Exploratory biomarker analyses were performed for BRAF and RAS mutations on tumor tissue and it was noted that LENVIMA® benefitted patients regardless of BRAFor RAS mutation status. The authors concluded that LENVIMA® decreased the risk of disease progression by 79% as compared with placebo and was associated with significant improvements in objective Response Rate among patients with RAI-refractory thyroid cancer. NEXAVAR® (Sorafenib), another multitargeted TKI, is presently available for this group of patients and therefore proper sequencing of LENVIMA® and NEXAVAR® remains unknown although it appears that LENVIMA® has a markedly higher Progression Free Survival compared to NEXAVAR®. Schlumberger M, Tahara M, Wirth LJ, et al. N Engl J Med 2015; 372:621-630

Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer The phase III DECISION trial

SUMMARY: Over 90% of all Thyroid cancers are classified as Differentiated Thyroid Cancers (DTC) with Papillary, Follicular and Hürthle cell histologies. Approximately 5% to 15% of these patients develop resistance to RadioActive Iodine (RAI). NEXAVAR® is a multi-targeted tyrosine kinase inhibitor and prevents cancer growth by inhibiting multiple kinases that are involved in cell proliferation and angiogenesis. These kinases include Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. The DECISION trial is a randomized, double-blind, multicenter phase III study in which the efficacy and safety of NEXAVAR® was compared with placebo, in patients with progressive RAI-refractory DTC. Four hundred and seventeen patients (417) were randomized to receive either NEXAVAR® 400 mg PO BID (n=207) or placebo (n=210). The median age was 63 yrs and only patients who had no prior chemotherapy or targeted therapy and with disease progression within the preceding 14 months, were included. Over 95% of the patients had metastatic disease and the most common sites of spread were lungs and lymph nodes. Treatment was continued until disease progression or until unacceptable toxicity was noted. Upon progression, patients in the placebo group were allowed to crossover and receive open-label NEXAVAR®. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (RR=Complete + Partial Response [PR]), and safety. The median PFS was 10.8 months with NEXAVAR® compared to 5.8 months with placebo (hazard ratio [HR] = 0.58; P <0.0001). Partial responses were observed in 12.2% of patients receiving NEXAVAR® compared with 0.5% in the placebo arm (P < 0.0001). The median duration of partial response was 10.2 months. Further, 42% of patients in the NEXAVAR® group had stable disease for 6 months or more compared to 33% in the placebo group. Median OS has not been reached. It should be noted that approximately 70% of patients in the placebo group were allowed to crossover to receive open-label NEXAVAR® and this may impact the OS data. The most common adverse events in the NEXAVAR® group included hand–foot skin reactions, diarrhea, rash/desquamation, fatigue and hypertension. The authors concluded that NEXAVAR® nearly doubled the PFS compared to placebo, in this select group of patients with advanced DTC and is the first and only FDA approved therapy for Differentiated Thyroid Cancers. Brose MS, Nutting C, Jarzab B, et al. J Clin Oncol 31, 2013 (suppl; abstr 4)

NEXAVAR® (Sorafenib)

The FDA on November 22, 2013 approved NEXAVAR® for the treatment of locally recurrent or metastatic, progressive, Differentiated Thyroid Carcinoma (DTC), refractory to radioactive iodine treatment. NEXAVAR® was previously approved for the treatment of Renal Cell Carcinoma in 2005 and HepatoCellular Carcinoma in 2007. NEXAVAR® tablets are a product of Bayer Healthcare Pharmaceuticals Inc.

Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer The phase III DECISION trial

SUMMARY: The FDA approved Sorafenib (NEXAVAR®) for the treatment of patients with locally recurrent or metastatic, progressive, Differentiated Thyroid Carcinoma (DTC), refractory to RadioActive Iodine (RAI) treatment. Over 90% of all thyroid cancers are classified as Differentiated Thyroid Cancers with Papillary, Follicular and Hürthle cell histologies. NEXAVAR® inhibits multiple kinases that are involved in cell proliferation and angiogenesis thereby preventing cancer growth. These kinases include Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. The DECISION trial is a randomized, double-blind, multicenter phase III study in which the efficacy and safety of NEXAVAR® was compared with placebo, in patients with progressive RAI-refractory DTC. Four hundred and seventeen patients (417) were randomized to receive either NEXAVAR® 400 mg po BID (n=207) or placebo (n=210). The median age was 63 yrs and only patients who had no prior chemotherapy or targeted therapy and with disease progression within the preceding 14 months, were included. Over 95% of the patients had metastatic disease and the most common sites of spread were lungs and lymph nodes. Treatment was continued until disease progression or until unacceptable toxicity was noted. Upon progression, patients in the placebo group were allowed to crossover and receive open-label NEXAVAR®. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (RR=Complete + Partial Response [PR]), and safety. Approximately 70% of patients in the placebo arm were allowed to crossover to receive open-label NEXAVAR®. The median PFS was 10.8 months with NEXAVAR® compared to 5.8 months with placebo (hazard ratio [HR] = 0.58; P <0.0001). Partial responses were observed in 12.2% of patients receiving NEXAVAR® compared with 0.5% in the placebo arm (P < 0.0001). Further, 42% of patients in the NEXAVAR® group had stable disease for 6 months or more compared to 33% in the placebo group. Median OS has not been reached. The most common adverse events in the NEXAVAR® group included hand–foot skin reaction, diarrhea, rash/desquamation, fatigue and hypertension. The authors concluded that NEXAVAR® extends PFS in a select group of patients with advanced DTC and is the first and only FDA approved therapy for DTC. Brose MS, Nutting C, Jarzab B, et al. J Clin Oncol 31, 2013 (suppl; abstr 4)

Oncoprescribe Blog Pazopanib in Thyroid Cancer

Pazopanib (Votrient) is a Tyrosine Kinase Inhibitor (TKI) that  targets Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived Growth Factor Receptor (PDGFR), c-kit and Ret. This drug is presently approved by the FDA for the treatment of metastatic renal cell carcinoma. Data presented at the ASCO 2010 demonstrated impressive responses using Pazopanib (Votrient) in advanced radioiodine-refractory Follicular, Papillary and even Hurthle cell thyroid carcinomas.

This is an important step forward, in addressing this malignancy, as the benefit seen with chemotherapy is at best marginal, in the subset of patients studied. VEGF (Vascular Endothelial Growth Factor) appears to play a very important role in the pathogenesis of Thyroid Carcinomas. Learning and targeting the molecular mechanism of a malignancy is clearly the wave of the future.