Category: Hem/Onc Updates

Infection Risk in Multiple Myeloma Patients Receiving New Generation Therapies

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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, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). 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 will eventually relapse, requiring multiple lines of therapy for disease control. The availability of newer agents has transformed Multiple Myeloma into a chronic disease. Patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

Infection is a leading cause of morbidity and mortality in patients with Multiple Myeloma. In a study of over 3000 newly diagnosed Multiple Myeloma patients, approximately 50% of early deaths (deaths occurring in less than 6 months following diagnosis) were associated with infections (J Clin Oncol. 2005;23:9219-9226). The increased susceptibility to infection in this patient group has been attributed to disease-related deficits in the innate or adaptive immune system, including hypogammaglobulinaemia, qualitative and quantitative abnormalities of dendritic cells, T cells, and Natural Killer cells, as well as renal function impairment, and therapies administered at different stages of the disease. Further, the introduction of new therapeutic agents such as Proteasome Inhibitors (PIs), Immunomodulatory drugs and monoclonal antibodies, with novel mechanisms of action, for first and later lines of therapy, for both Hematopoietic Stem Cell Transplantation eligible and ineligible patients, has significantly improved survival, but has also changed the spectrum of infections in patients with Multiple Myeloma. The epidemiology and risks for infection with the use of new therapeutic agents however remains unclear. The present study was conducted to determine patterns, risks and outcomes of infections in patients with Multiple Myeloma, managed with new therapeutic agents and monoclonal antibodies.

In this study, patients with Multiple Myeloma treated with second generation therapies and other monoclonal antibodies were identified from pharmacy and clinical databases, collected from 2 major tertiary referral centers for Multiple Myeloma management in Australia. Agents considered new generation therapies included Pomalidomide, Carfilzomib, Isatuximab, Daratumumab and Elotuzumab. Following commencement of new generation therapy, 60% of the patient’s had previously received Autologous Stem Cell Transplantation and 93% of the patient’s had Relapsed or Refractory Multiple Myeloma. Patients were then followed for episodes of infection, from the commencement of therapy with any newer agents, until completion of treatment, death or end of study, which ever occurred first. Prophylaxis with antibiotics for bacterial infections was not routinely used, but antiviral prophylaxis with Valaciclovir was used when patients received therapy with Proteasome Inhibitors. Patients received prophylaxis with Trimethoprim/Sulfamethoxazole for Pneumocystis jirovecii pneumonia when steroid doses exceeded 16-20 mg of Prednisone equivalent per day.

Each episode of infection was classified as Microbiologically Defined (MDI) when pathogens were isolated on microbiological testing, Clinically Defined (CDI) when sites of infection were identified but no pathogens were isolated on microbiological testing, and Fever of Unknown Focus (FUF) when patients had febrile episodes with no pathogen or site identified. Univariate and multivariate analyses were performed to determine risk factors for infection.

A total of 148 patients with Multiple Myeloma were followed for a median of 13.2 months, and 345 infection episodes were identified. Of these, 29% (100 out of 345) were defined as Microbiologically Defined Infections, 58% (200 out of 345) were defined as Clinically Defined Infections, and 13% (45 out of 345) were defined as Fever of Unknown Focus. Of those with Microbiologically Defined Infections, 50% of infections were attributed to viruses, whereas 45% were attributed to bacterial infection. Respiratory Syncytial Virus was the most frequently isolated virus accounting for 24% of episodes, followed by Rhinovirus at 16% and Influenza virus at 14%. E. coli was the most frequently isolated bacteria at 20%, followed by Haemophilus influenza at 11%. The most common infection site was the respiratory tract (56.8%), hospital admission occurred in 41.7% of infection episodes, and the 30-day all-cause mortality rate was 5.4%. Treatment with Proteasome Inhibitors resulted in 16.8 times increased risk for infections, combination of IMiD and PI was associated with 13.44 times higher risk, monoclonal antibody combination therapy was associated with 10.44 times higher risk, and more than 4 lines of therapy was associated with 7.72 times higher risk for infections (P<0.05).

It was concluded from this study that majority of infections are caused by viruses, in patients with Multiple Myeloma treated with newer therapeutic agents. Treatment with a Proteasome Inhibitor and more than 4 lines of therapy were associated with higher risk for infection.

Epidemiology and Risks of Infections in Patients With Multiple Myeloma Managed With New Generation Therapies. Lim C, Sinha P, Harrison SJ, et al. Clinical Lymphoma, Myeloma & Leukemia. 2021;21:444-450.

Real-world evidence: What can it inform us about the second-line treatment of metastatic squamous NSCLC?

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Written by Dr. Solly S. Chedid
Sponsored and developed by Boehringer Ingelheim Pharmaceuticals.

Immunotherapies have changed the way we initiate treatment for many patients with advanced squamous non-small cell lung cancer (NSCLC).1 As immunotherapy has become a standard first-line treatment, non-immunotherapy options are important to consider for second-line treatment. Currently, there is no clear standard of care for second-line therapy in patients with advanced squamous NSCLC who progress after immuno-chemotherapy. Therefore, an unmet need remains for studies designed to understand the effectiveness and safety of second-line treatments in these patients. Here we will review newly published real-world evidence on second-line treatments of patients with squamous NSCLC with afatinib (GILOTRIF®) following immuno-chemotherapy.

GILOTRIF is the only oral, chemotherapy-free option for treating patients with squamous NSCLC that has progressed after platinum-based chemotherapy.2 The efficacy and safety of GILOTRIF were demonstrated in the pivotal LUX-Lung 8 trial. In LUX-Lung 8, treatment with GILOTRIF led to statistically significant improvements in progression-free survival (median 2.4 vs 1.9 months) and overall survival (median 7.9 vs 6.8 months) compared with erlotinib. In LUX-Lung 8, the most common adverse reactions reported in the GILOTRIF treated patients (≥20% all grades) were diarrhea (75%), rash/acneiform dermatitis (70%), stomatitis (30%), decreased appetite (25%), and nausea (21%).

The Real-world Effectiveness of 2L Treatment of Squamous mNSCLC Study is the first to evaluate the real-world use of GILOTRIF following first-line immuno-chemotherapy in patients with squamous NSCLC.1 It is a retrospective, non-interventional, multisite cohort study using electronic medical records of patients with advanced or metastatic squamous NSCLC treated with pembrolizumab and platinum-doublet chemotherapy in the first line. Patients were treated with either GILOTRIF or physician’s choice chemotherapy in the second line. Study endpoints included patient demographics and clinical characteristics, time on second-line treatment, and incidence of severe (Grade ≥3) immune-related adverse events (irAEs). This study analysis was not powered to compare characteristics or outcomes between the cohorts. In addition, the results of this study are not intended for direct comparison with clinical trials. The main limitations of this study are its retrospective nature, potential for selection bias, and lack of a comparator arm.

A total of 200 patients were included in this study; 99 received GILOTRIF, and 101 received chemotherapy in the second line.1 More patients in the GILOTRIF cohort had mixed histology, were epidermal growth factor receptor (EGFR) mutation−positive, and were never smokers than those in the chemotherapy cohort. There were geographic differences between the cohorts; more patients from the Northeast received GILOTRIF, and more patients from the South received chemotherapy. In the GILOTRIF cohort, 45% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ranging from 0 to 1, while 55% had an ECOG PS of 2 or higher. In the chemotherapy arm, 50% of patients had ECOG PS 0 to 1, and 50% had ECOG PS of 2 or higher. Other characteristics, such as median age and stage at diagnosis, were similar in both cohorts.

The median time on treatment for the GILOTRIF cohort was 7.3 months. In patients with mixed histology, the median time on treatment was 8.1 months, and for patients with squamous histology it was 5.8 months.1 EGFR mutation−positive and EGFR mutation−negative patients remained on GILOTRIF for a median of 7.4 and 5.9 months, respectively. The median time on treatment from initiation of second-line chemotherapy was 4.2 months.

   Time on Treatment in the Real-World Effectiveness Study1
Time-on-GILOTRIF-Chemotherapy
The most common adverse drug reactions with GILOTRIF were diarrhea (26%), rash (6%), stomatitis, fatigue, and nausea (5% each).1 Six out of 99 patients experienced a Grade 3/4 irAE during second-line GILOTRIF therapy; each of these patients also experienced a Grade 3 irAE during first-line treatment. The 6 patients in the GILOTRIF cohort who experienced Grade 3/4 irAEs were treated with steroids, and none were hospitalized. Given the real-world nature of the study, adverse event data may be underreported or underdocumented; in addition, censoring may also bias results.

Such real-world evidence (RWE) studies have limitations, including their retrospective nature and potential for selection bias.1 However, in addition to clinical data collected in registrational clinical trials, data from RWE studies such as this can add important information to help evaluate the clinical utility of a drug in the real-world setting.3 RWE studies can be derived from rich data sources, such as electronic health records, registries, and claims databases, which reflect real-world use, outcomes, and the patient diversity seen in clinical practice.

Despite several limitations highlighted in this paper, the study adds to the body of evidence supporting the effectiveness and safety of GILOTRIF when given as a second-line treatment following immuno-chemotherapy in routine clinical practice.1

INDICATION AND USAGE

GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION FOR GILOTRIF® (AFATINIB) TABLETS
WARNINGS AND PRECAUTIONS

Diarrhea
• GILOTRIF can cause diarrhea which may be severe and can result in dehydration with or without renal impairment. In clinical studies, some of these cases were fatal.
• For patients who develop Grade 2 diarrhea lasting more than 48 hours or Grade 3 or greater diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and then resume at a reduced dose.
• Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal until loose stools cease for 12 hours.
Bullous and Exfoliative Skin Disorders
• GILOTRIF can result in cutaneous reactions consisting of rash, erythema, and acneiform rash. In addition, palmar-plantar erythrodysesthesia syndrome was observed in clinical trials in patients taking GILOTRIF.
• Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions. For patients who develop Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF. When the adverse reaction resolves to Grade 1 or less, resume GILOTRIF with appropriate dose reduction.
• Postmarketing cases of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. Discontinue GILOTRIF if TEN or SJS is suspected.
Interstitial Lung Disease
• Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in patients receiving GILOTRIF in clinical trials. In some cases, ILD was fatal. The incidence of ILD appeared to be higher in Asian patients as compared to white patients.
• Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.
Hepatic Toxicity
• Hepatic toxicity as evidenced by liver function tests abnormalities has been observed in patients taking GILOTRIF. In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal.
• Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. Discontinue treatment in patients who develop severe hepatic impairment while taking GILOTRIF.
Gastrointestinal Perforation
• Gastrointestinal (GI) perforation, including fatal cases, has occurred with GILOTRIF. GI perforation has been reported in 0.2% of patients treated with GILOTRIF among 3213 patients across 17 randomized controlled clinical trials.
• Patients receiving concomitant corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or anti-angiogenic agents, or patients with increasing age or who have an underlying history of GI ulceration, underlying diverticular disease, or bowel metastases may be at an increased risk of perforation.
• Permanently discontinue GILOTRIF in patients who develop GI perforation.
Keratitis
• Keratitis has been reported in patients taking GILOTRIF.
• Withhold GILOTRIF during evaluation of patients with suspected keratitis. If diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue GILOTRIF. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Embryo-Fetal Toxicity
• GILOTRIF can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
• Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.
ADVERSE REACTIONS
Adverse Reactions observed in clinical trials were as follows:
Previously Treated, Metastatic Squamous NSCLC
• In GILOTRIF-treated patients (n=392) the most common adverse reactions (≥20% all grades & vs erlotinib-treated patients (n=395)) were diarrhea (75% vs 41%), rash/acneiform dermatitis (70% vs 70%), stomatitis (30% vs 11%), decreased appetite (25% vs 26%), and nausea (21% vs 16%).
• Serious adverse reactions were reported in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
• Concomitant use of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
• Concomitant use of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib.
USE IN SPECIFIC POPULATIONS
Lactation
• Because of the potential for serious adverse reactions in breastfed infants from GILOTRIF, advise women not to breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose.
Females and Males of Reproductive Potential
• GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible.
Renal Impairment
• Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) have a higher exposure to afatinib than patients with normal renal function. Administer GILOTRIF at a starting dose of 30 mg once daily in patients with severe renal impairment. GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or who are on dialysis.
Hepatic Impairment
• GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

GF PROF ISI 10.21.19

References

1. Kim ES, Kish JK, Cseh A, et al. Second-line afatinib or chemotherapy following immunochemotherapy for the treatment of metastatic, squamous cell carcinoma of the lung: real-world effectiveness and safety from a multisite retrospective chart review in the USA. Clin Lung Cancer. 2021;S1525-7304(21)00029-2.
2. GILOTRIF. Prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2019.
3. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence — what is it and what can it tell us? N Engl J Med. 2016:8;375(23):2293-2297.

Please review the Full Prescribing Information and Patient Information.

Maintenance RUBRACA® in Patients with Advanced Pancreatic Cancer with a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2

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SUMMARY: The American Cancer Society estimates that for 2021, about 60,430 people will be diagnosed with pancreatic cancer and about 48,220 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 2%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States around 2021.

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 genes 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. BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in these genes predispose an individual to develop malignant tumors. It is well established that the presence of BRCA1 and BRCA2 mutations can significantly increase the lifetime risk for developing breast and ovarian cancer, as high as 85% and 40% respectively. BRCA1/2 mutations have been detected in 4-7% of patients with pancreatic cancer, with a 2-6 fold increase in risk, associated with these mutations. These patients tend to be younger. Among pancreatic cancer patients with Ashkenazi Jewish ancestry, the prevalence of BRCA1/2 mutations is 6-19%, with mutations more common for BRCA2. NCCN guideline recommends that germline testing should be considered for all patients with pancreatic cancer and is especially recommended for those with a personal history of cancer, family history or clinical suspicion of a family history of pancreatic cancer. Approximately 10% of pancreatic cancer cases have a familial component. When hereditary cancer syndrome is suspected in patients with pancreatic cancer, genetic counseling should be considered.

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 PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

LYNPARZA® (Olaparib) is a PARP inhibitor and is presently approved as maintenance therapy for patients with advanced pancreatic cancer demonstrating a germline BRCA1 or BRCA2 pathogenic variant. However, previously published studies have demonstrated the benefit of PARP inhibitors in breast, prostate and ovarian cancer patients, beyond germline BRCA pathogenic variants. Further, there is an unmet need to expand the group of patients with pancreatic cancer who may benefit from therapy with a PARP inhibitor, beyond those with germline BRCA pathogenic variants.

This investigator-initiated, single-arm Phase II study was conducted to assess the role of oral, small molecule PARP inhibitor RUBRACA® (Rucaparib), as maintenance therapy in advanced pancreatic cancer with germline or somatic pathogenic variants in BRCA1, BRCA2, or PALB2 genes. This study enrolled 46 patients with advanced pancreatic cancer with germline or somatic pathogenic variants in BRCA1, BRCA2, or PALB2, and had received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance, which was defined as growing tumors, new lesions, or a steadily rising tumor marker during or within 8 weeks of platinum therapy. The median age was 62 years, approximately 17% had germline BRCA1, 64% had germline BRCA2, 14% had germline PALB2 and 5% had somatic BRCA2 pathogenic variants. Majority of patients (95%) had metastatic disease and 5% had locally advanced disease. Ashkenazi Jewish founder mutation was found in 24% of patients. The Primary end point was Progression Free Survival (PFS) at 6 months (PFS). Secondary end points included Safety, Objective Response Rate (ORR), Disease Control Rate, Duration of Response, and Overall Survival.

The PFS at 6 months was 59.5% and the PFS at 12 months was 54.8%. The median PFS was 13.1 months and median Overall Survival was 23.5 months. The ORR in those with measurable disease was 42%, and the Disease Control Rate was 67%. The median Duration of Response was 17.3 months. These responses were noted across all germline and somatic pathogenic variants in BRCA1, BRCA2, and PALB2 genes, and no new safety signals were noted.

It was concluded from this study that maintenance RUBRACA® is a safe and effective therapy for platinum-sensitive, advanced pancreatic cancer patients, with a pathogenic variant in BRCA1, BRCA2, or PALB2. The authors added that the finding of efficacy in patients with germline PALB2 and somatic BRCA2 pathogenic variants, expands the population of patients likely to benefit from PARP inhibitors, beyond those with germline BRCA1 and BRCA2 pathogenic variants.

Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2. Reiss KA, Mick R, O’Hara MH, et al. J Clin Oncol. 2021;39:2497-2505.

FDA Approves TRODELVY® for Advanced Urothelial Cancer

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SUMMARY: The FDA on April 13, 2021, granted accelerated approval to TRODELVY® (Sacituzumab Govitecan) for patients with locally advanced or metastatic Urothelial Cancer who previously received a Platinum-containing chemotherapy, and either a Programmed Death receptor-1 (PD-1) or a Programmed Death-Ligand 1 (PD-L1) inhibitor. The American Cancer Society estimates that in the United States for 2021, about 83,730 new cases of bladder cancer will be diagnosed and approximately 17,200 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Patients with Urothelial Carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Treatment options for patients who progress after first and second line therapies are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%, with a median Overall Survival (OS) of 7-8 months.

Two new agents approved by the FDA include BALVERSA® (Erdafitinib), a pan-Fibroblast Growth Factor Receptor (FGFR) inhibitor, for patients with locally advanced or metastatic Urothelial Carcinoma with susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following Platinum-containing chemotherapy, as well as PADCEV® (Enfortumab Vedotin), an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule, highly expressed in Urothelial Cancers and other solid tumors. These two agents have Objective Response Rates (ORRs) of approximately 40%, and most patients will progress on these therapies. Further, FGFR alterations occur in only 20% of patients with metastatic Urothelial Carcinoma, limiting the use of BALVERSA®. Hence, there is an unmet need for novel therapies.

Trop-2 is a transmembrane glycoprotein and calcium signal transducer. It stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the Breast, Colon, Lung and Urothelial Cancer, and has limited expression in normal human tissues. TRODELVY® is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38.

TRODELVY® in a Phase I/II trial involving patients with advanced epithelial cancers, showed encouraging clinical activity across various solid tumors and was associated with a Objective Response Rate (ORR) of 31% in patients with relapsed or refractory metastatic Urothelial Carcinoma, including a 27% ORR among patients who had received prior checkpoint inhibitor and Platinum based therapy. The TROPHY-U-01 Phase II trial was designed to assess the activity of TRODELVY® and confirm these findings in patients with locally advanced unresectable or metastatic Urothelial Carcinoma. This trial includes 5 patient cohorts, evaluating the role of TRODELVY® in various groups of patients and in combination with various agents including checkpoint inhibitors. The authors in this publication reported the primary results from the full Cohort 1 of the TROPHY-U-01 study in patients with metastatic Urothelial Cancer who progressed after prior Platinum based and checkpoint inhibitor based therapies.

Cohort 1 included 113 patients who had received a median of three prior therapies. Patients received TRODELVY® 10 mg/kg IV, on days 1 and 8 of a 21-day treatment cycle, until disease progression or unacceptable toxicities. The median patient age was 66 years and 66% of patients had visceral metastases. The main efficacy endpoints were Objective Response Rate (ORR) and Duration of Response (DOR), evaluated by Independent Review, using RECIST 1.1 criteria.

At a median follow up of 9.1 months, the ORR was 27.7%, and 77% of patients had decrease in measurable disease. The Complete Response rate was 5.4% and 22.3% had Partial Responses. The median DOR was 7.2 months. The median Progression Free Survival was 5.4 months and Overall Survival was 10.9 months. Important Grade 3 or more treatment related adverse events included, neutropenia, anemia, diarrhea, and febrile neutropenia, with 6% of patients discontinuing treatment due to adverse events because of treatment-related adverse events.

It was concluded that TRODELVY® is an active agent and has notable efficacy, compared with historical controls, in pretreated metastatic Urothelial Cancer, that has progressed on both prior Platinum regimens and checkpoint inhibitors, and has manageable safety profile.

TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. Tagawa, ST, Balar AV, Petrylak DP, et al. J Clin Oncol. 2021;39:2474-2485.

Noninvasive Evaluation of Myelodysplastic Syndrome in Patients with Unexplained Anemia

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SUMMARY: 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).

Elderly patients with mildly symptomatic anemia (macrocytic anemia) or pancytopenia are initially evaluated for B12, folate and iron deficiency, as well as hypothyroidism and hemolysis. The next recommended test for unexplained anemia is bone marrow examination, which is the current gold standard for diagnosis of MDS. However, this procedure is invasive and can be painful, and is occasionally associated with infectious and bleeding complications. For these reasons, many patients and their physicians may avoid this procedure, potentially delaying access to effective treatments.

The researchers in this study developed a noninvasive algorithm, to help diagnose or exclude MDS, without bone marrow evaluation. To develop this web-based app, 502 patients diagnosed with MDS based on bone marrow evaluation were randomly selected from the European MDS registry and this sample was combined with 502 controls with unexplained anemia, aged 50 years and older, who had normal findings on bone marrow evaluation. Patients with bone marrow involvement as a part of a hematological or other disease or with any degree of bone marrow dysplasia could not serve as controls. The authors using a logistic regression model were able to classify patients into 1 of 3 categories: probable MDS, probably not MDS, and indeterminate. The initial model that was developed by the researchers was further improved using the new Gradient-Boosted Models (GBMs), adding more variables based on their known association with MDS. They included 10 routinely measured and readily available demographic, clinical, and laboratory variables such as Age, Sex, Hemoglobin, White Blood Cell count, Platelet count, Mean Corpuscular Volume, Neutrophils, Monocytes, Glucose, and Creatinine, as well as including more patients. A web app was developed that would help clinicians diagnose, and more importantly rule out MDS noninvasively, without bone marrow examination.

The researchers then calculated Positive Predictive Values and Negative Predictive Values assuming a 20% prevalence of MDS within the population of patients to which the model would be applied in practice (patients with unexplained anemia, in whom other causes of anemia have been excluded, who would likely undergo bone marrow examination in clinical practice). Approximately 90% of the MDS patients had anemia, about 35-40% of them had neutropenia, thrombocytopenia or bicytopenia, and about 15% had pancytopenia, all according to WHO criteria. Using the more severe cytopenia criteria as would be used for the International Prognostic Scoring System (IPSS) score, about 50% of MDS patients were severely anemic, about 20-25% of patients were neutropenic, thrombocytopenic, or bicytopenic, and 5% were pancytopenic.

It was noted that this tool was reliably able to separate patients with and without MDS. This model had a sensitivity of 88% and specificity of 95%. In this patient population with unexplained anemia, probable MDS and probably not MDS could be determined in 86% of patients, leaving it to the patient and the physician to discuss whether the bone marrow evaluation should be performed in the indeterminate group, to make the definitive diagnosis. The researchers also determined the robustness of this model in patients with neutropenia, thrombocytopenia, as well as in those with bicytopenia and pancytopenia. It was noted that the predictive model continued to be reliable, especially in its ability to rule out MDS in almost all of these categories, with Negative Predictive Values all above 90% and relatively narrow 95% Confidence Intervals (CIs). Moreover, the lower boundaries of the 95% CI were all above 90%. However, when it came to making a diagnosis of MDS, the accuracy was somewhat diminished. The researchers attributed this to smaller number of patients in these groups, and further added that patients with multiple cytopenias should have bone marrow evaluation, irrespective of the model prediction. Based on this algorithm, the researchers developed a web-based predictor calculator which would serve as a practical tool for clinicians. The limitations of this algorithm are that morphology, blast percentage, genetics, and cytogenetics have not yet been integrated into the model.

It was concluded that based on this MDS model, a web-based computer app has been developed, to help the physician community to primarily exclude MDS in a cytopenic individual and also predict the possibility of MDS, without performing an invasive bone marrow evaluation. The authors plan to not only improve the predictive power of the model by increasing the number of measured variables, but also validate this model with independent prospective patient data, and develop a predictive prognostic tool, in addition to diagnosis.

A predictive algorithm using clinical and laboratory parameters may assist in ruling out and in diagnosing MDS. Oster HS, Crouch S, Smith A, et al. Blood Adv. 2021;5:3066-3075.

FDA Approves TIBSOVO® for IDH1 Mutated Advanced Cholangiocarcinoma

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SUMMARY: The FDA on August 25, 2021, approved TIBSOVO® (Ivosidenib) for adult patients with previously treated, locally advanced or metastatic Cholangiocarcinoma, with an Isocitrate DeHydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test. The FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device, to aid in selecting patients with Cholangiocarcinoma for treatment with TIBSOVO®.

Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.

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 (AML) 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.MOA-of-Ivosidenib

TIBSOVO® (Ivosidenib) is an oral, targeted, small-molecule inhibitor of mutant IDH1. A previously published Phase I study demonstrated the safety and activity of TIBSOVO® in patients with IDH1 mutated advanced Cholangiocarcinoma. ClarIDHy is an international, randomized, double-blind, Phase III study, in which 187 previously treated patients with advanced Cholangiocarcinoma with an IDH1 mutation were randomly assigned 2:1 to receive TIBSOVO® 500 mg orally once daily (N=126) or matched placebo (N=61). All patients had advanced unresectable Cholangiocarcinoma. The median age was 62 years, 91% had intrahepatic Cholangiocarcinoma, 93% of patients had metastatic disease and 47% had received two prior therapies. The patient’s disease must have progressed following at least one, but not more than two prior regimens, including at least one Gemcitabine or 5-FU containing regimen. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Safety, Objective Response Rate (ORR) and Overall Survival (OS). Crossover from placebo to TIBSOVO® was permitted upon radiographic disease progression.

This study met its Primary endpoint and the median PFS was 2.7 months for patients treated with TIBSOVO® compared to 1.4 months with placebo (HR=0.37; P<0.0001). More importantly, the median PFS at 6 and 12 months were 32% and 22% in the TIBSOVO® group, whereas no patients randomized to the placebo group were progression-free for 6 or more months, at the time of data cutoff.
The authors also reported the results of final analysis which showed an improvement in the secondary endpoint of OS, favoring patients randomized to TIBSOVO® compared to those randomized to placebo. However, statistical significance was not reached. The median OS for patients in the TIBSOVO® arm was 10.3 months compared to 7.5 months for patients in the placebo arm (HR=0.79; 1-sided P=0.093). A high proportion of patients in the placebo arm (70.5%) crossed over to TIBSOVO®. After adjusting for crossover from placebo to TIBSOVO®, the median OS for patients in the placebo arm was 5.1 months (HR=0.49; 1-sided P<0.0001).

The 6-month survival rate for patients in the TIBSOVO® arm was 69% compared to 57% of patients in the placebo arm, not adjusted for crossover. The 12-month survival rate for patients in the TIBSOVO® arm was 43% compared to 36% for patients in the placebo arm, not adjusted for crossover. Treatment with TIBSOVO® preserved patients’ physical functioning from baseline, as assessed by the EORTC QLQ-C30 questionnaire, whereas patients in the placebo arm experienced decline from baseline starting cycle 2. The most common Adverse Events of any grade for TIBSOVO® were nausea (38%), diarrhea (33.1%) and fatigue (28.9%). Adverse Events leading to discontinuation were more common with placebo compared with total TIBSOVO® (8.5% versus 6.6%).

It was concluded that treatment with TIBSOVO® in patients with advanced Cholangiocarcinoma with an IDH1 mutation, resulted in significant improvement in Progression Free Survival as well as favorable Overall Survival trend, when compared to Placebo, despite a high rate of crossover. This is the first pivotal study demonstrating the clinical benefit of targeting IDH1 mutation in this patient group. This new oral, non-cytotoxic, targeted treatment option, with a tolerable safety profile, will be a welcome addition to treat this aggressive disease, for which there is an unmet need for new therapies.

Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. Zhu A, Macarulla T, Javle MM, et al. J Clin Oncol 39, 2021 (suppl 3; abstr 266)

Myelodysplastic Syndromes: Managing Anemia due to Ineffective Erythropoiesis in Patients with MDS Requiring RBC Transfusions

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Dr-M-Yair-Levy

Written by: Dr. M. Yair Levy, Texas Oncology
Promotional Content Sponsored by: Bristol Myers Squibb
Dr. Levy is a paid consultant for BMS and was compensated for his contribution in drafting this article.

 

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies characterized by multilineage cytopenias, including anemia.1 In MDS, stem cells lack the ability for differentiation and maturation, resulting in bone marrow dysfunction and poor blood cell production, in particular red blood cells (RBCs).2 Anemia is present in the majority of patients with MDS and, at diagnosis, anemia is the most common cytopenia present in patients with MDS.1 Anemia in MDS is linked to bone marrow dysfunction characterized by ineffective erythropoiesis.2

Ineffective erythropoiesis in MDS may lead to anemia requiring RBC transfusions and is characterized by increased proliferation of erythroid progenitors, increased death of erythroid precursors, and impaired erythroid maturation.3,4 In fact, 94% (515/546) of patients with MDS received RBC transfusions in the SEER-Sound registry from 2001 to 2007, 13% of whom had ring sideroblasts.5 Ring sideroblasts are erythroblasts with iron-loaded mitochondria associated with anemia that can be identified by iron staining and the results can be found on pathology reports.6

The presence of anemia despite increased proliferation of progenitor cells is indicative of ineffective erythropoiesis in MDS.3,4 There is a need to help address anemia due to ineffective erythropoiesis in patients with MDS requiring RBC transfusions after erythropoiesis stimulating agent (ESA) failure. REBLOZYL® (luspatercept-aamt), the first and only erythroid maturation agent, is approved for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).7 REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.7 The approval of REBLOZYL by the FDA marked the first new treatment indicated for patients with MDS in 14 years.8 In my clinical experience, the results that I’ve seen in patients with lower-risk MDS-RS are consistent with those seen in the MEDALIST clinical trial, as discussed below.

As the first and only erythroid maturation agent, REBLOZYL enhances erythroid maturation through differentiation of late-stage erythroid precursors. REBLOZYL works by binding several TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling and increasing the number and quality of mature RBCs in preclinical models.7

REBLOZYL was FDA approved for MDS-associated anemia based on the efficacy and safety outcomes of the pivotal phase 3 MEDALIST trial.7,9 The MEDALIST trial was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of 229 adult patients with IPSS-R very low-, low-, or intermediate-risk MDS-RS (<5% bone marrow blasts, presence of ring sideroblasts of ≥15% or ≥5% with an SF3B1 mutation) who required RBC transfusions (≥2 RBC units/8 weeks) were randomized 2:1 to REBLOZYL (n = 153) or placebo (n = 76).7,9 Patients were also required to have had an inadequate response to prior treatment with an ESA (defined as response that is no longer maintained after at least 8 doses of recombinant human erythropoietin or 4 doses of darbepoetin alfa), be intolerant of ESAs, or be ineligible for ESAs (serum EPO >200 U/L).7,9 The MEDALIST trial excluded patients who had del 5q MDS, a white blood cell count >13 Gi/L, neutrophils <0.5 Gi/L, platelets <50 Gi/L, or who had prior use of a disease-modifying agent for treatment of MDS.7

REBLOZYL was administered 1 mg/kg subcutaneously every 3 weeks for at least 24 weeks or until unacceptable toxicity, loss of efficacy, or disease progression. Patients could have their dose increased to 1.33 mg/kg and then to 1.75 mg/kg. Patients received dose increases if they did not achieve transfusion independence after two doses or 6 weeks at 1 mg/kg and 1.33 mg/kg. All patients received best supportive care, which included RBC transfusions as needed.7

In MEDALIST, 36% (83/229) of all patients in the trial were 75 years of age or older, including patients up to 95 years.7,9 95.2% (218/229) of all patients in the trial were ESA-exposed, while only 4.8% (11/229) were ESA-naive, with serum EPO >200 U/L.7,9 All patients in the trial had ring sideroblasts (≥15% ring sideroblasts or ≥5% ring sideroblasts with an SF3B1 mutation), and the majority (206/229) had an SF3B1 mutation.7,9 All patients except 1 were classified as having very low- to intermediate-risk MDS by the IPSS-R criteria.7 57% (130/229) of patients had a baseline RBC transfusion burden <6 RBC units/8 weeks.7

The primary endpoint in MEDALIST was RBC transfusion independence (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period occurring entirely within the first 24 weeks of treatment.7 Approximately 3 times greater percentage of patients receiving REBLOZYL achieved the primary endpoint of RBC transfusion independence than placebo: 37.9% (58/153) vs 13.2% (10/76; common risk difference [95% CI]: 24.6 [14.5, 34.6]; P < 0.0001), respectively.7 These data support that in patients requiring ≥2 RBC units/8 weeks, REBLOZYL should be started after at least 2 to 3 months of an inadequate response to ESAs.7,9

Key secondary endpoints in MEDALIST were based on RBC transfusion independence (absence of any RBC transfusions) during any consecutive 12-week period occurring entirely within weeks 1 to 24 and 1 to 48. 28.1% (43/153) of patients receiving REBLOZYL achieved transfusion independence ≥12 weeks occurring entirely within weeks 1 to 24 vs 7.9% (6/76) of patients receiving placebo (common risk difference [95% CI]: 20.0 [10.9, 29.1]; P = 0.0002). For weeks 1 to 48,* 33.3% (51/153) of patients receiving REBLOZYL achieved transfusion independence ≥12 weeks vs 11.8% (9/76) of patients receiving placebo (common risk difference [95% CI]: 21.4 [11.2, 31.5]; P = 0.0003).7
*The median (range) duration of treatment was 49 weeks (6–114 weeks) on the REBLOZYL arm and 24 weeks (7-89 weeks) on the placebo arm.

REBLOZYL provided RBC transfusion independence vs placebo in patients with MDS-RS and MDS/MPN-RS-T, based on the WHO 2016 classification. Of patients who were diagnosed with MDS-RS, 34.1% (46/135; 95% CI 26.1, 42.7) of patients receiving REBLOZYL achieved transfusion independence vs 12.3% (8/65; 95% CI 5.5, 22.8) receiving placebo. Of patients who were diagnosed with MDS/MPN-RS-T, 64.3% (9/14; 95% CI 35.1, 87.2) of patients receiving REBLOZYL achieved transfusion independence vs 22.2% (2/9; 95% CI 2.8, 60.0) receiving placebo. Of patients who were diagnosed with other types of MDS (MDS-EB-1, MDS-EB-2, and MDS-U), 75% (3/4; 95% CI 19.4, 99.4) of patients receiving REBLOZYL achieved transfusion independence vs 0% (0/2; 95% CI 0.0, 84.2) receiving placebo.7

RBC transfusion independence was also examined by baseline RBC transfusion burden. Of patients requiring 2 to 3 RBC units/8 weeks at baseline,† 80.4% (37/46; 95% CI 66.1, 90.6) of patients receiving REBLOZYL achieved transfusion independence vs 40% (8/20; 95% CI 19.1, 63.9) receiving placebo. Of patients requiring 4 to 5 RBC units/8 weeks at baseline,‡ 36.6% (15/41; 95% CI 22.1, 53.1) of patients receiving REBLOZYL achieved transfusion independence vs 4.3% (1/23; 95% CI 0.1, 21.9) receiving placebo. Of patients requiring ≥6 RBC units/8 weeks, 9.1% (6/66; 95% CI 3.4, 18.7) of patients receiving REBLOZYL achieved transfusion independence vs 3% (1/33; 95% CI 0.1, 15.8) receiving placebo.7

†Includes patients who received 3.5 units.
‡Includes patients who received 5.5 units.

The safety of REBLOZYL at the recommended dose and schedule was evaluated in 242 patients with MDS-RS (n = 192) or other myeloid neoplasms (n = 50). The median time on treatment with REBLOZYL was 50.4 weeks (range, 3-221 weeks), with 67% of patients exposed for 6 months or longer and 49% exposed for >1 year.7

Among the 242 patients treated with REBLOZYL, 5 (2.1%) had a fatal adverse reaction. 4.5% (11/242) of patients discontinued REBLOZYL due to an adverse reaction and 2.9% (7/242) of patients had their REBLOZYL dose reduced due to adverse reactions. The most common (≥10%) all-grade adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection. The majority of adverse reactions with REBLOZYL were Grade 1 or 2 (mild to moderate). The most common (≥2%) Grade ≥3 adverse reactions included fatigue, hypertension, syncope, and musculoskeletal pain.7

IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Thrombosis/Thromboembolism
In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension
Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-Fetal Toxicity
REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS
Grade ≥3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients.

The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection

LACTATION
It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

Please see full Prescribing Information for REBLOZYL

References:
1. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465.
2. Cazzola M, Malcovati L. Myelodysplastic syndromes—coping with ineffective hematopoiesis. N Engl J Med. 2005;352(6):536-538.
3. Santini V. Anemia as the main manifestation of myelodysplastic syndromes. Semin Hematol. 2015;52(4):348-356.
4. Fontenay-Roupie M, Bouscary D, Guesnu M, et al. Ineffective erythropoiesis in myelodysplastic syndromes: correlation with Fas expression but not with lack of erythropoietin receptor signal transduction. Br J Haematol. 1999;106(2):464-473.
5. Ramsey SD, McCune JS, Blough DK, et al. Patterns of blood product use among patients with myelodysplastic syndrome. Vox Sang. 2012;102(4):331-337.
6. Malcovati L, Cazzola M. Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts. Br J Haematol. 2016;174(6):847-858.
7. REBLOZYL [Prescribing Information]. Summit, NJ: Celgene Corporation; 2020.
8. Steensma, D.P. Myelodysplastic syndromes current treatment algorithm 2018. Blood Cancer J. 2018;8(5):47.
9. Data on file, Celgene Corporation. Summit, New Jersey.

© 2021 Celgene Corporation.
REBLOZYL is a trademark of Celgene Corporation, a Bristol Myers Squibb company.
REBLOZYL is licensed from Acceleron Pharma Inc.
08/21 2007-US-2100270

Immune Checkpoint Inhibitor Therapy and Risk of Venous Thromboembolism

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. Cancer patients have a 4-7 fold increased risk of thrombosis, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The etiology of thrombosis in cancer is multifactorial, and the vascular system is an important interface between the malignant cells and their systemic and external environments. Genetic alterations in malignant cells, as they respond to their microenvironment, can result in inflammation, angiogenesis, and tissue repair. This in turn leads to the local and systemic activation of the coagulation system. It has been postulated that the procoagulant effect of malignant cells may be related to the release of soluble mediators such as G-CSF into the circulation or by the shedding of procoagulant Extracellular Vesicles (EVs) harboring Tissue Factor. Previously published studies had entertained the notion that certain oncogenic mutations may deregulate hemostatic genes (coagulome) in cancer cells.
Immune Checkpoint Inhibitors (ICIs) have revolutionized cancer management. They bind to either PD-1 receptor or its ligand PD-L1 and block their interaction, thereby reversing the PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. This can however be accompanied by various off-target manifestations of autoimmunity induced by immune checkpoint inhibitors with resulting systemic inflammation on the hemostatic system. The risk of Venous ThromboEmbolism (VTE) and Arterial ThromboEmbolism (ATE) associated with ICIs is currently unclear. The goal of this study was to quantify the risk of VTE/ATE in patients with cancer, treated with ICIs, explore clinical impact, and investigate potential clinical risk factors.

The authors conducted a single-center, retrospective cohort study at the Medical University of Vienna, Austria, and included 672 patients with histologically confirmed cancer, who were treated with one or more doses of an Immune Checkpoint Inhibitor (Nivolumab, Pembrolizumab, Ipilimumab, Atezolizumab, or Avelumab), between 2015 and 2018. Patients received a median of 7 cycles of therapy. About a third of patients (30.4%) had Malignant Melanoma, whereas 24% had Non Small Cell Lung Cancer, 11% had Renal Cell Carcinoma, 10.4% had Head and Neck Squamous Cell Carcinoma and 5% had Urothelial cancer. Majority of patients (86%) had advanced disease at the time of ICI initiation. The median patient age was 64 years, 39% were female and most patients had an ECOG Performance Status of 0 or 1. Approximately 13% of patients had a history of VTE prior to the initiation of ICI therapy. Approximately 9% of patients had a history of ATE, and was associated with the current cancer diagnosis in 2.2% of the total cohort. At the time of ICI therapy initiation, 16.5% received continuous anticoagulation and 20% received antiplatelet therapy. The Primary outcomes of the study were cumulative incidence rates of VTE and ATE. Secondary outcomes included the association of VTE/ATE with Overall Survival (OS), Progression Free Survival (PFS), and radiological Disease Control Rate (DCR). The median follow up was 8.5 months.

It was noted that the cumulative incidences of VTE and ATE during ICI therapy were 12.9% and 1.8% respectively. The occurrence of VTE was associated with increased mortality with shorter OS. The median OS after the occurrence of VTE was 11.6 months compared with 25.5 months in those without VTE (P<0.001). The researchers noted that the number of fatal Pulmonary Embolisms were not high (N=2) in this study, suggesting that the impact of VTE goes beyond direct VTE-related mortality. The diagnosis of VTE was further associated with shorter PFS. Median PFS after VTE was 1.7 months compared with 6.7 months in those without VTE (P<0.001). The occurrence of ATE was not associated with risk of mortality or early progression of disease. However, this could have been due to relatively low number of ATE events and potential lack of statistical power. Therefore, definite conclusions cannot be drawn. Prior history of VTE predicted VTE occurrence. Distant metastasis was associated with VTE risk, although this was not statistically significant. The researchers did not find association of VTE with ECOG Performance Status or Khorana score, and the rates of VTE were comparable between tumor types and different immune Checkpoint Inhibitors. No association with VTE risk was observed for patients undergoing continuous anticoagulation or anti-platelet therapy at baseline.

It was concluded that despite the limitations of this study, patients with cancer undergoing treatment with Immune Checkpoint inhibitors are at a high risk of developing thromboembolic complications, especially VTE, and VTE occurrence was associated with increased mortality. The authors added that further studies are needed to better understand the risk of VTE and ATE associated with ICIs, and thus improve patient care by preventing thromboembolic complications.

Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Moik F, Chan WE, Wiedemann S, et al. Blood.2021;137:1669-1678.

FDA Approves LENVIMA® Plus KEYTRUDA® for Advanced Renal Cell Carcinoma

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SUMMARY: The FDA on August 10, 2021, approved the combination of LENVIMA® (Lenvatinib) plus KEYTRUDA® (Pembrolizumab) for first line treatment of adult patients with advanced Renal Cell Carcinoma (RCC). The American Cancer Society estimates that 76,080 new cases of kidney cancers will be diagnosed in the United States in 2021 and about 13,780 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. 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 less than 10% and there is a significant unmet need for improved therapies for this disease.

SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/smooth vessel cell wall, and is capable of specifically binding to tyrosine kinases inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® has been the standard first line intervention for treatment naïve patients with advanced RCC. In a large, multi-center, randomized, Phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival (OS) was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.

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. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

LENVIMA® (Lenvatinib) is an oral multitargeted TKI which targets Vascular Endothelial Growth Factor Receptor (VEGFR) 1-3, Fibroblast Growth Factor Receptor (FGFR) 1-4, Rearranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with antiangiogenesis properties by its ability to inhibit FGFR-1, thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting FGFR and PDGFR beta.

AFINITOR® (Everolimus) does not inhibit tyrosine kinases, but is a specific inhibitor of mTOR (Mammalian Target of Rapamycin), which is a serine/threonine kinase, normally activated further downstream in the signaling cascade. With the inhibition of mTOR, protein synthesis is inhibited resulting in decreased angiogenesis, cell proliferation and survival as well as decreased levels of HIF-1 alpha.

A combination of LENVIMA® plus AFINITOR® was shown to be associated with longer Progression Free Survival than AFINITOR® alone as second line treatment in advanced RCC (Lancet Oncol 2015;16:1473-1482). LENVIMA® plus KEYTRUDA® was shown to have promising antitumor activity in previously treated patients with RCC in a Phase IB-II trial (J Clin Oncol 2020;38:1154-1163). Based on this data, the authors conducted a multicenter, randomized, open-label, Phase III trial to compare the efficacy and safety of LENVIMA® in combination with KEYTRUDA® or AFINITOR® versus SUTENT® alone, in first line treatment of patients with advanced RCC.

The researchers randomly assigned 1069 patients with advanced RCC and no previous systemic therapy in a 1:1:1 ratio to receive LENVIMA® 20 mg orally once daily plus KEYTRUDA® 200 mg IV once every 3 weeks (N=355), LENVIMA® 18 mg orally once daily plus AFINITOR® 5 mg orally once daily (N=357) or SUTENT® 50 mg orally once daily, alternating 4 weeks on and 2 weeks off (N=357). The Primary end point was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety. The median follow up for OS was 26.6 months.

The median PFS was significantly longer with LENVIMA® plus KEYTRUDA® combination, compared to single agent SUTENT® (23.9 months versus 9.2 months, HR=0.39; P<0.001). The median PFS with the LENVIMA® plus AFINITOR® combination was also significantly longer, compared to single agent SUTENT® (14.7 months versus 9.2 months, HR=0.65; P<0.001). The PFS benefit favored the two LENVIMA® combination regimens over single agent SUTENT® across all evaluated subgroups, including those based on MSKCC prognostic risk group and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group. At interim analysis, the OS was significantly longer with LENVIMA® plus KEYTRUDA® than with SUTENT® (HR for death=0.66; P=0.005). This benefit was noted in most subgroups, including patients with PD-L1 positive or negative tumors, with an exception of patients with favorable risk disease as defined by IMDC criteria. Overall Survival with LENVIMA® plus AFINITOR® was however not significantly longer compared with SUTENT® (HR=1.15; P=0.30).

The confirmed ORR was 71% with LENVIMA® plus KEYTRUDA®, 53.5% with LENVIMA® plus AFINITOR®, and 36.1% with single agent SUTENT®. The Complete Response rate was 16.1% in the LENVIMA® plus KEYTRUDA® group, 9.8% in the LENVIMA® plus AFINITOR® group, and 4.2% in the SUTENT® group. The median Duration of Response in patients who had a confirmed response was 25.8 months in the LENVIMA® plus KEYTRUDA® group, 16.6 months in the LENVIMA® plus AFINITOR® group, and 14.6 months in the SUTENT® group. Grade 3 or higher Adverse Events occurred in 82.4% of the patients who received LENVIMA® plus KEYTRUDA® group, in 83.1% of the patients who received LENVIMA® plus AFINITOR®, and in 71.8% of the patients who received SUTENT®.

It was concluded that a combination of LENVIMA® plus KEYTRUDA® provided superior Progression Free Survival and Overall Survival compared to SUTENT®, in the first line treatment of patients with advanced Renal Cell Carcinoma.

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Motzer R, Alekseev B, Rha S-Y, et al. for the CLEAR Trial Investigators. N Engl J Med 2021; 384:1289-1300

KRAS Variant Status and Outcomes with Immune Checkpoint Inhibitor-Based Therapy in Advanced Non Small Cell Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.

Patients with advanced NSCLC without a driver mutation and with Programmed cell Death Ligand 1 (PD-L1) expression of 50% or greater, are often treated first line with Immune Checkpoint Inhibition (ICI) monotherapy or ICI in combination with chemotherapy. The choice between these two treatment regimens is usually based on tumor burden and patient comorbidities, as there are presently no biomarkers available to predict the risk and benefit of these treatment interventions. The KEYNOTE-042 study demonstrated that single agent Pembrolizumab given as first line therapy demonstrated Overall Survival (OS) benefit over chemotherapy, in patients with previously untreated advanced NSCLC, with PD-L1 expression of 1% or greater. In an exploratory analysis, this benefit was seen regardless of KRAS status, but was more pronounced in patients with KRAS variants than those without KRAS variants.

The KRAS (kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. When mutated, KRAS oncogene has the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS-G12C mutation occurs in approximately 12-15% of NSCLC and in 3-5% of Colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers, and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers.

The authors conducted this study to evaluate the association of KRAS status with outcomes following ICI monotherapy versus chemoimmunotherapy in patients with PD-L1 of 50% or greater. The researchers used the Flatiron Health database, comprising 280 cancer clinics across the US and analyzed 1127 patients with advanced non-squamous NSCLC with PD-L1 expression of 50% or greater, known KRAS variant status, and no alteration in EGFR, ALK, or ROS1, who were treated with first line ICI monotherapy or chemoimmunotherapy between January 2016 and May 2020. Of the patients analyzed, 50.8% had KRAS variant status and 49.2% had KRAS wild type status. Patients with KRAS variant status were more likely to be female (58.7% versus 47.1%; P =0.002) and had smoking history (96.4% versus 87.7%; P < .001). Other patient demographics and patient characteristics, including age, race, ethnicity, Performance Status, and stage at diagnosis, were well balanced among the groups analyzed. Patient groups were stratified by treatment type and KRAS status (variant or wild type), and Overall Survival (OS) was compared between the treatment groups. Adjusted Hazard ratios for death associated with KRAS status and treatment regimen was estimated, using Cox proportional hazards models.

It was noted that among patients treated with ICI monotherapy, KRAS variant status was associated with superior median survival compared with KRAS wild type (21.1 months versus 13.6 months; HR=0.77; P=0.03), and this was statistically significant. However, among patients treated with chemoimmunotherapy, there was no significant median survival difference between patients with KRAS variant and KRAS wild type status (20.0 months versus 19.3 months; HR=0.99; P=0.93).

Among patients with KRAS variant status, the median OS did not differ between those treated with ICI monotherapy and chemoimmunotherapy (21.1 months versus 20.0 months; P =0.78), whereas among patients with KRAS wild type status, those treated with ICI monotherapy had numerically worse median survival than those treated with chemoimmunotherapy, although this difference was not statistically significant (13.6 months versus 19.3 months; HR=1.19; P =0.06).

In conclusion, this data suggests that chemoimmunotherapy might be favored over ICI monotherapy for patients with KRAS wild type tumors associated with high PD-L1 expression. The authors caution that in this analysis KRAS variant subtype and co-mutation status including TP53 and STK11 was unknown, and further investigation is needed to selection appropriate therapies for patients with PD-L1 High NSCLC.

Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. Sun L, Hsu M, Cohen RB, et al. JAMA Oncol. 2021;7:937-939.