Category: Hem/Onc Updates

FDA Approves Ivosidenib for Myelodysplastic Syndromes

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SUMMARY: The FDA on October 24, 2023, approved Ivosidenib (TIBSOVO®) for adult patients with Relapsed or Refractory MyeloDysplastic Syndromes (MDS) with a susceptible Isocitrate DeHydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test. The FDA also approved the Abbott RealTime IDH1 Assay as a companion diagnostic device to select patients for Ivosidenib.

It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient’s disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years.

Patients with Low-risk MDS often present with symptomatic anemia and these patients are in chronic need for RBC transfusions. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200U per liter are less likely to respond to ESAs. A majority of patients with higher-risk MDS are treated with hypomethylating agents such as Azacitidine and Decitabine and these agents can favorably modify the natural history of the disease, and have been shown to improve survival. However, outcomes are poor and no therapies currently exist for patients with Isocitrate Dehydrogenase 1-mutant Relapsed or Refractory MDS, following failure on a hypomethylating agent.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

Ivosidenib is a first-in-class, oral, potent, targeted, small-molecule inhibitor of mutant IDH1. The FDA in 2018, approved Ivosidenib for adult patients with Relapsed or Refractory AML with a susceptible IDH1 mutation, and in 2019 approved Ivosidenib for newly diagnosed AML with a susceptible IDH1 (Isocitrate DeHydrogenase-1) mutation, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction.

The present FDA approval is supported by a pivotal Phase 1, open-label, multinational study, in which the safety, tolerability, and clinical activity of Ivosidenib was evaluated among patients with Relapsed or Refractory Myelodysplastic syndromes with an IDH1 mutation. In this study 18 eligible patients (N=18) received Ivosidenib 500 mg orally daily, continuous for 28-day cycles, until disease progression, unacceptable toxicity, or Hematopoietic Stem Cell Transplantation. The median treatment duration was 9.3 months. One patient underwent a Stem Cell Transplantation following Ivosidenib. IDH1 mutations were detected in peripheral blood or bone marrow by a local or central diagnostic test and confirmed retrospectively by the Abbott RealTime IDH1 Assay. The median age was 73 years and majority of patients had intermediate or high IPSS-R score at the time of screening for the study. The Primary efficacy end point was the Complete Response (CR) plus Partial Response (PR) rate. Secondary endpoints included duration of CR plus PR, duration of transfusion independence, and time to transfusion independence.

All observed responses were Complete Responses. The CR rate was 38.9%. The median time to Complete Response was 1.9 months and at the time of data cutoff, the median duration of Complete Responses was not estimable and ranged from 1.9 to 80.8+ months. Additionally, of the 9 patients who were transfusion dependent with Red Blood Cells or platelets at baseline, 67% became RBC and platelet transfusion independent during any 56-day post-baseline period. Of the 9 patients independent of both RBC and platelet transfusions at baseline, 78% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions included GI toxicities such as mucositis, diarrhea, constipation and nausea, fatigue, arthralgia, myalgia, cough, and rash. Differentiation syndrome was rare and manageable. It should be noted that Ivosidenib can also cause QTc prolongation.

It was concluded from this study that Ivosidenib induced durable remissions including a substantial proportion of Complete Remissions with an acceptable safety profile, in patients with Relapsed or Refractory Myelodysplastic syndromes with an IDH1 mutation. Further, a significant proportion of patients became or remained transfusion independent. This is the first targeted therapy approved for this indication.

UPDATED SUBSTUDY RESULTS FOR IVOSIDENIB IN IDH1-MUTANT RELAPSED/REFRACTORY MYELODYSPLASTIC SYNDROME. Dinardo C, Roboz G, Watts JM, et al. Hemasphere. 2023 Aug; 7(Suppl): e75740ab. DOI: 10.1097/01.HS9.0000969800.75740.ab.

Single Blood Test for Multi-Cancer Early Detection

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SUMMARY: The American Cancer Society estimates that in 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Although cancer mortality rates continue to decline with advances in treatment, improving early detection can reduce disease and treatment-related morbidity, improve treatment outcomes, quality of life and reduce financial burden both for the patient as well as the society as a whole. Currently the USPSTF (Unites States Preventive Services Task Force) and ACS (American Cancer Society) recommend screening for breast, cervical, colorectal, and lung cancers. Neither the ACS nor USPSTF have specific recommendations for prostate cancer screening. These cancers collectively account for only 42% of annual cancer incidence in people aged 50-79 years. It has been estimated that detection of cancer at an earlier stage could reduce cancer-related deaths by 15% or more within 5 years. Some of the available screening tests reduce cancer-specific mortality, but are associated with high false-positive rates, overdiagnosis, and overtreatment.

Galleri is a Multi-Cancer Early Detection (MCED) test developed for the early detection of multiple asymptomatic cancers that lack recommended screening tests, using a blood sample. DNA (cell free DNA) is shed into the blood stream both by tumor cells as well as healthy cells. The Galleri test uses Next Generation Sequencing (NGS) and machine-learning algorithms to isolate cell-free DNA and analyze more than 100,000 DNA regions and over a million specific DNA sites, to screen for a signal shared by cancers. The test looks for cell-free DNA and identifies whether it comes from healthy or cancer cells. DNA from cancer cells has specific methylation patterns that identify it as a cancer signal. Methylation patterns also contain information about the tissue type or organ associated with the cancer signal. So, once a cancer signal is detected, the Galleri test predicts the Cancer Signal Origin, or the tissue or organ where the cancer signal originated, to help guide diagnostic evaluation. The Galleri test is recommended for use in adults with an elevated risk for cancer, such as those aged 50 or older, and should be used in addition to routine cancer screening tests. Galleri is not recommended in individuals who are pregnant, 21 years old or younger, or undergoing active cancer treatment.

A validation study (Circulating Cell-free Genome Atlas study-CCGA) was conducted to evaluate the accuracy of the Galleri test. This study included 2,823 people with a known diagnosis of cancer and 1,254 healthy people. The overall Sensitivity for cancer signal detection was 51.5% and the Specificity was 99.5%. The sensitivity of the test increased with advanced cancer stages. Cancer signals were detected across over 50 cancer types and the overall accuracy of predicting Cancer Signal Origin in those who tested true positive was 88.7% (Ann Oncol. 2021;32:1167-1177).

PATHFINDER was a pilot, prospective cohort study conducted to investigate the feasibility of MCED testing for cancer screening. This study included 6,621 participants from oncology and primary care outpatient clinics at seven U.S. health networks who underwent MCED blood testing. Participants were 50 years or older, with no signs or symptoms of cancer, and majority were women (63.5%) and White (91.7%). Approximately 56% of participants had additional risk factors such as smoking, germline cancer predisposition, or personal history of treated cancer. The Primary outcome was time to diagnosis, and extent of diagnostic testing required to confirm the presence or absence of cancer.

MCED testing detected a cancer signal in 1.4% of the total patient sample of whom 38% had cancer confirmed (true positives), while 62% had no cancer (false positives). In patients in whom no cancer signal was detected, 95.5% were true negatives, 1.3% was false negatives, and 3.2% did not have cancer-status assessment at the end of the study. The tests accuracy in predicting the primary cancer location (Cancer Signal Origin) among the true positives was high at 97%. The median time to achieving a diagnostic resolution was 79 days, 57 days in true-positive patients and 162 days in false-positive ones. Fewer procedures were done in participants with false-positive results compared to true-positive results (30% versus 82% respectively) and few participants had surgery (one with a false-positive result and three with a true-positive result).

Among participants whose testing was true-positive and who had a confirmed new cancer diagnosis, nearly half (48%) were detected at an early stage (Stage I-II) when the potential for curative treatment is increased. Further, 74% of the MCED-detected cancers were cancer types that do not currently have USPSTF screening recommendations. These included cancers of the bile duct, pancreas, small intestine, and spindle cell neoplasm, which are all associated with high mortality rates and may be amenable to surgical resection at early stages.

In the 12 months study period, 121 cancers were diagnosed, of whom 29% had a cancer signal detected by MCED, while 31% were detected thru screening and 40% were detected clinically. The overall Positive Predictive Value of MCED was 38%, Negative Predictive Value was 98.6%, and specificity was 99.1%. The cancer yield rate was 0.53% (number needed to screen to find one MCED-detected cancer was 189).

The researchers concluded that this study demonstrates the feasibility of screening for multiple cancers using a blood test and lays the foundation for large, controlled trials necessary to establish clinical utility and cost-effectiveness. Multi Cancer Early Detection test was also able to accurately predict tumor origin, and the diagnosis of cancer was established in less than 2 months in the true-positive patients.

Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study. Schrag D, Beer TM, McDonnell CH, et al. The Lancet 2023;402:1251-1260.

KEYTRUDA® in Combination with HER2 Blockade Improves PFS in Gastric and GE Junction Cancer

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SUMMARY: Gastroesophageal cancers consist of a group of heterogeneous tumors, including gastric cancer, gastroesophageal junction cancer, and esophageal cancer. The majority of gastric and gastroesophageal junction cancers are adenocarcinomas, while the two main histological subtypes of esophageal cancer are esophageal adenocarcinoma and esophageal squamous cell carcinoma. The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases and 21,560 new esophageal cancers will be diagnosed in 2023 and about 11,130 and 16,120 people respectively, will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with gastric and gastroesophageal junction adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure.

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of advanced gastric and gastroesophageal (GE) junction cancers, overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody, Trastuzumab, as there is Overall Survival (OS) benefit with this combination regimen. Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor expressed on activated T cells, and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. In two Phase II studies, Pembrolizumab in combination with Trastuzumab and chemotherapy showed promising efficacy with manageable toxicities. The FDA in 2021 granted accelerated approval to Pembrolizumab in combination 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 adenocarcinoma, based on Overall Response Rates (ORR).

KEYNOTE-811 is an ongoing, global, multicenter, randomized Phase III trial which evaluated the benefit of adding Pembrolizumab to Trastuzumab and chemotherapy in patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma. In this study, 698 treatment naïve eligible patients (N=698) were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV (N=350) or placebo (N=348) every 3 weeks plus Trastuzumab and investigator’s choice of Fluorouracil/Cisplatin or Capecitabine/Oxaliplatin. Trastuzumab was given at 6 mg/kg IV once every 3 weeks after a loading dose of 8 mg/kg IV. Chemotherapy consisted of 5-FU 800 mg/m2 IV on days 1 to 5 of each 3-week cycle and Cisplatin 80 mg/m2 IV once every 3 weeks, or Capecitabine 1,000 mg/m2 orally twice daily on days 1 to 14 of each 3-week cycle and Oxaliplatin 130 mg/m2 IV once every 3 weeks. Treatment was continued for up to 35 cycles or until disease progression or unacceptable toxicity. Approximately 81% were male and patients were stratified by PD-L1 status, and chemotherapy received. Over 80% of patients had a PD-L1 Combined Positive Score of 1 or more. The dual Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS). Secondary end points included Objective Response Rate (ORR), Duration of Response, and Safety. The researchers reported the results at the third interim analysis, after a median follow up of 38.5 months.

At the third interim analysis, the results continued to show superiority with the addition of Pembrolizumab to Trastuzumab and chemotherapy. The median PFS with Pembrolizumab versus placebo was 10 months versus 8.1 months, respectively (HR = 0.73; P=0.0002). This represented a 27% reduction in risk for progression with Pembrolizumab versus placebo. The median OS showed numerical improvement and was 20.0 months versus 16.8 months (HR=0.84), but did not meet prespecified criteria for significance. Follow up for Overall Survival is continuing, and results will be updated at the final analysis. Patients whose tumors had PD-L1 Combined Positive Score of 1 or more benefitted the most, and there was little to no benefit among patients whose tumors had PD-L1 Combined Positive Scores less than 1. The researchers had previously reported an ORR of 74% in the the Pembrolizumab group and 52% in the placebo group, yielding a 22% improvement for the Pembrolizumab group (P=0.00006). Disease Control Rates were 96.2% versus 89.3% respectively. Grade 3 or more treatment-related adverse events were higher among patients assigned to Pembrolizumab versus placebo group (58% versus 51%). The most common treatment-related adverse events of any grade were diarrhea, nausea and anemia.

The authors concluded that Pembrolizumab when combined with first line Trastuzumab and chemotherapy significantly improved Progression Free Survival when compared to placebo, in metastatic HER2-positive gastroesophageal cancer. This benefit was specifically noted among patients with tumors with a PD-L1 Combined Positive Score of 1 or more. Follow up for Overall Survival is ongoing and will be updated at the final analysis.

Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Janjigian YY, Kawazoe A, Bai Y, et al. Published:October 20, 2023. DOI:https://doi.org/10.1016/S0140-6736(23)02033-0

FDA Approves Perioperative KEYTRUDA® for Resectable Early Stage Non Small Cell Lung Cancer

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SUMMARY: The FDA on October 16, 2023, approved KEYTRUDA® (Pembrolizumab) with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of single-agent KEYTRUDA® as post-surgical adjuvant treatment for resectable (tumors 4 cm or more or node positive) Non-Small Cell Lung Cancer (NSCLC). 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.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

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 platinum-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.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2.

The present FDA approval was based on the KEYNOTE-671 trial, which is a randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate whether a perioperative approach of combined neoadjuvant Pembrolizumab plus Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, would improve efficacy as compared with neoadjuvant Cisplatin-based chemotherapy and resection alone, in patients with resectable Stage II or III NSCLC. This study included patients with pathologically confirmed, resectable Stage II, IIIA, or IIIB (N2 disease-with involvement of 1 or more ipsilateral mediastinal lymph nodes or subcarinal lymph node) NSCLC. Eligible patients were randomly assigned in a 1:1 ratio to receive neoadjuvant Pembrolizumab 200 mg IV (N=397) or placebo (N=400) once every 3 weeks, each of which was given with Cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant Pembrolizumab 200 mg IV or placebo once every 3 weeks for up to 13 cycles. The median age was 64 years, 70% had Stage III disease, about 44% had N2 nodal stage, 57% has nonsquamous histology and 43% had squamous histology, about 36% had less than 1% PD-L1 Tumor Proportion Score (TPS), whereas 30% of patients had tumors with a TPS of 1-49% and 33% had TPS of 50% or more. The dual Primary end points were Event-Free Survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death), and Overall Survival (OS). Secondary end points included major pathological response, pathological Complete Response, and Safety.

The researchers reported the efficacy and safety data from the prespecified first interim analysis. The median follow-up was 25.2 months. The Event-Free Survival (EFS) at 24 months was 62.4% in the Pembrolizumab group and 40.6% in the placebo group. The median EFS was not reached in the Pembrolizumab group and was 17.0 months in the placebo group (HR=0.58; P<0.001). The EFS benefit with Pembrolizumab was consistent across all subgroups examined. The estimated 24-month Overall Survival was 80.9% in the Pembrolizumab group and 77.6% in the placebo group and this was not statistically significant (P=0.02) at this first interim analysis.

A major pathological response occurred in 30.2% of the patients in the Pembrolizumab group and in 11.0% of those in the placebo group (P<0.0001) and a pathological Complete Response occurred in 18.1% and 4.0%, respectively (P<0.0001). An exploratory analysis showed that the Event-Free Survival benefit was noted in the Pembrolizumab group regardless of whether participants had a major pathological response or a pathological Complete Response. The benefit with Pembrolizumab therapy appeared to be similar across both squamous and nonsquamous histologies. Approximately 45% of the patients in the Pembrolizumab group and 37% in the placebo group had treatment-related adverse events of Grade 3 or higher.

It was concluded that among patients with resectable Stage II, IIIA, or IIIB (N2 stage) NSCLC, the addition of Pembrolizumab to neoadjuvant Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, led to a significant improvement in Event-Free Survival, major pathological response, and pathological Complete Response, as compared with neoadjuvant chemotherapy alone followed by surgery. It should be noted that this trial was not designed to assess the relative contribution of adjuvant Pembrolizumab.

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. Wakelee H, Liberman M, Kato T, et al., for the KEYNOTE-671 Investigators. N Engl J Med 2023;389:491-503.

Hair Relaxer Use and Risk of Uterine Cancer

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SUMMARY: The American Cancer Society estimates that approximately 66,200 new cases of uterine cancer will be diagnosed in 2023 and about 13,030 will die of the disease. Uterine cancer is the second most prevalent gynecologic cancer in women worldwide, and its incidence has been increasing. Risk factors include age, factors that influence hormone levels such as obesity and estrogen replacement therapy, Type 2 diabetes, family history, diet and exercise, drugs such as Tamoxifen, and delayed menopause. Exposure to excess estrogen and a hormonal imbalance of estrogen and progesterone have been identified as key risk factors for uterine cancer. Further, synthetic estrogenic compounds such as endocrine-disrupting chemicals have been implicated, because of their ability to alter hormonal actions.

It is estimated that up to 95% of self-identified adult African American women in the U.S. report ever use of hair relaxers. Chemical straighteners or relaxers are commonly used by Black women to straighten curly or tightly coiled hair mostly due to societal pressure to straighten hair. As a result, chemical hair relaxers are heavily marketed to Black women. These straighteners have been found to have potentially harmful toxicants such as phthalates, parabens, cyclosiloxanes and metals that may act as carcinogens or endocrine disruptors, and may release formaldehyde when heated. These products when left on the hair longer than advised can injure the scalp, making it easier to absorb the chemicals. High concentrations of metabolites of phthalates and parabens have been detected in urine samples from women who use chemical hair relaxers.

Endocrine disrupting chemicals may cause hormonal imbalance through either estrogenic or anti-estrogenic activity and has been associated with earlier puberty, infertility, and uterine fibroids. A study published in the International Journal of Cancer in 2020 found that, women who used chemical hair straighteners more than 6 times a year, had about a 30% higher risk of breast cancer. In a study published in the journal Carcinogenesis in 2021 and in the Journal of the National Cancer Institute in 2022 (The Sister Study), women who used chemical hair straighteners more than 4 times a year, were twice as likely to develop ovarian cancer and more than twice as likely to develop uterine cancer as compared to women who did not use chemical hair straighteners. However in the Sister Study there were only 17 exposed cases among Black women. The researchers in this study sought to evaluate the possible association of hair relaxer use with uterine cancer risk in a large prospective cohort of Black women.

The US-based Black Women’s Health Study (BWHS) included 44,798 Black women with an intact uterus and no prior history of cancer, between the ages of 21 and 69, who were followed from 1997 until 2019. All participants completed a self-administered questionnaire about their personal and family medical history as well as behavioral and other factors such as medication use, cigarette smoking, and diet. The researchers used adjusted multivariable Cox proportional hazards regression models, to estimate Hazard Ratios (HRs) and 95% Confidence Intervals (CIs) for associations of hair relaxer use with risk of uterine cancer. The participants were followed for up to 22 years, and the rates of uterine cancer among women who reported frequent or long-term use of hair relaxers were compared to rates among women who never or rarely used them.

It was noted that compared to women who never used hair relaxers or used them infrequently (less than 4 years and 1-2 times or less/year), the Hazard Ratio for uterine cancer associated with heavy use (15 years or more and at least 5 times/year) was 1.18. However, among postmenopausal women, the rates of uterine cancer were statistically significantly higher for those who commonly used hair relaxers even after adjustment for other potential risk factors. In postmenopausal women compared to never/light use, the Hazard Ratio for moderate use was 1.60, the Hazard Ratio for heavy use was 1.64, and the Hazard Ratio for 20 or more years of use regardless of frequency was 1.71. Postmenopausal women who reported using hair relaxers more than twice a year, or for more than five years had a greater than 50% increased risk of uterine cancer, compared to women who never or rarely used hair relaxers.

It was concluded from this large study that long-term use of chemical hair relaxers was associated with increased risk of uterine cancer among postmenopausal women, even after adjustment for other potential risk factors, but not among premenopausal women. These findings suggest that hair relaxer use may be a potentially modifiable risk factor for uterine cancer and the researchers hope these results will raise awareness of the potential toxic effects of these products and promote efforts to reduce exposure.

Hair relaxer use and risk of uterine cancer in the Black Women’s Health Study. Bertrand KA, Delp L, Coogan PF, et al. Environmental Research 2023. Volume 239, Part 1, 15 December 2023, 117228. https://doi.org/10.1016/j.envres.2023.117228

Adjuvant KEYTRUDA® in Resected NSCLC Irrespective of PD-L1 Expression

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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.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

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 platinum-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.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

KEYNOTE-091/EORTC-1416-LCG/ETOP-8-15 – PEARLS trial is a multicenter, randomized, triple-blind, placebo-controlled Phase III trial, which compared the efficacy of KEYTRUDA® with placebo, among patients with resected NSCLC. In this study, 1,177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC with negative margins, and with tumor tissue available for PD-L1 testing were included. Systematic complete or lobe-specific mediastinal lymph node dissection was recommended. In the least, the subcarinal and 1 lobe-specific lymph node must have been examined. Eligible patients had not received neoadjuvant radiotherapy or chemotherapy, had ECOG PS of 0-1, and adjuvant chemotherapy for up to four cycles was optional. Adjuvant chemotherapy could be considered for those with Stage IB disease and was strongly recommended for those with Stage II and IIIA disease. Patients were randomized (1:1) to receive KEYTRUDA® 200 mg or placebo IV every three weeks and treatment was continued until disease recurrence, unacceptable toxicity, or up to 1 year. Both treatment groups were well balanced. The median patient age was 65 years, majority of patients (68%) were male, approximately 65% of patients had nonsquamous histology, 56% of patients had Stage II disease and 86% of patients had received adjuvant platinum-based chemotherapy following complete resection. Stratification factors included disease stage, receipt of adjuvant chemotherapy, PD-L1 Tumor Proportion Score and geographic region of the world. The median duration of exposure to KEYTRUDA® was 11.7 months and 68% of patients in the KEYTRUDA® group were exposed to KEYTRUDA® for at least 6 months. The dual Primary endpoints were Disease-Free Survival (DFS) in the overall population and in the population with PD-L1 Tumor Proportion Score (TPS) of 50% or greater. An additional efficacy outcome was Overall Survival (OS). The median follow up for this interim analysis was 35.6 months.

The trial met its Primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population. In the overall population, median DFS was 53.6 months in the KEYTRUDA® group versus 42.0 months in the placebo group (HR=0.76; P=0.0014), reducing the risk of disease recurrence or death by 24% versus placebo, regardless of PD-L1 expression. In the PD-L1 TPS of 50% or greater population, median DFS was not reached in either the KEYTRUDA® group or the placebo group. Overall survival Data were not mature.

It was concluded that these data support the benefit of KEYTRUDA® as a new adjuvant immunotherapy treatment option, for early-stage Non Small Cell Lung Cancer following complete resection, and if indicated, adjuvant chemotherapy, regardless of PD-L1 expression.

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091):an interim analysis of a randomised, triple-blind, phase 3 trial. O’Brien M, Paz-Ares L, Marreaud S, et al. Lancet Oncol. 2022;10:1274-1286.

Long Term Overall Survival Benefit with VIDAZA® plus VENCLEXTA® in Elderly AML Patients

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SUMMARY: The American Cancer Society estimates that in 2023, 20,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,310 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia, and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® (Venetoclax) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS), when compared to conventional care regimens, in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. The combination of VIDAZA® and VENCLEXTA® in a previously published Phase Ib study was highly efficacious, with significant responses, duration of response and Overall Survival benefit.

VIALE-A is a Phase III, multicenter, randomized, double-blind, placebo-controlled confirmatory trial, conducted to evaluate the efficacy and safety of a combination of VIDAZA® and VENCLEXTA®, as compared with VIDAZA® plus placebo (the control regimen), in previously untreated patients with AML, who were ineligible for intensive induction therapy. In this study, 431 patients (N=431) with previously untreated AML were randomly assigned in a 2:1 ratio to receive either VIDAZA® plus VENCLEXTA® (N=286), or VIDAZA® plus placebo (N=145). Enrolled patients were ineligible for standard induction chemotherapy because of coexisting conditions, 75 years of age or older, or both. All patients received VIDAZA® 75 mg/m2 subcutaneously or IV on days 1 through 7 of every 28-day cycle. Patients in the study group also received VENCLEXTA® 100 mg orally on day 1 and 200 mg on day 2 and target dose of 400 mg on day 3, and continued daily until day 28 during cycle 1, to mitigate Tumor Lysis Syndrome. The dose of VENCLEXTA® was initiated at 400 mg daily in all subsequent 28-day cycles. In the control group, a matching placebo was administered orally, once daily, in 28-day cycles. The median age was 76 years in both groups, approximately 60% were male and 76% were Caucasian. Molecular abnormalities of interest included FLT-3, observed in 14% of patients receiving VIDAZA® plus VENCLEXTA®, IDH1/2, observed in 25% of patients, TP53, observed in 23.3% of patients and NPM1, observed in 16.6% of patients. Secondary AML was reported in 25% of the patients in the VIDAZA® plus VENCLEXTA® group and in 24% of the patients in the control group. All the patients were hospitalized on or before day 1 of cycle 1 and for at least 24 hours after receiving the final dose of VENCLEXTA®, in order to receive prophylaxis against the Tumor Lysis Syndrome and for monitoring. The Primary endpoint was Overall Survival (OS). The Secondary end points included Complete Remission (CR) rates, composite Complete Remission (Complete Remission or Complete Remission with incomplete hematologic recovery), RBC and platelet transfusion independence, and Quality of Life according to Patient-Reported Outcomes.

At a median follow up of 20.5 months, the median OS was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.66; P<0.001). VIDAZA® plus VENCLEXTA® combination resulted in a CR rate of 36.7% versus 17.9%; P<0.001 and composite CR of 66.4% versus 28.3%; P<0.001, when compared to the control regimen. Most responses were seen after the first 28-day cycle. The median time to first response was 1.3 versus and 2.8 months respectively, duration of CR was 17.5 months versus 13.3 months and median duration of composite CR was 17.5 months in the VIDAZA® plus VENCLEXTA® group and 13.4 months in the control group. RBC transfusion independence occurred in 59.8% of the patients in the VIDAZA® plus VENCLEXTA® group and in 35.2% of those in the control group (P<0.001), and platelet transfusion independence occurred in 68.5% and 49.7% (P<0.001), respectively. The benefits with VIDAZA® plus VENCLEXTA® were noted in almost all molecular subgroups compared to the control regimen. The response rates were highest among patients with FLT3 mutations (72.4% versus 36.4%, P=0.02) and those with IDH1 or IDH2 mutations (75.4 % versus 10.7%, P<0.001), respectively.

The researchers conducted 2 years of additional follow-up to determine the long-term survival benefit of VIDAZA® plus VENCLEXTA® combination and at this meeting reported the analysis of VIALE-A trial, after the occurrence of 100% of the pre-planned survival events. With a median follow-up of 43.2 months, the median Overall Survival (OS) benefit since the interim analysis in the overall population was maintained and was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.58; P<0.001). Among patients with Measurable Residual Disease (MRD) <10-3 who had achieved either Complete Remission (CR) or CR with incomplete hematologic recovery (CRi), the median OS was reached at 34.2 months in the VIDAZA® plus VENCLEXTA® group and 25.0 months in the control group. For patients in the IDH1/2 mutant subgroup, the median OS at final analysis with VIDAZA® plus VENCLEXTA® was 19.9 months and was 6.2 months in the control group (HR=0.31; P<0.001). Overall safety profiles were comparable between the treatment groups.

The 2-year follow up analysis of the VIALE-A trial confirmed the sustained Overall Survival benefit of VIDAZA® plus VENCLEXTA® combination in patients with AML, ineligible for intensive chemotherapy, with no new safety findings noted.

Long-Term Follow-up of the Phase 3 Viale-a Clinical Trial of Venetoclax Plus Azacitidine for Patients with Untreated Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy. Pratz KW, Jonas BA, Pullarkat VA, et al. Presented at the 64th ASH Annual Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana. Abstract # 219

Non-Hormonal Treatments for Menopausal Symptoms – NA Menopause Society 2023 Position Statement

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SUMMARY: It is estimated that the 50 million women will attain menopause annually. Natural menopause occurs in women between age 49-52 years. Vasomotor symptoms (VMS) manifesting as hot flashes and night sweats are the most common symptoms of menopause. These symptoms occur in up to 80% of menopausal women lasting from 7-10 years and sometimes even longer, significantly impacting their quality of life. Compared to other ethnic groups, menopausal symptoms tend to be less severe in Asian women and more severe in African American women.

Hormone Replacement Therapy remains the most effective treatment and should be considered in menopausal women younger than 60 years, within 10 years of their final menstrual periods, with no contraindications. However, the use of Hormone Replacement Therapy has declined substantially, following the Women’s Health Initiative (WHI) hormone therapy trials recommendation, not to prescribe menopausal hormone therapy for chronic disease prevention due to the complex pattern of risks and benefits, including increases in invasive breast cancer, stroke and pulmonary embolism.

Nonhormonal interventions have therefore been important considerations for symptomatic menopausal women. The North American Menopause Society convened an advisory panel of clinicians and research experts in the field of women’s health, to review and evaluate the literature published after the Position Statement of The North American Menopause Society in 2015.

This advisory panel assessed the most current and available literature to recommend or not recommend use, with the level of evidence assigned, on the basis of these categories:

• Level I: Good and consistent scientific evidence.
• Level II: Limited or inconsistent scientific evidence.
• Level III: Consensus and expert opinion

The following are the evidence-based updated guidelines:

Level I
Cognitive-Behavioral Therapy: CBT has been shown to reduce the bother and interference associated with VMS.
Clinical hypnosis: Clinical hypnosis has been shown to reduce VMS frequency and severity.
Selective Serotonin Reuptake Inhibitors (SSRIs)/ Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): SSRIs and SNRIs are associated with mild to moderate improvements in vasomotor symptoms.
SSRIs: Paroxetine 7.5 mg daily is approved by the FDA for the treatment of moderate to severe vasomotor symptoms. Paroxetine however should be avoided in women taking Tamoxifen to treat or prevent breast cancer. Other SSRIs include Citalopram and Escitalopram which have less of an effect on the CYP2D6 enzyme.
SNRIs: Venlafaxine may be a safer choice in women using Tamoxifen as coadministration of SSRIs such as Paroxetine or Fluoxetine with Tamoxifen may lead to inhibition of CYP2D6 (the enzyme that converts Tamoxifen to its most active metabolite, endoxifen).
Gabapentin: Gabapentin is approved by the FDA as an antiepileptic drug, and is often used to treat diabetic neuropathy and postherpetic neuralgia. However, several trials studying the dose of 900 mg (300 mg three times/day) show that this has improved the frequency and severity of vasomotor symptoms.
Fezolinetant (VEOZAH®): Fezolinetant is a first-in-class neurokinin B antagonist that is FDA approved for management of vasomotor symptoms. It modulates the neuronal activity in the thermoregulatory center of the brain.
Oxybutynin: Oxybutynin is an antimuscarinic, anticholinergic therapy that is used for the treatment of overactive bladder and urinary urge incontinence. Oxybutynin has been shown to reduce moderate to severe vasomotor symptoms, although in older adults, long-term use may be associated with cognitive decline
Pregabalin and Clonidine are not recommended for vasomotor symptoms

Level II-III
Weight Loss: The limited available evidence suggests that weight loss may be used to improve vasomotor symptoms for some women.
Stellate ganglion blockade: This procedure is a widely used to treat migraine and complex regional pain syndrome by injecting an anesthetic agent at the lower cervical or upper thoracic region. This blockade might help alleviate moderate to very severe vasomotor symptoms in select women. Because of the potential risks and adverse events, its potential use for vasomotor symptoms should be carefully evaluated.

The following interventions have NOT BEEN PROVEN beneficial and NOT RECOMMENDED interventions:
Paced respiration, Supplements/Herbal remedies, avoiding triggers such as alcohol, caffeine, spicy foods or hot foods, Cooling techniques, Exercise, Yoga, Mindfulness-based intervention such as meditation, Relaxation, Suvorexant, Soy foods and Soy extracts, Soy metabolite equol, Cannabinoids, Acupuncture, Calibration of neural oscillations, Chiropractic interventions, and Dietary modification.

The panel concluded that the most effective treatment for vasomotor symptoms is hormonal therapy and should be considered in menopausal women within 10 years of their final menstrual periods. For women who are not candidates for hormone therapy because of contraindications (estrogen-dependent cancers or cardiovascular disease) or personal preference, it is important for healthcare professionals to be well informed about the evidence-based nonhormone treatment options, for reducing vasomotor symptoms.

NAMS POSITION STATEMENT: The 2023 nonhormone therapy position statement of The North American Menopause Society. Menopause: The Journal of The North American Menopause Society 2023;30:573-590. DOI: 10.1097/GME.0000000000002200

Zolbetuximab plus CAPOX in Biomarker Positive Advanced Gastric or GEJ Cancer

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SUMMARY: The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases will be diagnosed in 2023 and about 11,130 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction (GEJ) adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 6%. These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6 or CAPOX. Patients with HER2-positive disease are usually treated with chemotherapy plus Trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor, or checkpoint inhibitor alone, if the tumors express PD-L1.

CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed on the surface of the cancer cells and accessible to targeted therapies with antibodies. CLDN18.2 is expressed in 35% of Gastric adenocarcinomas.

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death. About 30-40% of patients with Gastric cancer have CLDN18.2 expression.

SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. This study met the Primary endpoint and the median Progression Free Survival (PFS) was 10.61 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The Overall Survival (OS) was also significantly improved (18.23 versus 15.54 months, HR=0.750; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population.

GLOW trial is a global, multi-center, double-blind, randomized Phase III study, conducted to assess the efficacy and safety of Zolbetuximab plus CAPOX (N=254) versus placebo plus CAPOX (N=253) as a first-line treatment for patients with CLDN18.2-positive/HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. In this trial, 507 eligible patients were randomly assigned 1:1 to receive Zolbetuximab 800 mg/m2 IV as a loading dose on cycle 1, day 1, of the first 21-day cycle, followed by 600 mg/m2 IV on day 1 of subsequent cycles, along with CAPOX regimen consisting of Capecitabine 1000 mg/m2 orally twice daily on days 1-14 of each cycle and Oxaliplatin 130 mg/m2 IV on day 1 of each cycle, or the same CAPOX regimen plus placebo. CAPOX was given for 8 cycles in both treatment groups and patients could continue beyond 8 cycles with Zolbetuximab or placebo plus Capecitabine at investigator’s decision, and treatment continued until disease progression or unacceptable toxicities. CLDN18.2 positive was defined as at least 75% of tumor cells with moderate-to-strong membranous CLDN18.2 staining and patients were stratified by region (Asia versus non-Asia), number of organs with metastases, and prior gastrectomy (yes versus no). The median patient age was 60 years, majority of patients were male from Asia, not having prior gastrectomy, having stomach as the primary tumor site, and having an ECOG performance status of 1. Basline characteristics were similar in both treatment groups. The Primary end point was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), and Safety.

At a median follow up of 12.6 months, the combination of Zolbetuximab plus CAPOX significantly improved PFS, and the median PFS was 8.2 months, compared with 6.8 months for those given placebo plus CAPOX (HR=0.687; P=0.0007). The median OS was 14.4 months versus 12.2 months respectively (HR=0.771; P=0.01). The PFS and OS benefits were sustained at 24 months, and the benefits were observed across most subgroups. The most common side effects were nausea and vomiting and the authors recommended increasing the infusion duration time, or splitting the dose over a 2 day period, in addition to the administration of prophylactic antiemetics.

The researchers concluded that the addition of first-line Zolbetuximab to CAPOX significantly improved PFS and OS in patients with CLDN18.2-positive, HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. The authors added that Zolbetuximab plus CAPOX represents a potential new first-line therapy for this patient group. Taken together, both GLOW and SPOTLIGHT trials showed a similar reduction in the risk of disease progression or death and a similar reduction in the risk of death with the addition of Zolbetuximab to chemotherapy, when compared with placebo plus chemotherapy.

Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Shah MA, Shitara K, Ajani JA, et al. Nature Medicine 2023; 29:2133–2141

Osimertinib Plus Chemotherapy Superior to Osimertinib Alone in Advanced 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 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.