Category: Hem/Onc Updates

FDA Approves Frontline TECENTRIQ® with Carboplatin and nab-Paclitaxel for Metastatic Non-Squamous NSCLC

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SUMMARY: The FDA on December 3, 2019 approved TECENTRIQ® (Atezolizumab) in combination with nab-Paclitaxel and Carboplatin for the first-line treatment of adult patients with metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019, about 228,150 new cases of lung cancer will be diagnosed and 142,670 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.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immuno-Oncology (IO) therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation and a therapeutic response. Immunotherapy with PD-1 (Programmed cell Death 1) and PD-L1 (Programmed cell Death Ligand 1) inhibitors have demonstrated a clear survival benefit both as a single agent or in combination, compared with standard chemotherapy, in both treatment-naive and previously treated patients for advanced NSCLC. It is now standard therapy for patients with lung cancer. TECENTRIQ® is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1, expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors and thus enabling the activation of T cells. Unleashing-T-Cell-Function-with-Anti-PD-1-and-Anti-PD-L1-Antibodies

IMpower 130 is an international, multicentre, open-label, randomized, Phase III study, evaluating the efficacy and safety of TECENTRIQ® in combination with Carboplatin and nab-Paclitaxel versus chemotherapy (Carboplatin and nab-Paclitaxel) alone, for chemotherapy-naïve patients with Stage IV non-squamous NSCLC. This study enrolled 724 patients who were randomly assigned 2:1 to receive TECENTRIQ® 1200 mg IV on Day 1, along with Carboplatin AUC 6 on Day 1 and nab-Paclitaxel 100 mg/m2 IV, on days 1, 8 and 15 of each 21-day cycle, for 4 or 6 cycles followed by maintenance TECENTRIQ®, or Carboplatin and nab-Paclitaxel alone (control group), followed by Best Supportive Care during the maintenance treatment phase or Switch maintenance to Pemetrexed every 3 weeks. Stratification factors included gender, baseline liver metastases, and PD-L1 expression. The co-Primary endpoints were investigator-assessed Progression Free Survival and Overall Survival in the intention-to-treat EGFR and ALK wild-type population. The median follow up in the population studied was 19 months.

There was a significant improvement in median Overall Survival in the TECENTRIQ® plus chemotherapy group at 18.6 months compared to 13.9 months in the chemotherapy alone group (HR=0.79; P=0.033), as well as improvement in the median Progression Free Survival (7 months versus 5.5 months, respectively, HR=0.64; P<0.0001). The most common adverse reactions reported in 20% or more of patients in the TECENTRIQ® and chemotherapy group were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite.

It was concluded that first-line TECENTRIQ® in combination with chemotherapy significantly improved Overall Survival and Progression Free Survival, compared to chemotherapy alone, in patients with advanced non-squamous NSCLC without ALK or EGFR mutations. This IO-chemotherapy combination is the second FDA approval for this patient population. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. West H, McCleod M, Hussein M, et al. Lancet Oncol. 2019;20:924-937

Overall Survival Benefit with ONIVYDE® and Characteristics of Long Term Survivors in Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that for 2019, about 56,770 people will be diagnosed with Pancreatic cancer and about 45,750 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 2020.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

NAPOLI-1 is an open-label, Phase III study in which 417 patients with Gemcitabine-refractory metastatic Pancreatic adenocarcinoma were randomly assigned in a 1:1:1 ratio to receive either ONIVYDE® monotherapy (N=151), ONIVYDE® plus 5-FluoroUracil (N=117) or 5-FU with Leucovorin (N=149). Sixty one percent (61%) of patients had cancer in the head of the Pancreas and 68% had liver metastases. Treatment consisted of ONIVYDE® 120 mg/m2 IV over 90 minutes every 3 weeks in Group A, ONIVYDE® 80 mg/m2 IV given over 90 minutes followed by 5-FU 2400 mg/m2 given over 46 hours and racemic Leucovorin 400 mg/m2 IV given over 30 minutes every 2 weeks in Group B and 5-FU 2000 mg/m2 IV given over 24 hours plus racemic Leucovorin 200 mg/m2 IV given over 30 minutes weekly for 4 weeks followed by 2 weeks of rest in Group C (Control group). Each of the two ONIVYDE® containing groups was compared with the 5FU/Leucovorin control group. Treatment groups were well balanced. The Primary study endpoint was Overall Survival and Secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR). The authors in this publication reported the updated Overall Survival analysis from a longer follow up in the NAPOLI-1 trial, as well as baseline characteristics associated with long term survivors (survival of 1 year or more) in the NAPOLI-1 trial. The authors also provided the updated safety and tolerability data.

The combination of ONIVYDE®, 5-FU and Leucovorin maintained its median OS of 6.2 months compared with 4.2 months with 5-FU and Leucovorin alone, with an unstratified Hazard Ratio of 0.75 (P=0.04), and stratified Hazard Ratio of 0.63 (P=0.002). The estimated one-year survival rates were 26% in the ONIVYDE®, 5-FU and Leucovorin arm versus 16% in the 5-FU and Leucovorin combination control arm. Patient characteristics associated with long term survival in the ONIVYDE®, 5-FU and Leucovorin combination arm included Karnofsky Performance Status of 90 or more, age 65 years or less, lower serum CA19-9 levels, Neutrophil-to-Lymphocyte ratio of 5 or less and no liver metastases. There was again no OS advantage with ONIVYDE® monotherapy, when compared with 5-FU and Leucovorin (4.9 versus 4.2 months). The median PFS was 3.1 months in patients receiving ONIVYDE®, 5-FU and Leucovorin and 1.5 months in those receiving 5-FU and Leucovorin combination alone (HR=0.57; P < 0.0001), and was 2.7 months for ONIVYDE® monotherapy compared with 1.6 months for 5-FU and Leucovorin combination control group. The ORR was significantly higher with ONIVYDE®, 5-FU and Leucovorin combination (17%) compared with 1% for the 5-FU and Leucovorin combination (P < 0.0001) and the Disease Control Rate was also higher with ONIVYDE®, 5-FU and Leucovorin combination (52%) versus 24% for the 5-FU and Leucovorin combination control group. No new safety concerns were detected in the current updated analysis.

The authors concluded that for patients with metastatic Pancreatic adenocarcinoma, a combination of ONIVYDE®, 5-FU and Leucovorin improves Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate, with an acceptable safety profile, and represents a new standard of care following Gemcitabine-based therapy. This updated analysis also identified prognostic markers associated with longer survival. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Wang-Gillam A, Hubner RA, Siveke JT, et al. European Journal of Cancer 2019;108:78-87

Isatuximab Combination Significantly Improves Progression Free Survival in Relapsed/Refractory Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32,110 new cases will be diagnosed in 2019 and 12,960 patients are expected to die of the disease. Multiple Myeloma (MM) in 2019 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity.

CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38 and was approved for use in combination with POMALYST® (Pomalidomide) and Dexamethasone in 2017, for the treatment of patients with multiple myeloma who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

Isatuximab is a CD38-targeting monoclonal antibody, similar to DARZALEX®, but unlike DARZALEX®, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from DARZALEX® could position Isatuximab for use in cases when DARZALEX® fails. Additionally, Isatuximab infusions are less cumbersome.

ICARIA-MM trial is an open-label, randomized, multicentre Phase III study in which 307 adult patients with Relapsed and Refractory multiple myeloma who had received at least two previous lines of treatment, including REVLIMID® and a Proteasome Inhibitor were eligible. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. Patients were randomly assigned 1:1 to receive either Isatuximab along with POMALYST® and low-dose Dexamethasone (N =154) or POMALYST® and low-dose Dexamethasone (N = 153). Treatment consisted of 28-day cycles of Isatuximab 10 mg/kg given IV on days 1, 8, 15, and 22 in the first cycle and days 1 and 15 in subsequent cycles. Both groups received POMALYST® 4 mg orally on days 1 to 21 of each cycle and Dexamethasone 40 mg (20 mg for patients aged 75 years or older) oral or IV on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression or unacceptable toxicity. The Primary endpoint was Progression Free Survival, determined by an Independent Response Committee, and assessed in the intent-to-treat population.

At a median follow-up of 11.6 months, the median PFS was 11.5 months in the Isatuximab group versus 6.5 months in the control group (HR= 0.596; P=0.001). In prespecified subgroup analyses, which included patients with poor prognostic features, and those refractory to REVLIMID®, a Proteasome Inhibitor, or both, the Hazard Ratios were consistently in favor of Isatuximab.(HR=0.58). The most common adverse events of any grade in the Isatuximab vs control groups were infusion reactions (38% versus 0%, of which 3% were Grade 3 or 4), upper respiratory tract infection (28% versus 17%), and diarrhea (26% versus 20%).

It was concluded that the addition of Isatuximab to POMALYST® and Dexamethasone significantly improves Progression Free Survival in patients with Relapsed and Refractory multiple myeloma, and is an important new treatment option for the management of patients who become refractory to REVLIMID® and a Proteasome Inhibitor. Multiple myeloma patients will soon have the opportunity to choose between two equally effective treatment options with various modes of administration. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Attal M, Richardson PG, Rajkumar SV, et al. The Lancet. November 14, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)32556-5

FDA Approves CALQUENCE® for Chronic Lymphocytic Leukemia

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SUMMARY: The FDA on November 21, 2019, approved CALQUENCE® (Acalabrutinib), for adults with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). The American Cancer Society estimates that for 2019, about 20,720 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 3,930 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies.

Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. CALQUENCE® is a highly selective, oral, covalent irreversible Bruton Tyrosine Kinase (BTK) inhibitor with minimal activity against other kinases. CALQUENCE® inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. The present FDA approval was based on two randomized, actively controlled trials, ELEVATE-TN and ASCEND in patients with CLL.

ELEVATE-TN is a randomized, multicentre, open-label Phase III trial which evaluated the safety and efficacy of CALQUENCE® alone or in combination with GAZYVA® (Obinutuzumab) versus Chlorambucil in combination with GAZYVA®, in previously-untreated patients with CLL. GAZYVA® is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody. In this trial, 535 patients were randomized 1:1:1 to receive CALQUENCE® monotherapy 100 mg twice daily orally continuously (N=179) or in combination with GAZYVA® (N=179), or Chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for 6 cycles along with GAZYVA® (N=177). The dose of GAZYVA® was 100 mg on day 1 and 900 mg on day 2 of Cycle 1, 1000 mg on day 8 and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2–6, of each 28 day cycle. Pts were stratified by del(17p) status, ECOG status (1 or less versus 2), and geographic region. The median patient age was 70 years and 69% had high risk and 12% had very high risk CLL IPI scores. The Primary endpoint was PFS in the CALQUENCE® plus GAZYVA® group compared to the Chlorambucil and GAZYVA® group, assessed by an independent review committee (IRC). A key secondary endpoint was PFS in the CALQUENCE® monotherapy arm, compared to the chlorambucil and GAZYVA® arm. Other secondary endpoints included Objective Response Rate, time to next treatment and Overall Survival.

At a median follow-up of 28 months, the combination of CALQUENCE® plus GAZYVA® significantly prolonged PFS compared to Chlorambucil plus GAZYVA® (median Not Reached versus 22.6 months; HR 0.10, P<0.0001), reducing the risk of progression or death by 90%. CALQUENCE® monotherapy also significantly prolonged PFS compared to Chlorambucil plus GAZYVA® (HR=0.20; P<0.0001). PFS improvement with CALQUENCE® plus GAZYVA® as well as CALQUENCE® monotherapy was consistent across all subgroups examined including del(17p). The median OS was not reached in any treatment group. The ORR was higher with CALQUENCE® plus GAZYVA® versus Chlorambucil plus GAZYVA® (94% versus 79%; P<0.0001). The ORR with CALQUENCE® monotherapy was 85%. Complete Response rates were higher with CALQUENCE® plus GAZYVA® versus Chlorambucil plus GAZYVA® (13% versus 5%).

ASCEND is a global, randomized, multicentre, open-label Phase III trial which evaluated the efficacy and safety of CALQUENCE® versus physician’s choice of Rituximab/ZYDELIG® (Idelalisib) or Rituximab/Bendamustine combination in patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL). This study included 310 eligible patients who were randomly assigned 1:1 to receive CALQUENCE® 100 mg orally twice daily until disease progression versus Rituximab/ ZYDELIG® combination (ZYDELIG® 150 mg orally twice daily in combination with up to eight IV infusions of Rituximab 375 or 500 mg/m2) or Rituximab/Bendamustine combination (Bendamustine 70 mg/m2 IV on day 1 and 2 of each cycle in combination with Rituximab 375 or 500 mg/m2 IV on day 1 of each 28-day cycle for up to six cycles). The median age was 67 years and patients were stratified by del(17p) status, ECOG performance scale and prior lines of therapy. The Primary endpoint was Progression Free Survival as assessed by Independent Review Committee (IRC) and Secondary end points included Overall Response Rate and Duration of Response, as well as Overall Survival. Patients with confirmed disease progression on Rituximab/ ZYDELIG® or Rituximab/Bendamustine, were allowed to cross over to receive CALQUENCE®.

At a median follow-up of 16.1 months, there was a statistically significant and clinically meaningful improvement in PFS with CALQUENCE® monotherapy compared to a combination regimen of Rituximab plus physician’s choice of ZYDELIG® or Bendamustine. The PFS with CALQUENCE® monotherapy was not reached versus 16.5 months with the comparators (HR= 0.31, P<0.0001). This represented a 69% reduction in risk of progression or death. Progression Free Survival was improved with CALQUENCE® monotherapy across subgroups including del(17p), TP53 mutation, and Rai stage. There was however no significant difference in the Overall Response Rates among the treatment groups and 23% of the patients randomly assigned to Rituximab/ ZYDELIG® or Rituximab/Bendamustine combinations crossed over to receive subsequent treatment with CALQUENCE®. The most common side effects of CALQUENCE® were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain.

In conclusion, CALQUENCE® monotherapy as well as in combination with GAZYVA®, significantly improved Progression Free Survival in Relapsed/Refractory CLL, as well as treatment naïve patients with CLL, respectively.

ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL). Sharman JP, Banerji V, Fogliatto LM, et al. Blood. 2019 Nov 13;134(Supplement_1):31.

ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelasib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Ghia P, Pluta A, Wach M, et al. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, Netherlands. Abstract LB2606.

First Line Combination of TECENTRIQ® and AVASTIN® Improves Survival in Hepatocellular Carcinoma

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SUMMARY: The American Cancer Society estimates that for 2019, about 42,030 new cases of primary liver cancer will be diagnosed in the US and 31,780 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide and majority of patients typically presents at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors, and thus enabling the activation of T cells. AVASTIN® (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds VEGF (Vascular Endothelial Growth Factor) and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells, thereby preventing endothelial cell proliferation and new blood vessel formation. The use of TECENTRIQ® in combination with AVASTIN® has a strong scientific rationale, as this combination can potentially enhance the immune system to combat a broad range of malignancies. AVASTIN® in addition to its established anti-angiogenic properties can further enhance TECENTRIQ®’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.

IMbrave150 is a global, open-label, multicenter, randomized, Phase III study in which a combination of TECENTRIQ® and AVASTIN® was compared with standard-of-care NEXAVAR®, in patients with previously untreated locally advanced or metastatic HCC. Patients were randomized 2:1 to receive TECENTRIQ® 1200 mg IV on day 1 along with AVASTIN® 15 mg/kg on day 1 of each 21-day cycle (N=336) or NEXAVAR® 400 mg orally twice daily, each day of the 21-day cycle (N=165). Treatment was continued until disease progression or unacceptable toxicity. The treatment groups were well balanced and enrolled patients had an ECOG performance status of 0 or 1, Child-Pugh Class A disease, and adequate hematologic and end-organ function. The two co-Primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS). The key Secondary endpoints included Overall Response Rate (ORR), Time To Progression (TTP) and Duration of Response (DOR), as well as Patient-Reported Outcomes (PROs), Safety and Pharmacokinetics.

With a median follow up of 8.6 months, the OS was not yet reached in the TECENTRIQ® and AVASTIN® combination group compared with 13.2 months in the NEXAVAR® group (HR=0.58; P=0.0006). The median PFS was 6.8 months versus 4.3 months respectively (HR=0.59; P<0.0001). The ORR was 27% versus 12% (P<0.0001) based on the Independent Review Facility RECIST 1.1 criteria, in favor of the combination regimen. This benefit was seen across clinical subgroups and the combination regimen delayed deterioration of Quality of Life compared with NEXAVAR®. Grade 3 and 4 Adverse Events were similar and occurred in 57% and 55% of the combination and control arms, respectively.

It was concluded that a combination of TECENTRIQ® and AVASTIN® demonstrated statistically significant and clinically meaningful improvement in both Overall Survival and Progression Free Survival compared with NEXAVAR®, in treatment naïve patients with unresectable Hepatocelluar Carcinoma. The authors added that this is the first study in 11 years to show an improvement in Overall Survival with a new first line treatment option, compared to NEXAVAR®, and has the potential to be a practice changing treatment in Hepatocellular Carcinoma. IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Cheng A-L, Qin S, Ikeda M, et al. Annals of Oncology, Volume 30, 2019 Supplement 9. LBA3

Higher Levels of IGF-1 and Free Testosterone Increase the Risk of Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The etiology of Prostate cancer remains unclear, and North American Blacks are at the highest risk whereas risk is lowest in Asians, with the risk among Caucasians somewhere in between.

The Insulin-like Growth Factor (IGF) system has been reported to regulate normal and malignant cell growth, proliferation and differentiation, tissue homeostasis and cellular metabolism, and its relevance in carcinogenesis has been well established. The role of IGF system in Prostate cancer was initially recognized from epidemiological studies which showed that higher serum IGF-1 concentrations correlated with an increased risk of Prostate cancer. Testosterone in the circulation is bound primarily to Sex Hormone Binding Globulin (SHBG) while the unbound, or free testosterone, is the most bioavailable and active form.

The authors in this large prospective study investigated the association of circulating levels of IGF-I, free (biologically active testosterone) and total testosterone, and Sex Hormone Binding Globulin (SHBG) with Prostate cancer incidence and mortality, in a large cohort of patients. This study included 200,452 male participants who were free of cancer when they were enrolled in the study, and were not taking any hormone therapy. Baseline blood samples were obtained from these men and tested for levels of total testosterone and IGF-1. Free testosterone level was calculated from measured total testosterone and binding protein concentrations.

After a mean follow up of 6.9 years, 5412 men were diagnosed with Prostate cancer and 296 had died from the disease. It was noted that higher levels of circulating IGF-I was associated with an elevated risk of Prostate cancer diagnosis, as well as Prostate cancer mortality. Higher free testosterone level was associated with an elevated risk of incident Prostate cancer, whereas higher SHBG was associated with a lower risk, but neither was associated with Prostate cancer mortality. Total testosterone levels were not associated with Prostate cancer incidence or mortality. For every 5 nanomoles increase in the concentration of IGF-1 per liter of blood (5 nmol/L), men were 9% more likely to develop Prostate cancer. For every 50 picomoles increase of free testosterone per liter of blood (50 pmol/L), there was a 10% increase in Prostate cancer risk. The researchers added that their findings correspond to a 25% greater risk of Prostate cancer in men who have the highest levels of IGF-1, compared to those with the lowest, and men with the highest free testosterone levels have a 18% greater risk of Prostate cancer, compared to those with the lowest levels.

It was concluded from this study that circulating levels of IGF-I and free testosterone play a role in the development of Prostate cancer and these two hormones could be one of the several mechanisms that links diet, lifestyle, and body size with the risk of Prostate cancer, taking us one step closer to Prostate cancer prevention. Serum hormones and prostate cancer incidence and mortality in UK Biobank. Travis R, Watts E, Fensom G, et al. Presented at the 2019 NCRI Cancer Conference. Abstract#2904

FDA Approves ADAKVEO®, A New Targeted Therapy for Sickle Cell Disease

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SUMMARY: The FDA on November 15, 2019 approved ADAKVEO® (Crizanlizumab-tmca), a treatment to reduce the frequency of vaso-occlusive crisis, for patients age 16 years and older. Vaso-occlusive crisis is a common and painful complication of Sickle Cell Disease (SCD), that occurs when blood circulation is obstructed by sickled red blood cells. Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the United States is approximately 40-60 years.

HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (vaso-occlusive crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 thalassemia (double heterozygote for HbS and b-0 thalassemia) is clinically indistinguishable from HbSS disease.

P-Selectin is a Cell Adhesion Molecule (CAM) expressed on the surfaces of activated vascular endothelial cells and platelets. In unactivated endothelial cells and platelets, it is stored in Weibel-Palade bodies and alpha granules respectively. P-Selectin is released from endothelial cells and platelets when activated by inflammation or trauma and mediates the binding of erythrocytes and leukocytes to the vessel wall. In patients with Sickle Cell Disease (SCD), adherent masses of sickled red cells and leukocytes contribute to vaso-occlusive pain crises. ADAKVEO® is a first-in-class humanized anti-P-Selectin antibody, and the SUSTAIN study evaluated the safety and efficacy of ADAKVEO® on the frequency of Sickle Cell-related Pain Crises (SCPC) in Sickle Cell Disease patients.

The present FDA approval of ADAKVEO® was based on SUSTAIN, a multicenter, randomized, placebo controlled, double-blind clinical trial in which 198 Sickle Cell Disease patients with a history of vaso-occlusive crisis, were randomly assigned to receive ADAKVEO® at doses of 5 mg/kg, 2.5 mg/kg, or placebo, administered intravenously, 14 times over 52 weeks. Treatment groups were well balanced and patients receiving Hydroxyurea or Erythropoietin were included, if prescribed for the preceding 6 months and dose was stable for at least 3 months. The Primary end point was Sickle Cell-related Pain Crises (SCPC), defined as acute sickle cell-related pain that resulted in a visit to a medical facility and required a parenteral or oral narcotic or parenteral NSAID. Acute Chest Syndrome (ACS), priapism, hepatic and splenic sequestration were also included in this definition.

Treatment with ADAKVEO® experienced fewer health care visits for vaso-occlusive crisis annually and significantly lowered the median annual rate of vaso-occlusive crisis by 45% from 2.98 visits to 1.63 visits, compared with placebo. Reductions in the frequency of vaso-occlusive crisis were observed among patients regardless of Sickle Cell Disease genotype and/or Hydroxyurea use. More than one third (36%) of patients who received ADAKVEO® did not experience vaso-occlusive crisis during the study, compared with 17% of placebo-treated patients. ADAKVEO® delayed the time that patients first experienced vaso-occlusive crisis after starting treatment from a median of 1.4 months to 4.1 months. Common side effects associated with ADAKVEO® included back pain, nausea, fever and arthralgia. Patients should be monitored for infusion-related reactions and treatment should be discontinued for severe reactions. Patients should also be monitored for interference with automated platelet counts or platelet clumping and it is advised that CBC be performed using citrate tubes to avoid platelet activation.

It was concluded that ADAKVEO® significantly reduced Sickle Cell-related Pain Crises (SCPC) and increased the time to first and second SCPC. The authors added that chronic inhibition of P-Selectin with once a month IV dosing of ADAKVEO® represents a novel and potentially new disease-modifying, prophylactic treatment option for patients with Sickle Cell Disease. SUSTAIN: A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 12-Month Study to Assess Safety and Efficacy of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell-Related Pain Crises. Ataga KI, Kutlar A, Kanter J, et al. N Engl J Med 2017; 376:429-439

Late Breaking Abstract – ASTRO 2019 Detectable HPV Circulating Tumor DNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression

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SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a significant increase in incidence during the past several decades. They represent approximately 70% of all OPSCC in the United States and Canada. HPV is a non-enveloped, double-stranded, DNA virus that infects epithelial cells and majority of the HPV subtypes cause epithelial lesions such as warts or papillomas, which are of low malignant potential. However, there is a subset of high-risk HPV that can cause cancer by integrating its DNA into the host genome, with the resulting expression of two important oncogenes E6 and E7 in the host cell. The E6 oncogene binds and degrades tumor suppressor TP53 via ubiquitin-mediated processes thereby preventing the host cell from engaging in cell cycle checkpoints and enduring an apoptotic response. The E7 oncogene binds to and destabilizes tumor suppressor retinoblastoma (pRb) resulting in transcription of genes involved in proliferation and cell cycle progression. One of the main molecular pathways amplified through E7 is the CDKN2A/p16 gene pathway, which results in the overexpression of p16 protein. E7 also induces cellular proliferation by disrupting the activity of Cyclin Dependent Kinase inhibitors p21 and p27. In essence, HPV infection induces failures in cell cycle checkpoints, resulting in genetic instability and over time, progression of premalignant lesions to invasive Squamous Cell Carcinoma. Unlike tobacco induced HNSCC where TP53 and pRb pathways are nullified due to mutation and epigenetic alterations, in HPV-related HNSCC, wild-type TP53 and pRb are functionally inactivated by the viral oncogenes.

Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV infection. The HPV-positive primary Squamous Cell Carcinoma tends to be smaller in size, with early nodal metastases, and HPV status particularly in OroPharyngeal Squamous Cell Carcinoma is an independent prognostic factor for Overall Survival (OS) and Progression Free Survival (PFS). These patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Further, HPV positive patients demonstrate higher Response Rates to chemoradiation as well as an improved Overall Survival. However, approximately 20% of patients diagnosed with HPV-positive OPSCC experience cancer progression within 5 years.

The role of circulating tumor DNA (ctDNA) as a cancer biomarker in the post-operative surveillance of patients with HPV-associated OPSCC has remained unclear. The authors in this study aimed to investigate ctDNA detectability rates by post-op risk category and association with prognosis in this patient population. The researchers prospectively collected and tested serum samples from 29 patients with HPV-associated OPSCC who had not yet undergone treatment, for assay validation. As a control, 7 HPV negative OPSCC patients were included. A cohort of 46 patients with HPV-associated OPSCC who had undergone surgery for the disease had serum samples collected prior to beginning adjuvant therapy. The serum collected from this total group of 82 patients (N=29+7+46) was analyzed in a blinded fashion for E6/E7 HPV ctDNA using ddPCR multiplex assay (HPV 16, 18, 31, 33), and HPV ctDNA detectability was compared statistically across groups. Associations of patient and tumor characteristics with recurrence were assessed and estimates of Progression Free Survival (PFS) and Overall Survival (OS) were made using the Kaplan-Meier (KM) method.

The researchers found that ctDNA was detectable in 27 of 29 patients who had not yet undergone treatment, for a sensitivity rate of 93%, whereas none of the 7 HPV-negative patients had detectable ctDNA, for a specificity rate of 100%. Post-op serum was collected at a median of 25 days after surgery prior to beginning adjuvant therapy and ctDNA was detectable in 43% of patients including 47% with high-risk features (Extra Nodal Extension or R1-microscopic residual tumor). All detected ctDNA was HPV type 16.

At a median follow up of 20 months for the post-op HPV-OPSCC cohort, 24% of these patients had recurrent disease. Among those who recurred, 64% had detectable ctDNA compared with 35% whose disease did not recur (P=0.1). There was a significant association between detectable ctDNA and 24-month Progression Free Survival (45% versus 84%; P=0.04) and Overall Survival (80% versus 100%; P=0.02). Overall, detectable ctDNA, T4 tumors, and more than 4 positive lymph nodes were positively associated with disease recurrence.

It was concluded that detectable HPV circulating tumor DNA is a highly sensitive and specific means of determining HPV-status and was significantly associated with worsened Progression Free Survival and Overall Survival among post-op patients with Human Papilloma Virus (HPV)-associated OroPharyngeal Squamous Cell Carcinoma. HPV circulating tumor DNA as a cancer biomarker may also assist in risk stratification, treatment assessment, and surveillance. Detectable HPV ctDNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression. Routman DM, Chera BS, Jethwa KR, et al. International Journal of Radiation Oncology • Biology • Physics 2019;105, 682-683. LBA5

Early Adjuvant Chemotherapy Dose Reductions Can Impact Breast Cancer Survival

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of invasive breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy and this is even more so true for HER positive and triple negative (ER, PR and HER negative) breast cancer patients, who are at an increased risk to develop recurrent disease. Meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has shown a 20-25% relative risk reduction in breast cancer mortality with first-generation adjuvant chemotherapy regimens such as CMF (Cyclophosphamide/Methotrexate/Fluorouracil) and additional survival benefit with the Anthracyclines and Taxane based regimens.

Chemotherapy dose reductions are often considered for patients with obesity, BSA of more than 2.0 m2, age over 65 years, comorbidities such as kidney disease or diabetes, and febrile neutropenia. ASCO guidelines recommend full weight-based chemotherapy doses in the treatment of obese patients. Dose reductions to less than 85% of the optimal (total cumulative) chemotherapy dose (mg/m2) and cycle delay have shown inferior survival outcomes in both prospective and some retrospective studies. However, it is unclear if dose reductions made for third-generation Anthracycline/Taxane-based regimens as well as sequential regimens such as Taxanes following Anthracycline based regimens, has an impact on survival.

The authors therefore performed a retrospective analysis to evaluate the effect of Total Cumulative Dose (TCD) of adjuvant chemotherapy, on breast cancer outcomes, in women diagnosed with Stage I-III, Hormone Receptor positive or negative, HER2-negative breast cancer, treated with adjuvant FEC (5-FU 500 mg/m2, Epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2) for 3 cycles followed by Docetaxel 100 mg/m2 for 3 cycles (FEC-D chemotherapy regimen) from 2007 through 2014. Using the historical cutoff of 85% as the optimal Total Cumulative Dose (TCD), this study focused on data from the Alberta Cancer Registry on 1,302 women with Stage I to III breast cancer.

The TCD for cycles 1-6 of less than 85% or 85% and more was calculated. The majority of patients (84%) received 85% or more of the TCD across all six cycles. Sixteen percent (16%) received reduced doses (less than 85% of TCD). Those receiving a TCD of 85% or more were more likely to be younger (median age of 54 yrs) and premenopausal, with a lower number of comorbidities, compared with those with a TCD of less than 85%. The average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy, to explore the effects of early (FEC) versus late (Docetaxel only) dose reduction. The median follow up was 60 months.

It was noted that the amount of chemotherapy delivered had a significant impact on survival. Patients receiving a TCD of 85% or more had a 5-year Disease Free Survival (DFS) of 85.9% versus 79.2% for those receiving a lower TCD (P=0.025). The 5-year Overall Survival (OS) was also superior at 88.8% versus 80.7% (P<0.001), respectively. When the researchers split the lower TCD group into two cohorts based on dose reduction during cycles 1-3 versus cycles 4-6, they found that outcomes were not compromised when dose reduction occurred only during the later cycles (which were the only cycles to include Docetaxel), suggesting that late dose reductions in chemotherapy may not have as much of an impact on DFS and OS, compared with early dose reductions. The authors hypothesized that majority of cancer cells that are sensitive to chemotherapy are eradicated during the first few treatments, rather than in the later treatments. Further, the amount of Docetaxel that was prescribed in the last three cycles may be higher than needed for the FEC-D regimen. Menopausal status, use of G-CSF and dose delay of 14 days or more, were not shown to affect OS.

It was concluded that early dose reductions in adjuvant FEC-D chemotherapy results in inferior outcomes, with adverse affect on DFS and OS. Conversely, late reductions in chemotherapy dose (Docetaxel only) appear to have minimal impact on survival. Based on this data, the authors recommended that Medical Oncologists should strive to deliver full-dose FEC when prescribing adjuvant FEC-D chemotherapy for breast cancer. Impact of Cumulative Chemotherapy Dose on Survival With Adjuvant FEC-D Chemotherapy for Breast Cancer. Veitch Z, Khan OF, Tilley D, et al. J Natl Compr Canc Netw. 2019;17:957-967.

Single Agent XOSPATA® for FLT3 Mutated AML

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SUMMARY: The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive 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.MUTATED-FLT3-INDUCES-LIGAND-INDEPENDENT-PATHWAY-ACTIVATION

The Fms-Like Tyrosine kinase 3 (FLT3) is a cytokine receptor tyrosine kinase in the PDGF family of growth factor receptors. It is located on the cell surface (transmembrane) of early hematopoietic stem and progenitor cells and regulates their proliferation and differentiation. It plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. FLT3 mutations occur most often as Internal Tandem Duplications (FLT3-ITD) or point mutations at codon D835 (FLT3-Tyrosine Kinase Domain or TKD). Approximately 80% of AML patients with a FLT3 mutation will have the FLT3-ITD, and about 15% will have both FLT3-ITD and FLT3-TKD, and about 5% will have FLT3-TKD alone. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations are predicted to have poor outcomes with shorter remission duration and significantly decreased leukemia-free and Overall Survival. FLT3-TKD can confer resistance to other Tyrosine Kinase Inhibitors and frequently do not respond to salvage chemotherapy.

XOSPATA® (Gilteritinib) is a highly selective oral FLT3/AXL Tyrosine Kinase Inhibitor with activity against both FLT3-ITD and FLT3-TKD mutations. Tyrosine Kinase AXL has been implicated in FLT3 inhibitor resistance. Another FLT3 inhibitor, RYDAPT® (Midostaurin), is also approved, but in combination with standard Cytarabine and Daunorubicin-based chemotherapy for patients with newly diagnosed FLT3-mutated AML. However, for patients with relapsed or refractory AML, RYDAPT® has not conferred durable clinical benefit as a single agent. Unlike XOSPATA®, RYDAPT® is a not selective and is a multikinase inhibitor and inhibits FLT3, PDGFR, c-KIT (CD 117), VEGFR, and protein kinase C. Single-agent XOSPATA®, in a phase 1-2 study, resulted in a 41% composite Complete Remission rate (Complete Remission with or without normal hematologic recovery), among patients with relapsed or refractory FLT3-mutated AML. Based on this information, the authors conducted a multicenter, randomized trial comparing XOSPATA® with conventional salvage chemotherapy regimens in patients with relapsed or refractory FLT3-mutated AML.

The ADMIRAL trial is an international, multicenter, randomized, Phase III study in which 371 patients with relapsed or refractory FLT3 mutated AML were randomly assigned in a 2:1 ratio to receive either XOSPATA® 120 mg orally once daily or salvage chemotherapy, in 28-day cycles. The median age was 62 years, approximately 60% of the patients had relapsed AML and 39% had primary refractory disease. Over 85% of patients had received previous induction therapy with Anthracyclines but not FLT3 inhibitors. The two Primary end points were Overall Survival and the percentage of patients who had Complete Remission with full or partial hematologic recovery. Secondary end points included Event-Free Survival (freedom from treatment failure – relapse or lack of remission or death) and the percentage of patients who had Complete Remission. The median duration of follow up for Overall Survival was 17.8 months.

The median Overall Survival in the XOSPATA® group was significantly longer than that in the chemotherapy group (9.3 months versus 5.6 months) with a 36% reduction in the risk of death, compared to salvage chemotherapy (HR for death=0.64; P<0.001). The median Event-Free survival was 2.8 months in the XOSPATA® group and 0.7 months in the chemotherapy group (HR for treatment failure or death=0.79). The percentage of patients who had Complete Remission with full or partial hematologic recovery was 34.0% in the XOSPATA® group and 15.3% in the chemotherapy group and the Complete Remission rates were 21.1% and 10.5%, respectively. The median Overall Survival as well as Complete Remission rates were similar among those with FLT3 ITD mutations alone and those with FLT3 TKD mutations, when treated with XOSPATA®. Further, longer survival was observed with XOSPATA® than with chemotherapy across all cohorts of patients with co-mutations, particularly in those patients with double mutation (DNMT3A and NPM1), and baseline levels of AXL expression did not influence survival with XOSPATA®. Serious adverse events occurred less frequently in the XOSPATA® group than in the chemotherapy group and the most common adverse events of Grade 3 or higher were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).

It was concluded that treatment with single agent XOSPATA® resulted in significantly longer Overall Survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. Perl AE, Martinelli G, Cortes JE, et al. N Engl J Med 2019; 381:1728-1740