The FDA on July 10, 2018 granted accelerated approval to YERVOY® (Ipilimumab), for use in combination with OPDIVO® (Nivolumab), for the treatment of patients 12 years of age and older with MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) metastatic Colorectal Cancer (mCRC), that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. YERVOY® and OPDIVO® are products of Bristol-Myers Squibb Company Inc.
Author: RR
FDA Approves OPDIVO® and YERVOY® Combination for Metastatic Colorectal Cancer
SUMMARY: The FDA on July 10, 2018, granted accelerated approval to YERVOY® (Ipilimumab) for use in combination with OPDIVO® (Nivolumab), for the treatment of patients 12 years of age and older with MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) metastatic ColoRectal Cancer, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. The FDA in July, 2017, granted accelerated approval to single agent OPDIVO® (Nivolumab) for treatment of this same group of patients. ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%).
The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and when sporadic, the DNA MisMatchRepair gene is MLH1. Defective MisMatchRepair can also manifest as a germline mutation occurring in 1 of the 4 MisMatchRepair genes which include MLH1, MSH2, MSH6, PMS2. This produces Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC), an Autosomal Dominant disorder and is the most common form of hereditary colon cancer, accounting for 35% of the MSI colorectal cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors. MSI (Micro Satellite Instability) testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). MLH1 gene is often lost in association with PMS2. NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer.
OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.
This new FDA approval was based on data from the ongoing CheckMate-142, which is a multicenter, open-label, phase II trial, designed to determine within the dMMR/MSI-H population, whether OPDIVO® alone or in combination with another checkpoint inhibitor YERVOY®, could result in meaningful responses in patients with metastatic CRC, following at least one prior line of therapy. This study was not designed to compare the outcomes in cohorts receiving single agent OPDIVO® and combination checkpoint inhibitors. The rationale behind combining OPDIVO® a PD-1 inhibitor and YERVOY®, a CTLA-4 inhibitor, was based on the synergy between these two agents, to promote T-cell antitumor activity, thereby improving upon single-agent activity of OPDIVO®.
This study enrolled 74 patients, who received single agent OPDIVO® 3 mg/kg IV every 2 weeks and 119 patients who received OPDIVO® 3 mg/kg IV plus YERVOY® 1 mg/kg IV, every 3 weeks for four doses, followed by OPDIVO® 3 mg/kg as a single agent every 2 weeks, until unacceptable toxicity or radiographic progression. In this study, from a cohort of 119 patients with MSI-H or dMMR mCRC, 82 patients received prior treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. Among the cohort of 119 patients receiving OPDIVO® plus YERVOY®, the median age was 58 years, 29% had a known history of Lynch syndrome, 24% had BRAF mutations, 37% had KRAS mutations and 22% of patients had high PD-L1 expression (1% or more) on tumor cells at baseline. Primary tumor location was in the right colon in 55% of patients, 25% had left and sigmoid colon disease and 13% had primary tumor in the transverse colon. Seventy six percent (76%) of patients had two or more prior lines of therapy. The Primary end point was investigator-assessed ORR (Overall Response Rate) and Secondary end points included DCR (Disease Control Rate – CR, PR, or stable disease) Safety and tolerability, PFS (Progression Free Survival) and OS (Overall Survival).
At median follow-up of 13.4 months, the ORR in those patients receiving OPDIVO® plus YERVOY®, was 55% and the Disease Control Rate for 12 or more weeks was 80%. Median duration of response was not reached and 94% of the responses were ongoing at data cutoff. PFS and OS rates at 1 year were 71% and 85%, respectively. Further, clinically meaningful and statistically significant improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life. Approximately 13% of patients who discontinued treatment because of toxicities still had an ORR of 63%, consistent with that of the overall population. Grade 3 to 4 toxicities occurred in 32% of patients and were manageable. Indirect comparisons in this nonrandomized CheckMate-142 trial suggested that OPDIVO® plus YERVOY® provided numerically higher response rates and improved long term clinical benefit relative to OPDIVO® monotherapy.
It was concluded that OPDIVO® plus YERVOY® results in a high response rates, encouraging PFS and OS at 12 months, with manageable toxicities. These data from the CheckMate-142 study support the use of OPDIVO® as a single agent or in combination with YERVOY®, for the treatment of patients with previously treated dMMR/MSI-H metastatic CRC. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair–Deficient/Microsatellite Instability–High Metastatic Colorectal Cancer. Overman MJ, Lonardi S, Wong KYM, et al. J Clin Oncol. 2018;36:773-779
Updated Chronic Lymphocytic Leukemia Guidelines
SUMMARY: The American Cancer Society estimates that for 2018, about 20,940 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4,510 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.
The National Cancer Institute sponsored International Workshop on CLL, issued an update to its consensus guidelines originally published in 2008, prompted by the recent advances in the biology and treatment of patients with CLL. The goal of the updated guidelines is to integrate these new findings into clinical practice and CLL clinical trials.
The following are the major changes or additions reflected in the guidelines
Molecular Genetics
Patients with 17p deletion and TP53 mutations have inferior outcomes and have disease, resistant to standard chemotherapy regimens. These genetic abnormalities can also be acquired over the course of the disease. Patients with CLL should therefore be evaluated for these genetic abnormalities at the time of initial diagnosis and prior to any subsequent line of treatment. These patients have better outcomes when treated with non-chemotherapeutic agents, such as Bruton’s Tyrosine Kinase (BTK) inhibitors, Phosphatidylinositol 3-Kinase (PI3K) inhibitors and BCL2 inhibitors. Even though mutations in NOTCH1 or SF3B1 identified by Next-Generation sequencing have pathogenic as well as prognostic significance, the importance of these mutations has not been validated in prospective trials and their use is therefore not recommended in routine practice.
IGHV Mutational status
Retrospective studies have suggested that patients with CLL whose leukemic cells have clonotypically rearranged immunoglobulin genes in germline configuration (Unmutated IGHV gene) demonstrated more aggressive disease and shorter survival time compared to those patients with somatic hypermutations in their IGHV genes (Mutated IGHV gene). The presence of mutated IGHV genes, when combined with additional prognostic factors such as favorable cytogenetics or attainment of a Minimal Residual Disease (MRD) negative state after therapy, characterizes a subgroup of CLL patients with excellent outcome following chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab. Assessment of IGHV stereotypes however is presently not a part of the routine prognostic work up in CLL.
Serum Biomarkers
Serum markers such as levels of soluble CD23, Thymidine Kinase, and Beta 2-microglobulin are poor prognostic factors and have been shown in several studies to be associated with inferior Overall Survival or Progression Free Survival. Of these, Beta 2-microglobulin has retained independent prognostic value in several multiparameter scores. Assays for these markers should be standardized, and used in prospective clinical trials to validate their relative value in the management of patients with CLL.
Clinical Staging
The two widely accepted staging systems for use in both patient care and clinical trials, the Rai and Binet staging systems rely solely on a physical examination and standard laboratory tests and do not require imaging studies. They are simple and inexpensive and can be readily and consistently applied by physicians worldwide.
Response Definition after Treatment of CLL patients
Assessment of response should include a careful physical examination and evaluation of the blood and bone marrow. For continued therapies or treatment strategies that contain a maintenance phase, the assessment of response should be performed at least 2 months after patients achieve their maximum response or at a time point that is predefined in the protocol and it is not necessary to interrupt therapy for response assessment. The updated guidelines also recommended monitoring for lymphadenopathy, splenomegaly, and hepatomegaly to define relapsed disease and treatment failure, and suggested that the use of imaging in CLL does not typically add much information to the detection of progression or relapse.
MRD Assessment
The desired outcome is complete eradication of the leukemic cells.It was recommended that MRD assessment via multicolor Flow Cytometry, Polymerase Chain Reaction, or Next-Generation sequencing after therapy, be evaluated in the blood and bone marrow, and in clinical trials should be reported with the intent-to-treat population as the denominator and not as a proportion of the responders.
Antiviral Prophylaxis
Patients treated with agents such as Alemtuzumab and Idelalisib (alone or in combination) should be monitored for symptoms or laboratory evidence of opportunistic infections such as Pneumocystis jiroveci or Herpes viridae (Herpes Simplex virus, Varicella-Zoster virus, Cytomegalo virus, Epstein-Barr virus). HBV serological status should be evaluated before treatment with anti-CD20 antibodies as patients may experience reactivation of HBV infections. Appropriate antiviral prophylaxis should be initiated in patients with a history of HBV infection. Infections with JC virus should be ruled out in situations of unclear neurological symptoms, as Progressive Multifocal Leukoencephalopathy has been reported in a few CLL patients treated with anti-CD20 antibodies.
iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Hallek M, Cheson BD, Catovsky D, et al.Blood 2018 131:2745-2760
Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer ASCO Clinical Practice Guideline
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 164,690 new cases of prostate cancer will be diagnosed in 2018 and 29,430 men will die of the disease. Prostate cancer patients with newly diagnosed radiographic evidence of metastatic disease, either as part of a de novo diagnosis of prostate cancer, or as a manifestation of disease progression from an earlier clinical disease state, are considered to have “clinical metastatic: non-castrate” disease, by Prostate Cancer Working Group, provided that they have testosterone levels in the non-castrate level (more than 50 ng/dL). These patients may or may not have received limited courses of Androgen Deprivation Therapy (ADT) for their earlier clinical states.
The standard therapy for newly diagnosed metastatic non-castrate prostate cancer has been ADT alone. Upon progression, these patients are described as having metastatic Castration Resistant Prostate Cancer (mCRPC). These patients are continued on ADT and are offered additional treatments.
The ASCO multidisciplinary Expert Panel developed this guideline, following a systematic review of all phase III randomized controlled trials and meta-analyses, published from 2015 through October 2017. These studies included men with metastatic non-castrate prostate cancer (testosterone levels more than 50 ng/dL), being considered for treatment with Docetaxel (TAXOTERE®) or Abiraterone (ZYTIGA®), in addition to ADT. The Clinical Practice Guidelines are provided by the American Society of Clinical Oncology, (ASCO) to assist providers in clinical decision making.
This clinical practice guideline addresses the addition of Abiraterone or Docetaxel to Androgen-Deprivation Therapy (ADT) for metastatic prostate cancer, that has not been treated (or has been minimally treated) with testosterone-lowering agents.
Guideline Question: Is there an Overall Survival (OS) advantage associated with the addition of Docetaxel or Abiraterone to Androgen-Deprivation Therapy (ADT) in men with metastatic non-castrate prostate cancer? Other outcomes of interest include Progression-Free Survival (PFS), Failure-Free Survival (FFS), PSA response, Overall Response Rate, and Quality of Life (QOL).
Target Population: Men with metastatic non-castrate prostate cancer being considered for treatment with ADT.
Key Recommendations and Qualifying Statements:
ADT Plus Docetaxel
1) Docetaxel in addition to to ADT should be offered for men with metastatic non-castrate prostate cancer with High-Volume Disease (HVD), who are candidates for treatment with chemotherapy, as the strongest evidence of benefit for Docetaxel is for those men who were diagnosed with de novo metastatic disease or HVD, per CHAARTED study.
2) CHAARTED trial is a randomized phase III trial in which patients with newly diagnosed metastatic prostate cancer, were randomly assigned to receive either Androgen Deprivation Therapy alone or ADT plus Docetaxel. The addition of Docetaxel to ADT significantly prolonged Overall Survival in men with High-Volume Disease.
3) In the CHAARTED study, High-Volume Disease was defined as four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or the presence of any visceral disease. The criteria were agnostic to the presence or absence of nodal disease.
4) For patients with Low-Volume Disease (LVD) and who are candidates for chemotherapy, Docetaxel plus ADT may be offered per CHAARTED study. However, the strength of the evidence to support an OS benefit is less compelling for men who do not have de novo metastatic disease and/or who do not meet the HVD criteria. A subset analysis of CHAARTED did not demonstrate a survival benefit for Low-Volume Disease, and the GETUG-15 trial was negative.
5) The appropriate regimen of Docetaxel is 75 mg/m2 every 3 weeks for 6 cycles either alone or with prednisolone.
ADT Plus Abiraterone
1) For men with high-risk, de novo metastatic non-castrate prostate cancer, Abiraterone in addition to ADT should be offered per LATITUDE study.
2) LATITUDE is a randomized, double-blind, placebo-controlled, phase III trial, which evaluated the clinical benefit of adding Abiraterone along with Prednisone to Androgen Deprivation Therapy (ADT), as compared with ADT and placebo, in patients with newly diagnosed, metastatic non-castrate prostate cancer. The addition of Abiraterone to ADT significantly increased Overall Survival and radiographic Progression Free Survival, in this patient group.
3) LATITUDE trial defined high-risk factors associated with a poor prognosis and included at least two of the following three high-risk factors: a Gleason score 8 or greater, 3 or more bone lesions, and presence of measurable visceral disease.
4) For men with lower-risk de novo metastatic non-castrate prostate cancer, Abiraterone may be offered per STAMPEDE study. STAMPEDE trial did not include a high risk definition.
5) LATITUDE and STAMPEDE are mutually supportive for treating high-risk disease with ADT and Abiraterone, with only STAMPEDE furnishing evidence that includes men with lower-risk disease.
6) The appropriate regimen is Abiraterone 1000 mg with either prednisolone or prednisone 5 mg orally once daily, until treatment(s) for mCRPC are initiated.
Docetaxel and Abiraterone
Docetaxel and Abiraterone should be considered as two separate standard treatments for metastatic non-castrate prostate cancer. These two standards have not been compared head to head, and their benefits seem to be quite similar. It is not known which patient subgroups might do better with one standard as opposed to the other and therefore practical factors should be taken into consideration. The use of both standards in combination or in series has not been assessed and therefore cannot be recommended.
In summary, the addition of either Docetaxel or Abiraterone to ADT in men with newly diagnosed metastatic prostate cancer offers a survival benefit, as compared with the use of ADT alone. In the absence of randomized data comparing the addition of Docetaxel versus Abiraterone to ADT in men with metastatic non-castrate disease, additional variables including patient comorbidities, toxicity, QOL considerations, drug availability, and cost will ultimately need to be taken into consideration.
Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Morris MJ, Rumble RB, Basch E, et al. J Clin Oncol 2018;36:1521-1539.
Late Breaking Abstract – ASCO 2018 Blood Test Demonstrates High Specificity for Detection of Early Stage Lung Cancer
SUMMARY: 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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Survival rates however are significantly higher when lung cancer is diagnosed early. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas, and 10% are Large cell carcinomas.
Although the U.S. Preventive Services Task Force (USPSTF) has recommended annual screening for lung cancer with Low-Dose Computed Tomography (LDCT) for individuals with significant smoking history, screening is vastly underutilized, with a screening rate of less than 2% among smokers eligible for screening. Screening for lung cancer using a peripheral blood sample may improve lung cancer screening rates. Analysis of cell-free DNA (cfDNA) from peripheral blood (Liquid Biopsy), is presently approved to select EGFR targeted therapies (cobas EGFR mutation test), in patients with advanced Non Small Cell Lung Cancer. However, the role of cell-free DNA analysis for early detection of lung cancer is not well established.
The Circulating Cell-Free Genome Atlas (CCGA) is a prospective, multi-center, observational study and is the largest study ever initiated, to develop a noninvasive, liquid biopsy assay for early cancer detection, based on cell-free DNA (cfDNA). This study has currently enrolled 10,012 of a planned 15,000 participants, including people with a recent cancer diagnosis and also a control group of individuals with no known malignancy (70% with cancer, 30% without cancer), across 141 sites in the United States and Canada. This report is one of the first pre-planned sub-studies from the CCGA, involving investigation of blood samples from 1,627 participants (878 patients with newly diagnosed untreated cancer including 127 patients with lung cancer and 749 controls – 580 controls and 169 technical assay controls ), across 20 tumor types and all clinical stages.
The cell-free DNA was isolated from the peripheral blood and analyzed using the following three sequencing methods that were designed to detect cancer-defining signals (mutations and other genomic changes), that could be utilized for early cancer detection.
Targeted sequencing to detect somatic (non-inherited) mutations, such as Single Nucleotide Variants and small insertions and/or deletions, in specific sections of the genome.
Whole-Genome Sequencing (WGS) to detect somatic gene copy number changes across the genome.
Whole-Genome Bisulfite Sequencing (WGBS) of cfDNA to detect abnormal patterns of cfDNA methylation (epigenetic changes)
In this initial sub-study, the authors explored the ability of the above three different assays to detect cancer in 127 people with stage I-IV lung cancer. It was noted that biologic signals suggesting lung cancer were detected and comparable across all assays, and the signal increased with cancer stage. At 98% specificity, the Targeted sequencing detected 51% of early-stage (stage I-IIIA) lung cancers and 89% of late-stage (stage IIIB-IV) lung cancers. Whole-Genome Sequencing detected 38% of early-stage cancers and 87% of late-stage cancers. Whole-Genome Bisulfite Sequencing had similar efficacy, detecting 41% of early stage lung cancers and 89% of late-stage cancers. Similar sensitivities were noted across all assays for adenocarcinoma, squamous cell and small cell lung cancer. False positive rates were low. Of the 580 control participants without cancer at study enrollment, less than 1% (five participants) had cancer-like signal across all three assays, of whom two were subsequently diagnosed with cancer. This highlights the potential for these assays to detect early stage cancers. The authors caution that a large proportion of cell-free DNA is derived from White Blood Cells (WBCs) and DNA mutations in the WBC population can also be generated by processes other than cancer such as clonal hematopoiesis during human aging. In this study, signal generated from the WBCs was subtracted resulting in a cleaner signal, only from tumor related variants.
It was concluded that based on the initial results from the CCGA study, it is possible to detect early-stage lung cancer, with a high degree of specificity, from a simple blood test, using genome sequencing. The authors plan to further optimize the assays and validate results in a larger group of people. Genome-wide sequencing for early stage lung cancer detection from plasma cell-free DNA (cfDNA): The Circulating Cancer Genome Atlas (CCGA) study. Oxnard GR, Maddala T, Hubbell E, et al. J Clin Oncol. 2018;36(suppl; abstr LBA8501)
REVLIMID® plus RITUXAN®, A Potential Chemo-Free Frontline Therapy for Follicular Lymphoma
SUMMARY: The American Cancer Society estimates that in 2018, about 74,680 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,910 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).
Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab).
REVLIMID® (Lenalidomide) is an oral immunomodulatory agent (IMiD) with activity in lymphoid malignancies, primarily through immune modulation (repair T-cell immune synapse dysfunction and Natural Killer cell/T-cell effector augmentation). It additionally has antiproliferative effects. Chemo-free combination immunotherapy with REVLIMID® and RITUXAN® or the R2 regimen, has shown promising activity in phase II studies.
RELEVANCE is a global, randomized, open-label, phase III study, conducted in partnership with the Lymphoma Academic Research Organisation (LYSARC). This study evaluated the investigational regimen of REVLIMID® plus RITUXAN® (R2), followed by RITUXAN® maintenance, compared to the standard of care treatment of RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance, in patients with previously untreated Follicular Lymphoma.
In this study, 1030 patients with treatment naïve, advanced Follicular Lymphoma, were randomized to R2 regimen (N=513) and R-Chemo regimen (N=517). Patients had Grade 1-3a Follicular Lymphoma, requiring therapy according to GELF criteria. Patients in the R2 group received REVLIMID® 20 mg orally daily on Days 2 thru 22 every 28 days for 6-12 cycles and continued responders received REVLIMID® 10 mg orally daily on Days 2 thru 22 every 28 days, for a total of 18 cycles. RITUXAN® was administered at 375 mg/m2 IV on Days 1, 8, 15, and 22 of cycle 1 and Day 1 of cycles 2 thru 6, and then continued in responders for 12 additional cycles every 8 weeks. R-Chemo group received investigators choice of standard R-CHOP (72%), R-Bendamustine (23%) or R-CVP (5%), and responding patients continued with RITUXAN® 375 mg/m2 IV every 8 weeks, for 12 cycles. The median age of the patients was 59 years. The co-Primary endpoints were Complete Response/unconfirmed Complete Response at 120 weeks and Progression Free Survival (PFS) during the preplanned analysis.
At a median follow up of 37.9 months, PFS was similar in both treatment groups and the 3-year PFS rate was 77% in the R2 group compared with 78% for the R-Chemo group (HR=1.10; P=0.48). The Complete Response/unconfirmed Complete Response at 120 weeks were 48% in the R2 group and 53% in the R-chemo group and this was also not statistically significant (P=0.13). Preliminary Overall Survival outcomes (Secondary endpoint) showed a 3-year survival rate of 94% in both treatment groups. Adverse events were different in the two treatment groups, with a higher incidence of neutropenia and febrile neutropenia in the R-Chemo group, and higher incidence of cutaneous events in the R2 group.
It was concluded that in this first randomized phase III comparison of a chemo-free regimen (R2) with standard R-Chemo, in previously untreated Follicular Lymphoma, a combination of REVLIMID® and RITUXAN® (R2) showed similar efficacy, with a more favorable safety profile, making it a potential chemo-free, firstline option, for patients with Follicular Lymphoma. RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. Fowler NH, Morschhauser F, Feugier P, et al. J Clin Oncol 36, 2018 (suppl; abstr 7500)
Late Breaking Abstract – ASCO 2018 First Line TECENTRIQ® plus Chemotherapy in Advanced Squamous NSCLC
SUMMARY: 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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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 Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas, and 10% are Large cell carcinomas. Non Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, and less than 15% of patients with advanced Squamous NSCLC survive a year after diagnosis and less than 5% of patients survive for five years or longer. Immunotherapy is an accepted second line intervention after Platinum-based chemotherapy, in patients with advanced NSCLC, and is an approved first line therapy, for patients with high PD-L1 expressing tumors (50% or more).
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. TECENTRIQ® was approved by the FDA in October 2016 for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose disease progressed during or following Platinum-containing chemotherapy. In this present publication, the authors studied the efficacy of TECENTRIQ® given along with combination chemotherapy, in patients with advanced Squamous NSCLC.
IMpower131 is a multicenter, open-label, phase III study, in which 1021 chemotherapy-naïve patients with stage IV Squamous NSCLC were randomly assigned in 1:1:1 ratio to receive TECENTRIQ® along with Carboplatin, and Paclitaxel (Group A, N=338), TECENTRIQ® along with Carboplatin, and ABRAXANE® (nab-paclitaxel) (Group B, N=343) and the control arm of Carboplatin and ABRAXANE® (Group C, N=340). Patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and TAXOL® (Paclitaxel) 200 mg/m2 IV, all drugs given on Day 1, every 21 days. Patients in Group B received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 IV on Day 1 and ABRAXANE® 100mg/m2 IV on Days 1, 8, and 15 of each 21-day cycle. Patients in Group C (control group) received Carboplatin AUC 6 IV on Day 1 and ABRAXANE® 100mg/m2 IV on Days 1, 8, and 15 of each 21-day cycle. Patients received 4-6 cycles of this combination treatment and in Groups A and B, TECENTRIQ® alone was continued as long as there was a clinical benefit, without evidence of disease progression. Tumors were tested for PD-L1 expression, but patients were included in the study regardless of PD-L1 expression level. Patients with tumors demonstrating EGFR or ALK gene changes should have received molecularly targeted treatments before enrolling in this study. The co-Primary endpoints for this study were Progression Free Survival (PFS) and Overall Survival (OS). As per the study design, the current analysis compared the outcomes of patients in Group B with Group C. Outcomes data comparing Group A with Group C are not yet available.
At the time of primary analysis, with a median follow up of 17.1 months, the median PFS across all PD-L1 subgroups was 6.3 months with the addition of TECENTRIQ® to chemotherapy (Group B) versus 5.6 months in Group C, with chemotherapy alone (HR=0.71; P=0.0001). This represented a 29% reduction in the risk of disease progression or death, with the addition of TECENTRIQ® to chemotherapy. The 12-month PFS rates in Groups B and C were 24.7% versus 12.0%, respectively, suggesting a doubling of PFS benefit with the addition of TECENTRIQ® to chemotherapy. The PFS benefit was more pronounced in those with higher tumor PD-L1 expression. Overall Survival data are not yet mature. The most common side effects with the addition of TECENTRIQ® to chemotherapy included skin rash, colitis, and hypothyroidism.
The authors concluded that this is the first phase III trial of an immunotherapy-based treatment regimen, to demonstrate a significant improvement in Progression Free Survival, in advanced Squamous NSCLC. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. Jotte RM, Cappuzzo F, Vynnychenko I, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA9000)
FDA Approves DARZALEX®/VMP Combination for Newly Diagnosed Multiple Myeloma
SUMMARY: The FDA on May 7, 2018 approved DARZALEX® (Daratumumab) in combination with VELCADE® (Bortezomib), a proteasome inhibitor, Melphalan, an alkylating agent and Prednisone VMP regimen), for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for Autologous Stem Cell Transplant (ASCT). Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). With a record number of regulatory approvals for myeloma treatment over the past 12 years, the median survival for patients with myeloma is over 10 years.
The incidence of multiple myeloma increases with age and the median age of patients diagnosed with multiple myeloma is approximately 70 yrs. Elderly patients with myeloma in the US are often treated with a combination of REVLIMID® (Lenalidomide) and Dexamethasone, whereas Melphalan, Prednisone, and Thalidomide (MPT) and VELCADE® (Bortezomib), Melphalan and Prednisone (VMP) are the most widely used regimens outside the US. These regimens are associated with a PFS of 18-24 months and an OS of 4-5 years. For patients with newly diagnosed multiple myeloma who are ineligible for ASCT, treatment with VMP regimen has been a standard effective regimen, based on the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial.
DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) 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. In previously treated patients with myeloma, DARZALEX® in combination with REVLIMID® and Dexamethasone (POLLUX trial) as well as in combination with VELCADE® and Dexamethasone (CASTOR trial), induced higher Response Rates and significantly prolonged PFS, reducing the risk of disease progression or death by over 60% in previously treated myeloma patients.
ALCYONE is a multicenter, randomized, open-label, active-controlled, phase III trial in which DARZALEX® given along with VELCADE®, Melphalan and Prednisone (VMP regimen) was compared with VMP alone (control group), in patients with newly diagnosed multiple myeloma, who were ineligible for Autologous Stem Cell Transplantation (ASCT). Of the 706 enrolled patients, 350 were assigned to the DARZALEX® group and 356 to the control group. The median age was 71 yrs. All the patients received up to nine 6 week cycles of VELCADE® 1.3 mg/m2 SQ, twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), Melphalan 9 mg/m2 orally, once daily on days 1-4 of each cycle, and Prednisone 60 mg/m2 once daily on days 1-4 of each cycle. In the study group, patients received DARZALEX® 16 mg/kg IV administered with Dexamethasone 20 mg oral or IV (to manage infusion reactions), once weekly for a total of 6 doses, every 3 weeks for a total of 16 doses and every 4 weeks thereafter until disease progression or unacceptable toxicity. The Primary end point was PFS. Secondary end points included Overall Response Rate, rates of Very Good Partial Response, Complete Response rate, Minimal Residual Disease negativity and Overall Survival.
At a median follow up of 16.5 months in a prespecified interim analysis, the 18-month PFS was 71.6% in the DARZALEX® group and 50.2% in the control group (HR=0.50; P<0.001). This meant a 50% reduction in the risk of disease progression or death when DARZALEX® was added to VMP regimen. The median PFS for DARZALEX® plus VMP had not yet been reached, compared to a median PFS of 18.1 months for patients who received VMP alone. The Overall Response Rate was 90.9% in the DARZALEX® group, as compared with 73.9% in the control group (P<0.001), and the rate of Complete Response or better (including stringent Complete Response) was 42.6%, versus 24.4% (P<0.001). In the DARZALEX® group, 22.3% of the patients were negative for Minimal Residual Disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events were cytopenias noted in both treatment groups, and with the exception of infections (23% versus 15%), combining DARZALEX® with VMP regimen did not increase overall toxicities. DARZALEX® associated infusion-related reactions occurred in 28% of the patients.
It was concluded that DARZALEX® is the first monoclonal antibody approved for newly diagnosed multiple myeloma patients who are not eligible for a Autologous Stem Cell Transplant, and in combination with VMP regimen significantly improved Progression Free Survival and Response Rates. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. Mateos MV, Dimopoulos MA, Cavo M, et al. for the ALCYONE Trial Investigators. N Engl J Med 2018; 378:518-528
Higher Plasma Vitamin D Levels Associated with Lower Colorectal Cancer Risk
SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer and third leading cause of cancer-related deaths in both men and women in the United States. The American Cancer Society estimates that approximately 140,250 new cases of ColoRectal Cancer will be diagnosed in the United States in 2018 and over 50,630 patients are expected to die of the disease. The lifetime risk of colorectal cancer is 4.2% (1 in 24) in women and 4.5% (1 in 22) in men.
Vitamin D is known for its role in maintaining bone health and there is a growing body of evidence suggesting that Vitamin D has colon cancer preventing properties and may induce antitumor immunity. A study by Song and colleagues (Gut. 2015;64:260-271) showed that high plasma level 25-Hydroxy Vitamin D [25(OH)D] was associated with lower risk of colorectal cancer with intense immune reaction, supporting that vitamin D through tumor-host interaction may play a role in cancer immunoprevention. There also appears to be a strong association between plasma 25(OH)D level and colorectal cancer (CRC) specific mortality, with better outcomes in CRC patients with higher plasma levels of 25(OH)D, treated with a combination of chemotherapy and biologic agents. However the plasma concentrations of 25(OH)D that minimize colorectal cancer risk are unknown and even though epidemiological studies suggest a protective role for vitamin D in colorectal carcinogenesis, the evidence has been inconclusive. The current recommendations regarding vitamin D intake are based only on bone health. Sources of vitamin D include fatty fish like salmon, tuna and mackerel, foods fortified with vitamin D like some dairy products, cereals and orange juice as well as egg yolks. It is recommended that vitamin D be obtained through diet whenever possible rather than sun exposure, because of the risk of skin cancer with excessive UV radiation.
The Institute of Medicine defines vitamin D deficiency as plasma 25(OH)D level of less than 50 nmol/L and the plasma 25(OH)D threshold for fracture prevention is 75 nmol/L. All adults aged 50-70 years and more than 70 years will require at least 600 and 800 IU (15-20 μg) of vitamin D3 per day, respectively, for optimal bone health and muscle function. However, to raise the plasma level of 25(OH)D above 75 nmol/L, individuals will require at least 1500-2000 IU (37.5–50 μg) per day of supplemental vitamin D. Doses of up to 10 000 IU (250 μg) per day have been proven to be safe.
This present study was conducted to address inconsistencies in prior studies, on the protective role for vitamin D in colorectal cancer, and to investigate associations in population subgroups. The authors analyzed participant-level data, collected before colorectal cancer diagnosis, from 17 prospective cohorts which included 5706 colorectal cancer cases and 7107 control participants, from the US, Europe, and Asia, with a wide range of plasma 25(OH)D concentrations. A single, widely accepted assay and laboratory was used for new plasma 25(OH)D measurements, and calibration of previously measured plasma 25(OH)D. This calibration approach enabled the authors to systematically explore risk, utilizing the same assay, over the broad range of vitamin D levels seen internationally.
It was noted that compared to participants with plasma 25(OH)D concentrations sufficient for bone health (50-62.5 nmol/L), those with deficient 25(OH)D levels (less than 30 nmol/L) had a 31% higher risk of colorectal cancer during follow-up, which averaged 5.5 years. In contrast, individuals with plasma 25(OH)D levels above sufficiency for bone health, (75 to less than 87.5 nmol/L) had 19% lower risk and among those with plasma 25(OH)D levels 87.5 to less than 100 nmol/L, the risk of developing colorectal cancer was even lower at 27%. The risk however, did not continue to decline at plasma 25(OH)D levels of 100 nmol/L or greater. The protective association of high levels of plasma 25(OH)D persisted even after adjusting for known colorectal cancer risk factors such as Body Mass Index, physical activity, and other risk factors, and was seen in all subgroups examined. The protective association was more significant in women than men at plasma 25(OH)D levels above bone health sufficiency. For each 25 nmol/L increment in plasma 25(OH)D levels, colorectal cancer risk was 19% lower in women and 7% lower in men.
It was concluded that higher plasma 25(OH)D levels (75-100 nmol/L) was associated with a statistically significant lower colorectal cancer risk in women and non-statistically significant lower risk in men. This study suggested that the optimal plasma 25(OH)D level concentrations for colorectal cancer risk reduction appear higher than the levels recommended for bone health. Circulating Vitamin D and Colorectal Cancer Risk: An International Pooling Project of 17 Cohorts. McCullough ML, Zoltick ES, Weinstein SJ, et al. JNCI: Journal of the National Cancer Institute, https://doi.org/10.1093/jnci/djy087. Published: 14 June 2018.
BRAFTOVI® (Encorafenib) and MEKTOVI® (Binimetinib)
The FDA on June 27, 2018 approved BRAFTOVI® and MEKTOVI® in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. BRAFTOVI® and MEKTOVI® are products of Array BioPharma Inc.