Osimertinib Plus Chemotherapy Superior to Osimertinib Alone in Advanced EGFR Mutated Non Small Cell Lung Cancer

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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.

Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor 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, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.

In the Phase III FLAURA trial, among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with Osimertinib significantly improved median Overall Survival, compared with Erlotinib and Gefitinib, and should therefore has been the preferred regimen in this patient group. The FLAURA2 trial builds on the favorable results observed in the Phase III FLAURA trial.

FLAURA2 is a randomized, open-label, multi-center, global, ongoing Phase III trial, in which 557 enrolled treatment naïve patients (N=557) with nonsquamous locally advanced (Stage IIIB-IIIC) or metastatic EGFR mutated NSCLC were randomly assigned 1:1 to receive Osimertinib plus chemotherapy (N=279) or Osimertinib monotherapy (N=278). Patients in the combination group received Osimertinib 80 mg oral tablets once daily in combination with chemotherapy consisting of Pemetrexed 500 mg/m2 IV plus Cisplatin 75 mg/m2 IV or Carboplatin (AUC5), every three weeks for four cycles, followed by Osimertinib with Pemetrexed maintenance every three weeks. The median patient age was 62 years, approximately 62% were women and 64% were Asian. Approximately 76% of patients completed four cycles of platinum therapy. The Primary end point was investigator-assessed Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety.

In this final analysis of the Primary endpoint of PFS, results from this study showed a significant improvement in Progression Free Survival (PFS) with the Osimertinib plus chemotherapy combination versus Osimertinib alone, with an 8.8-month improvement in median PFS with the combination regimen (HR=0.62; P<0.0001). This represented a 38% reduction in disease progression risk, compared to Osimertinib monotherapy. In addition, median PFS determined by blinded Independent Central Review showed a 9.5-month improvement with the combination regimen. The Objective Response Rate with the combination regimen was 83%, compared to 76%, in the Osimertinib monotherapy group. Grade 3 or higher hematologic adverse events occurred more frequently in the combination regimen group and were manageable. Data for Overall Survival were immature at the time of the analysis, and this ongoing trial will continue to assess the Secondary endpoint of Overall Survival.

The authors concluded that FLAURA2 provides compelling evidence that the addition of chemotherapy to Osimertinib in the first line treatment of nonsquamous, locally advanced or metastatic EGFR mutated NSCLC, can further improves outcomes, compared to Osimertinib alone, and can delay resistance to therapy and disease progression.

FLAURA2 results demonstrate osimertinib plus chemotherapy superior compared to osimertinib alone (press release). Available at: https://www.iaslc.org/iaslc-news/press-release/flaura2-results-demonstrate-osimertinib-plus-chemotherapy-superior. Published Sept.10, 2023.

Germline Testing to Identify 11 Genes Linked to Aggressive Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 288,300 new cases of Prostate cancer will be diagnosed in 2023 and 34,700 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer, and is the first treatment intervention. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The malignant transformation of prostatic epithelial cell as well as the development of CRPC has been attributed to deleterious alterations in a variety of genes including loss-of-function alterations in Homologous Recombination Repair (HRR) genes.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes that recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1, BRCA2, PALB2, CHEK2 and ATM genes. Mutations in these genes predispose an individual to develop malignant tumors. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

The current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer (version 1.2022) recommend germline testing for the subsets of patients with prostate cancer who are more likely to have germline DNA repair mutations. They include men with node positive, high-risk or very high-risk localized prostate cancer, men with metastatic prostate cancer, and men meeting family history criteria. NCCN recommends considering germline testing for men with personal history of prostate cancer and intermediate risk prostate cancer and intraductal/cribriform histology and personal history of exocrine pancreatic, colorectal, gastric, melanoma, pancreatic, upper tract urothelial, glioblastoma, biliary tract or small intestinal cancers. Germline testing panel sizes vary from dedicated BRCA1/2 testing to extended 91 plus-gene panels

The goal of this study was to investigate the association between rare deleterious variants and Variants of Unknown Significance (VUS) across the genome and in candidate genes, particularly DNA repair genes, and identify genes associated with aggressive prostate cancer.

The researchers conducted a two-stage exome-sequencing genetic association study, to identify rare genetic variants associated with aggressive prostate cancer. This analysis included 17,546 patients of European ancestry with prostate cancer from 18 epidemiological studies across the US, Europe and Australia. The study population included 9185 men with aggressive prostate cancer and 8361 men with nonaggressive prostate cancer. Aggressive prostate cancer was defined as at least one of the following: T4 disease, T3 plus a Gleason score of 8 or more, metastatic disease, or death from prostate cancer, while nonaggressive prostate cancer was defined as localized T1/T2 disease and a Gleason score of 6 or less. The researchers focused their study on 29 DNA repair pathway and cancer susceptibility genes previously linked with prostate cancer, in addition to a group of 167 genes thought to be related to DNA damage repair. They then looked for associations between deleterious genetic variants or Variants of Uncertain Significance (VUS) and aggressive versus nonaggressive prostate cancer, using a relatively modest threshold for significance.

The strongest evidence of association with aggressive or metastatic prostate cancer was noted for rare deleterious variants in known prostate cancer risk genes BRCA2 and ATM (P<0.0000019), followed by NBN (P=0.00017). This study found nominal evidence (P <0.05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes analyzed, TP53, RAD51D, BARD1, GEN1, and SLX4, had evidence of greater risk with an Odds Ratio (OR) of 2 or more, but carrier frequency differences between aggressive and nonaggressive prostate cancer were not statistically significant. Deleterious variants of the 11 candidate genes identified in the study were carried by 2.3% of patients with nonaggressive prostate cancer, 5.6% with aggressive prostate cancer, and 7.0% with metastatic prostate cancer.

In conclusion, the researchers from this analysis of the largest cohort of prostate cancer patients were able to identify DNA repair pathway gene variants, associated with aggressive prostate cancer. Testing should be extended to men without aggressive prostate cancer, as men carrying deleterious variants in these genes are likely to develop advanced disease.

Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer. Darst BF, Saunders E, Dadaev T, et al. JAMA Oncol. Published online September 21, 2023. doi:10.1001/jamaoncol.2023.3482

FDA Approves Pralsetinib for Non Small Cell Lung Cancer with RET gene fusions

SUMMARY: The FDA on August 9, 2023, granted regular approval to Pralsetinib (GAVRETO®) for adult patients with metastatic Rearranged during Transfection (RET) fusion-positive Non-Small Cell Lung Cancer (NSCLC) as detected by an FDA approved test. Pralsetinib was previously granted accelerated approval for the NSCLC indication in Sept. 2020, based on initial Overall Response Rate (ORR) and Duration of Response (DOR) in 114 patients enrolled in the ARROW trial. The conversion to regular approval was based on data from an additional 123 patients and 25 months of additional follow up, to assess Durability of Response.

Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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 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, MET, KRAS, 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.

Patients without a driver mutation are often treated with a platinum-doublet cytotoxic chemotherapy with/without Immune checkpoint inhibitors, or with Immune checkpoint inhibitor monotherapy. However, outcomes with immune checkpoint inhibitors remain poor in patients with RET fusion–positive NSCLC, regardless of PD-L1 expression.

Pralsetinib (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 Pralsetinib 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). Phase I Pralsetinib dose escalation study determined 400 mg QD as the recommended Phase II trial dose. Phase II trial evaluated Pralsetinib in multiple expansion groups, defined by disease type and treatment history.

The FDA regular approval was based on the efficacy of Pralsetinib in a total of 237 patients (N=237) with locally advanced or metastatic RET fusion-positive NSCLC. Patients received Pralsetinib 400 mg once daily until disease progression or unacceptable toxicity. Among the patients studied, 107 (N=107) were treatment-naïve and 130 patients (N=130) were previously treated with platinum-based chemotherapy. The main efficacy outcome measures were Overall Response Rate (ORR) and Duration of Response, as determined by a Blinded Independent Review Committee, using RECIST criteria.

The median age of the 107 patients in the treatment-naïve group was 63 years and 28% of patients had a history of or active CNS/brain metastases. The ORR in this group was 78%, with a Complete Response (CR) rate of 7%. The median Duration of Response was 13.4 months and 45% of patients experienced a Duration of Response of 12 months or longer.

The median age of the 130 patients in the group that was previously treated with platinum-based chemotherapy, was 59 years and 41% had a history of or active CNS/brain metastases. The ORR in this group was 63% with a CR rate of 6%. The median Duration of Response of 38.8 months and 66% of patients experienced a Duration of Response of at least 12 months.

In patients with measurable intracranial metastases, the intracranial response rate was 70%.

The most common adverse reactions were fever, fatigue, cough, constipation, diarrhea, musculoskeletal pain, hypertension and edema.

It was concluded from this study that treatment with Pralsetinib produced robust efficacy including intracranial activity, in patients with advanced RET fusion–positive NSCLC who are treatment-naive or are refractory to standard-of-care chemotherapy. Results from the confirmatory Phase III AcceleRET Lung study of Pralsetinib versus standard of care in the first-line setting are eagerly awaited and may further support the use of Pralsetinib for RET fusion-positive NSCLC in the first-line setting.


FDA Approves Momelotinib for Patients with Myelofibrosis and Anemia

SUMMARY: The FDA on September 15, 2023 approved Momelotinib (OJJAARA®) for the treatment of adult patients with intermediate or high-risk myelofibrosis, including Primary myelofibrosis or Secondary myelofibrosis, and anemia. Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. It affects approximately 25,000 patients in the United States. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be Primary (PMF) or Secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET).

The JAK-STAT signaling pathway has been implicated in the pathogenesis of myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STATs (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression.

In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the systemic symptoms often reported by patients with myelofibrosis, in addition to bone marrow fibrosis, and clonal proliferation resulting in extramedullary hematopoiesis and splenomegaly. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.
Chronic inflammation also drives hyperactivation of ACVR1 (Activin A receptor type 1), elevated hepcidin, dysregulated iron metabolism, and anemia of myelofibrosis. Approximately 40% of patients have moderate to severe anemia at the time of diagnosis of myelofibrosis, and almost all patients develop anemia over the course of the disease.

Momelotinib is a first-in-class inhibitor of three signaling pathways, Activin A receptor type 1 (ACVR1) as well as JAK1 and JAK2. Inhibition of ACVR1 leads to a decrease in circulating hepcidin, which is elevated in myelofibrosis and contributes to anemia, whereas inhibition of JAK1 and JAK2 may improve constitutional symptoms and splenomegaly.

The FDA approval was based on the findings from the pivotal Phase III MOMENTUM trial, and data from a subpopulation of adult patients with anemia enrolled in the SIMPLIFY-1 Phase III trial.

MOMENTUM is an ongoing Phase III, global, multicentre, randomized, double-blind study, conducted to evaluate the safety and efficacy of Momelotinib compared to Danazol, in patients with myelofibrosis who were symptomatic and anemic, and had been previously treated with an approved JAK inhibitor. This study was designed to evaluate the benefit of Momelotinib in reducing the key manifestations of myelofibrosis including constitutional symptoms, blood transfusion requirements due to anemia and splenomegaly. In this study, 195 eligible patients, with a confirmed diagnosis of Primary myelofibrosis, post-Polycythemia Vera (PV) myelofibrosis, or post–Essential Thrombocytopenia (ET) myelofibrosis were randomized 2:1 to receive Momelotinib 200 mg orally daily along with a placebo (N=130) or Danazol 600 mg orally daily along with a placebo (N=65). Enrolled patients were symptomatic with a Total Symptom Score (TSS) of at least 10, hemoglobin less than 10 gm/dL and platelet count 25,000/L or more. The median age was 70 years, approximately 50% of patients were Transfusion Dependent requiring 4 or more units of RBC transfusions in the 8 weeks before randomization and approximately 35% were Transfusion Requiring, who required RBC transfusions but did not meet the criteria for Transfusion Dependence. The Primary end point was achievement of a Myelofibrosis Symptom Assessment Form (MFSAF v4.0) TSS reduction of 50% or more at week 24 compared to baseline. Patients in the Danazol group were allowed to cross over to Momelotinib after week 24. It was noted that at week 24, 25% of patients in the Momelotinib group experienced a TSS reduction of 50% or more, compared with 9% in the Danazol group (P=0.0095). At week 24, 31% of patients who received Momelotinib achieved Transfusion Independence, compared with 20% in the Danazol group. Further, 39% of patients in the Momelotinib group experienced a splenic volume response of at least 25% by week 24, compared to 6% in the Danazol group (P<0.0001).

SIMPLIFY-1 was a multicentre, randomized, double-blind, Phase III study in which the efficacy and safety of Momelotinib was compared Ruxolitinib in patients with myelofibrosis who had not received prior treatment with a JAK inhibitor. In this study 432 eligible patients (N=432) received Momelotinib 200 mg orally once daily or Ruxolitinib (JAKAFI®) at an adjusted dose twice daily for 24 weeks. Subsequently, those in the Ruxolitinib arm were able to switch to open-label Momelotinib. Safety and efficacy results for SIMPLIFY-1 were based upon a subset of patients with anemia (hemoglobin less than 10 g/dL) at baseline. The efficacy of Momelotinib in the treatment of patients with myelofibrosis in SIMPLIFY-1 was based on spleen volume response (reduction by 35% or greater). In this study, Transfusion Independence was significantly improved at week 24 with Momelotinib compared to Ruxolitinib. Results in this study were mixed and Momelotinib offered less symptom control than Ruxolitinib, but there was comparable spleen volume reduction and a potential benefit in terms of anemia.

These findings support the potential use of Momelotinib as an effective treatment in patients with myelofibrosis, particularly in patients with anemia and thrombocytopenia, thus fulfilling an unmet need for these patients.

Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GSK. September 15, 2023. Accessed September 15, 2023. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia/

OMISIRGE® (Omidubicel-onlv)

The FDA on April 17, 2023, approved OMISIRGE® for use in adult and pediatric patients (12 years and older) with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning, to reduce the time to neutrophil recovery and the incidence of infection. OMISIRGE® is a product of Gamida Cell Ltd.