Author: RR

KEYTRUDA® (Pembrolizumab)

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The FDA on November 7, 2023, revised the existing indication of KEYTRUDA® (Pembrolizumab) with Trastuzumab, Fluoropyrimidine, and Platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma. This updated indication, which remains approved under accelerated approval regulations, restricts its use to patients whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-approved test. KEYTRUDA® is a product of MERCK & Co., Inc.

LOQTORZ® (Toripalimab-tpzi)

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The FDA on October 27, 2023, approved LOQTORZ® (Toripalimab-tpzi) with Cisplatin and Gemcitabine for the first-line treatment of adults with metastatic or recurrent, locally advanced Nasopharyngeal carcinoma. The FDA also approved LOQTORZ® as a single agent for adults with recurrent unresectable or metastatic Nasopharyngeal carcinoma with disease progression on or after a platinum-containing chemotherapy. LOQTORZ® is a product of Coherus BioSciences, Inc.

FDA Approves Two Gene Therapies to Treat Patients with Sickle Cell Disease

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SUMMARY: The FDA on December 8, 2023, approved CASGEVY® and LYFGENIA®, representing the first cell-based gene therapies for the treatment of Sickle Cell Disease in patients 12 years and older. Both products are made from the patients’ own hematopoietic stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a Hematopoietic Stem Cell Transplant. Prior to treatment, a patients’ own stem cells are collected, and then the patient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells.

Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder caused by mutations in the hemoglobin beta-globin gene, and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the US is approximately 40-60 years.

HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (Vaso-Occlusive Crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 Thalassemia (double heterozygote for HbS and b-0 Thalassemia) is clinically indistinguishable from HbSS disease. Management of Sickle Cell Disease includes pain control, transfusion support and Hydroxyurea. None of the presently available therapies addresses the underlying cause of this disease nor do they fully ameliorate disease manifestations. Allogeneic bone marrow transplantation can cure this genetic disorder, but less than 20% of eligible patients have a related HLA-matched donor. There is therefore a great unmet need to find new therapies for Sickle Cell Disease.

CASGEVY&reg: (Exagamglogene Autotemcel)
Fetal hemoglobin which consists of two alpha and two gamma chains is produced in utero, but the level of gamma-globulin decreases postnatally as the production of beta-globin and adult hemoglobin, which consists of two alpha and two beta chains, increases. It has been noted that elevated levels of fetal hemoglobin facilitates oxygen delivery, prevents the sickling of red blood cells, and is associated with decreased morbidity and mortality in patients with Sickle Cell Disease. BCL11A gene is a repressor of gamma-globin expression and fetal hemoglobin production in adult red blood cells. Downregulating BCL11A can therefore reactivate gamma-globin expression and increase fetal hemoglobin in RBC.

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nuclease gene editing technique can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. The modified hematopoietic stem cells are transplanted back into the patient where they engraft within the bone marrow and increase the production of fetal hemoglobin. The researchers in this study used this gene-editing technique in Hematopoietic Stem and Progenitor Cells at the erythroid-specific enhancer region of BCL11A to down-regulate BCL11A expression in erythroid-lineage cells, restore gamma-globin synthesis, and reactivate production of fetal hemoglobin. CASGEVY® is the first FDA-approved treatment to utilize CRISPR/Cas9, a type of genome editing technology, to modify patients hematopoietic stem cells.

The FDA approval of CASGEVY® is based on the ongoing single-arm, multi-center trial, involving adult and adolescent patients with Sickle Cell Disease. The trial focused on individuals with a history of at least two protocol-defined severe Vaso-Occlusive Crises (VOCs) during each of the two years prior to screening. The Primary efficacy outcome was freedom from severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period. Out of the 44 patients treated with CASGEVY®, 31 had sufficient follow-up time to be evaluable. Remarkably, 29 of these patients, representing 93.5%, achieved the Primary efficacy outcome, which is freedom from severe VOC episodes for at least 12 consecutive months. Notably, all treated patients achieved successful engraftment, a crucial aspect confirming the efficacy of the CRISPR/Cas9 genome editing technology in modifying hematopoietic stem cells. Importantly, no instances of graft failure or rejection were reported, affirming the safety and viability of CASGEVY® as a therapeutic option. This high success rate underscores the therapeutic potential of CASGEVY® in mitigating the recurrent and debilitating crises associated with Sickle Cell Disease. The most common side effects were stomatitis, cytopenias, febrile neutropenia, nausea, vomiting, headache and itching.

LYFGENIA® (Lovotibeglogene Autotemcel)
LYFGENIA® is a cell-based gene therapy that uses a lentiviral vector as the gene delivery vehicle to add a functional gene to the hematopoietic stem cells, thereby enabling production of HbAT87Q, which is a gene therapy-derived hemoglobin, that functions similarly to hemoglobin A (normal adult hemoglobin produced in persons not affected by Sickle Cell Disease). Red blood cells containing HbAT87Q have a lower risk of sickling , resulting in VOCs. These modified stem cells are then delivered to the patient.

The safety and effectiveness of LYFGENIA® was based on the analysis of data from a single-arm, 24-month, multicenter study in patients with Sickle Cell Disease and history of Vaso Occlusive Events (VOEs). The assessment of efficacy was based on the complete resolution of VOEs between 6 and 18 months after LYFGENIA® infusion. Of the 32 patients included in the study, 88% (28 patients) achieved complete resolution of VOEs within the stipulated timeframe. The most common side effects included stomatitis, cytopenias and febrile neutropenia. Hematologic malignancy has occurred in patients treated with LYFGENIA®, and patients receiving this product should have lifelong monitoring for these malignancies.

In conclusion, the two revolutionary cell-based gene therapies with CASGEVY® and LYFGENIA® heralds a transformative era in the management of Sickle Cell Disease (SCD), for individuals aged 12 and above.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease

FDA Approves AUGTYRO® for ROS1-positive Non-Small Cell Lung Cancer

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SUMMARY: The FDA on November 15, 2023, approved AUGTYRO® (Repotrectinib) for locally advanced or metastatic ROS1-positive Non-Small Cell Lung Cancer (NSCLC). This is the first FDA approval that includes patients with ROS1-positive NSCLC who have previously received a ROS1 Tyrosine Kinase Inhibitor (TKI), in addition to patients who are TKI naïve.

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. There are currently two FDA-approved treatment options for ROS1-positive metastatic NSCLC- Crizotinib and Entrectinib.

Repotrectinib is a next-generation TKI targeting ROS1 or NTRK-positive locally advanced or metastatic solid tumors, including NSCLC. Repotrectinib was designed to improve durability of response and with favorable properties to enhance intracranial activity.

The FDA approval was based on the results of the TRIDENT-1 global, multicenter, single-arm, Phase I/II, open-label, multi-cohort clinical trial, designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of Repotrectinib, in patients with advanced solid tumors, including locally advanced or metastatic NSCLC. Phase I component of the trial evaluated the safety and pharmacokinetics, whereas in the Phase II component of the study included six distinct expansion cohorts, including TKI-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors. Eligibility requirements included locally advanced or metastatic solid tumors harboring ROS1 or NTRK1-3 gene fusions. Patients with asymptomatic CNS metastases were allowed. Patients received Repotrectinib 160 mg once daily, orally for 14 days, followed by 160 mg twice daily until disease progression or unacceptable toxicities. The Primary endpoint was Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR), and Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and Clinical Benefit Rate (CBR). The efficacy was evaluated in ROS1 TKI-naïve patients (N=71) who received up to one prior line of platinum-based chemotherapy and/or immunotherapy, and in patients who received one prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy (N=56).

In TKI-naïve patients with median follow-up of 24.0 months, the confirmed Objective Response Rate by BICR was 79%, median Duration of Response was 34.1 months and PFS was 35.7 months. In patients with measurable brain metastases at baseline (N=9), intracranial ORR per BICR was 89% and these responses were prolonged.

In patients who received one prior ROS1 TKI with no prior chemotherapy or immunotherapy, at a median follow-up of 21.5 months, the confirmed Objective Response Rate by BICR was 38%, median Duration of Response was 14.8 months and PFS was 9.0 months. In this subset of patients with measurable brain metastases at baseline (N=13), intracranial ORR per BICR was 38%.

The most common adverse reactions were fatigue, dizziness, dyspnea, dysgeusia, peripheral neuropathy, constipation, ataxia, cognitive disorders, and muscular weakness.

It was concluded that the TRIDENT-1 trial demonstrated the efficacy of Repotrectinib in both, TKI-naïve and previously treated patients, showcasing high response rates and durable outcomes. These data will provide physicians with valuable insights into the clinical benefits with Repotrectinib , paving the way for its potential adoption as a new standard of care, in the treatment of ROS1-positive NSCLC. TRIDENT-1 trial is ongoing to assess long term outcomes and additional endpoints across patient populations with ROS1-positive locally advanced or metastatic NSCLC, and NTRK-positive advanced solid tumors.

Repotrectinib in patients with ROS1 fusion-positive (ROS1+) NSCLC: Update from the pivotal phase 1/2 TRIDENT-1 trial. Cho BC, Camidge DR, Lin JJ, et al. Presented at the IASLC 2023 World Conference on Lung Cancer; September 10-12, 2023; Singapore. Abstract OA03.06.

Late Breaking Abstract – ASH 2023: Daratumumab Combination Superior to VRd in Newly Diagnosed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730new cases will be diagnosed in 2023 and 12,590 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease.

Transplantation-eligible patients with newly diagnosed multiple myeloma are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd) induction therapy followed by Autologous Stem-Cell Transplantation, consolidation therapy with VRd, and maintenance therapy with Lenalidomide. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Daratumumab (DARZALEX®) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. Daratumumab exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, Daratumumab may have a role in immunomodulation by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

PERSEUS trial is an open-label, multicenter, randomized Phase III study, conducted to evaluate the efficacy and safety of subcutaneous Daratumumab combined with VRd induction and consolidation therapy and with Lenalidomide maintenance therapy (D-VRd group), as compared with VRd induction and consolidation therapy and Lenalidomide maintenance therapy alone (VRd group), for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma. The subcutaneous formulation of Daratumumab was chosen as it has been found to be noninferior to intravenous Daratumumab, as it is associated with a lower incidence of infusion-related reactions, can be administered in a single dose for all patients, and has a shorter duration of administration of 3-5 minutes.

In this study, 709 eligible patients were randomly assigned in a 1:1 ratio to receive either subcutaneous Daratumumab combined with VRd induction therapy before transplantation, with VRd consolidation therapy after transplantation, and with Lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and Lenalidomide maintenance therapy alone (VRd group). All patients received VRd in six 28-day cycles (four induction cycles and two consolidation cycles) and VRd consisted of Bortezomib 1.3 mg/m2 subcutaneous on days 1, 4, 8, and 11 of each cycle, Lenalidomide 25 mg orally on days 1 through 21 of each cycle, and Dexamethasone 40 mg oral or IV given on days 1-4 and days 9-12 of each cycle. Patients in the D-VRd group also received Daratumumab 1800 mg given subcutaneous weekly during cycles 1 and 2, 1800 mg subcutaneous every 2 weeks cycles 3-6. Patients underwent Autologous Stem-Cell Transplantation after the completion of induction therapy (cycle 4) and consolidation therapy began 30-60 days after transplantation. After completion of consolidation therapy (cycle 6), all the patients received Lenalidomide 10 mg orally in 28-day maintenance cycles until disease progression or unacceptable toxicities. Patients in the D-VRd group also received maintenance therapy with subcutaneous Daratumumab 1800 mg subcutaneous every 4 weeks for at least 24 months and Daratumumab therapy was discontinued in patients who had a Complete Response or better and had sustained Minimal Residual Disease (MRD)–negative status (defined as absence of malignant cells at a sensitivity threshold of 10−5 or lower) for at least 12 months. The median age was 60 years and randomization was stratified according to the Stage (I, II, or III) and cytogenetic risk (standard risk or high risk, defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16] cytogenetic abnormality). The Primary end point was Progression Free Survival. Secondary end points included a Complete Response or better and Minimal Residual Disease negative status.

At a median follow-up of 47.5 months, at the first interim analysis, the risk of disease progression or death in the D-VRd group was significantly lower than the risk in the VRd group. The 4-year PFS was 84.3% in the D-VRd group and 67.7% in the VRd group (HR for disease progression or death=0.42; P<0.001). The percentage of patients with a Complete Response or better was higher in the D-VRd group than in the VRd group (87.9% versus 70.1%; P<0.001). The same was true with MRD-negative status (75.2% versus 47.5% respectively, P<0.001). Serious adverse events occurred in 57% of the patients in the D-VRd group and 49.3% of those in the VRd group. Treatment discontinuation due to adverse events however occurred less often in the quadruplet group.

The researchers concluded that the addition of subcutaneous Daratumumab to VRd induction and consolidation therapy and to Lenalidomide maintenance therapy conferred a significant and clinically meaningful benefit with respect to Progression Free Survival, Complete Response rate and MRD-negative status, with a favorable benefit–risk profile, among transplantation-eligible patients with newly diagnosed multiple myeloma.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. for the PERSEUS Trial Investigators. Published on December 12, 2023, at NEJM.org. DOI: 10.1056/NEJMoa2312054.

FDA Approves WELIREG® for Advanced Renal Cell Carcinoma

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SUMMARY: The FDA on December 14, 2023, approved Belzutifan (WELIREG®) for patients with advanced Renal Cell Carcinoma (RCC) following a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) inhibitor and a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor (VEGF-TKI). The American Cancer Society estimates that 81,800 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2023 and about 14,890 people will die from this disease. Clear cell Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer in adults. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five-year survival of patients with advanced RCC is about 14% and there is a significant need for improved therapies for this disease.

Patients with advanced RCC are often treated with immune checkpoint inhibitors and Vascular Endothelial Growth Factor Receptor (VEGFR) targeted Tyrosine Kinase Inhibitors, either in combination or sequentially. However upon progression on these therapies, there are limited treatment options and there is an unmet medical need.

The VHL (Von Hippel-Lindau) protein is a tumor suppressor gene located on the short arm of chromosome 3p. It is frequently mutated and inactivated in approximately 90% of clear cell Renal Cell Carcinomas (ccRCC). The VHL gene under normal conditions binds to Hypoxia-Inducible Factors (HIFs) and facilitates degradation of this factor. Under hypoxic conditions and in patients having biallelic loss of function and mutation of VHL genes, HIFs are not degraded. High HIF levels and subsequent overproduction of VEGF, PDGF and TGF-alpha, resulting in increased angiogenesis, increased tumor cell proliferation and survival, as well as metastasis.

Belzutifan (WELIREG®) is a a first-in-class, oral, HIF-2alfa inhibitor approved in the US for adult patients with Von Hippel-Lindau (VHL) disease who require therapy for associated Renal Cell Carcinoma (RCC), Central Nervous System (CNS) Hemangioblastomas, or Pancreatic NeuroEndocrine Tumors (pNET), not requiring immediate surgery. This approval was based on the Overall Response Rate (ORR) and Duration of Response (DOR) data from the Phase II LITESPARK-004 trial.

The present FDA approval was based on LITESPARK-005, which is a randomized, open-label, Phase III trial, in which Belzutifan was compared with Everolimus in pretreated advanced Renal Cell Carcinoma (RCC). In this study, 746 enrolled patients with metastatic clear cell RCC whose disease progressed after treatment with both an immune checkpoint inhibitor, such as a PD-1 or PD-L1 inhibitor, and VEGF-TKI, in sequence or in combination, were randomly assigned 1:1 to receive either Belzutifan 120 mg orally daily (N=374) or Everolimus 10 mg orally daily (N=372), until disease progression or unacceptable toxicity. The dual Primary endpoints were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary endpoints included Overall Response Rate (ORR) by BICR and Safety.

At the first pre-specified interim analysis at a median follow up of 18.4 months, Belzutifan significantly reduced the risk of disease progression or death by 25% compared to Everolimus (HR=0.75; P<0.001). The results at the second pre-specified interim analysis were consistent with first interim analysis. At a median follow-up of 25.7 months, Belzutifan significantly reduced the risk of disease progression or death by 26% compared to Everolimus (HR=0.74; P<0.001). The estimated 12-month PFS rate was 33.7% for patients who received Belzutifan versus 17.6% for patients who received Everolimus, and the estimated 18-month PFS rate was 22.5% and 9.0%, respectively. The Overall Survival data favored Belzutifan compared to Everolimus at both the first and second interim analysis, but did not reach statistical significance and will be tested at a subsequent analysis.

There was a statistically significant improvement in ORR at both the first and second interim analysis, and the ORR was 22.7% with a Complete Response rate 3.5% for patients who received Belzutifan versus an ORR of 3.5% with no patients achieving a Complete Response for patients who received Everolimus (P<0.00001). The time to response with Belzutifan was about three months. Quality of Life favored Belzutifan.

Treatment-related adverse events and in particular Grade 3 adverse events were similar in both treatment groups. Adverse events leading to treatment discontinuation occurred in 5.9% of patients who received Belzutifan and 14.7% among those who received Everolimus. The most common side effects associated with Belzutifan were anemia, fatigue, nausea, constipation, peripheral edema, dyspnea and arthralgia.

It was concluded that Belzutifan was associated with a statistically significant improvement in Progression Free Survival and Overall Response Rate compared to Everolimus in patients with advanced clear cell Renal Cell Carcinoma, after immune checkpoint and anti-angiogenic therapies. They added that this is the first Phase III trial to show positive results in advanced RCC following standard therapies and the first drug with a new mechanism of action to demonstrate efficacy in this group of patients.

Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Randomized open-label phase III LITESPARK-005 study. Albiges L, Rini BI, Peltola K, et al. DOI:https://doi.org/10.1016/j.annonc.2023.10.090. LBA88