Category: Hem/Onc Updates

Survival Benefit Significantly More in North America with Frontline ADCETRIS® Chemotherapy Combination in Advanced Classical Hodgkin Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2018, about 8,500 new cases of Hodgkin Lymphoma will be diagnosed and about 1,050 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin Lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells, collectively known as Hodgkin and Reed-Sternberg cells (HRS).WHO-Classification-of-Hodgkin-Lymphoma

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (Stage III-IV) Classical Hodgkin Lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

ADCETRIS® (Brentuximab vedotin) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin Lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. ADCETRIS® is presently approved by the FDA for previously untreated Stage III or IV Classical Hodgkin Lymphoma (cHL), in combination with chemotherapy, for treatment of Classical Hodgkin lymphoma at high risk of relapse or progression, as post-autologous Hematopoietic Stem Cell Transplantation (auto-HSCT) consolidation, and for treatment of Classical Hodgkin Lymphoma after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens, in patients who are not auto-HSCT candidates.

ECHELON-1 study, which is an international, open-label, randomized, multicenter, phase III trial, compared A+AVD with ABVD, as frontline therapy in patients with Stage III or IV Classical Hodgkin Lymphoma. This study included 1334 previously untreated patients with Stage III or IV Classical Hodgkin Lymphoma, who were randomly assigned in a 1:1 ratio to receive A+AVD (N=664), which consisted of ADCETRIS® 1.2 mg/kg , Doxorubicin 25 mg/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2 or ABVD (N=670), which consisted of Doxorubicin 25 mg/m2, Bleomycin 10 units/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2, given intravenously on days 1 and 15 of each 28-day cycle, for up to 6 cycles. The Primary end point was “modified” Progression Free Survival (mPFS), defined as progression, death, or the receipt of additional treatment, for patients not achieving CR at the completion of frontline therapy. It was previously reported that at a median follow up of 24.6 months, the 2 year modified PFS in the A+AVD and ABVD groups were 82.1% and 77.2% respectively (HR=0.77; P=0.04), suggesting an approximately 5% benefit with A+AVD.

The North American subgroup analysis of the ECHELON-1 study was conducted because of potential regional differences in the outcomes in the primary study and mPFS benefit was not equally distributed globally. The authors in this prespecified analysis examined the efficacy and safety of A+AVD vs ABVD in North America, as these patients accounted for approximately 40% of the over 1300 patients included in the ECHELON-1 study. This population group included 497 North American patients with advanced Classical Hodgkin Lymphoma, randomized 1:1 to receive up to six cycles of A+AVD or ABVD.

This subgroup analysis revealed an absolute difference of 10.6% in the mPFS per IRF-Independent Review Facility (A+AVD and ABVD groups were 84.3% and 73.7% respectively, HR=0.60; P=0.012) and an 11.7% difference in PFS per investigator review (A+AVD and ABVD groups were 88.1% and 76.4% respectively, HR=0.50; P=0.002), at 2 years. This analysis suggested that a larger proportion of patients in North America benefitted with the A+AVD regimen (10%-12% in North America as opposed to 5% globally). It is postulated that there may be biologic differences in the disease, regional differences in drug metabolism and differences in practice patterns, between countries. Toxicity profile was similar globally. There was a higher incidence of neutropenia in the A+AVD group and G-CSF prophylaxis should be a part of the regimen when A+AVD is used, in contrast to ABVD. Use of G-CSF primary prophylaxis was associated with a lower rate of ADCETRIS® dose delays and dose reductions compared to those without. There was a higher incidence of peripheral neuropathy in the A+AVD group as well, with majority of these events being grade 1 and 2, and this improved or resolved over time. Pulmonary toxicity was lower in patients receiving A+AVD compared to those receiving ABVD.

It was concluded that for patients treated in North America on the ECHELON-1 trial, the absolute difference between A+AVD and ABVD at 2 years for mPFS by IRF was 10.6% and for PFS per Investigator review was 11.7% (10%-12% benefit in North America as opposed to 5% globally). A prospective clinical trial is planned in advanced stage Hodgkin Lymphoma patients treated with A+AVD, to confirm these safety and efficacy findings, in the North American community setting. Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results. Ramchandren R, Advani RH, Ansell SM, et al. J Clin Oncol.2018;36(suppl; abstr 7541). doi: 10.1200/JCO.2018.36.15.

IMFINZI® after Chemoradiotherapy Significantly Improves Overall Survival in Stage III NSCLC

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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), approximately 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas, and 10% are Large cell carcinomas.

Approximately one third of all patients with NSCLC have stage III, locally advanced disease at the time of initial presentation. Worldwide, about 500,000 patients are diagnosed with unresectable, stage III NSCLC, each year. These patients include those with locally advanced primary tumors with tumor invading the vital mediastinal organs, as well as those with involvement of locoregional mediastinal lymph nodes. These patients are often treated with platinum-based doublet chemotherapy with concurrent radiation and have a median Progression Free Survival (PFS) of approximately 8 months and 5 year survival of only 15%. There is hence a significant unmet need for this patient group, with no major treatment advances thus far.

Preclinical evidence had suggested that chemotherapy and radiotherapy may upregulate PD-L1 expression in tumor cells. IMFINZI® (Durvalumab) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) receptor and CD80, thereby unleashing the T cells to recognize and kill tumor cells. IMFINZI® showed encouraging antitumor activity in an early phase clinical study involving multiple advanced solid tumors, including stage IIIB or IV NSCLC.

PACIFIC trial is a randomized, double-blind, international, phase III study in which IMFINZI® as consolidation therapy was compared with placebo, in patients with stage III, locally advanced, unresectable NSCLC, that had not progressed following platinum-based chemoradiotherapy. Eligible patients received two or more cycles of platinum-based doublet chemotherapy concurrently with definitive radiation therapy (54-66 Gy). Following completion of concurrent chemoradiation treatment, 713 patients were randomized, of whom 709 patients in a 2:1 ratio received consolidation treatment, within 6 weeks after completion of chemoradiation, with IMFINZI® 10 mg/kg every 2 weeks (N=473) or placebo (N=236), for up to 12 months. The median age was 64 years, and the majority of patients were men (70%) and 46% had a squamous histology. The co-Primary end points were Progression Free Survival (PFS) and Overall Survival (OS). Secondary end points included 12-month and 18-month PFS rates, Objective Response Rate (ORR), Duration of Response, time to death or distant metastasis, and safety.

The authors had previously reported the results of the first preplanned interim analysis, after a median follow up of 14.5 months. The median PFS from randomization to consolidation treatment was 16.8 months with IMFINZI® versus 5.6 months with placebo (HR=0.52; P<0.001). This meant a 11.2-month improvement in PFS with IMFINZI® versus placebo, and a 48% decrease in the probability of disease progression with IMFINZI®. This improvement was consistent across all patient subgroups that were analyzed.

The authors in this publication report the results for the second Primary end point of Overall Survival. At a median follow up of 25.2 months, the 24-month Overall Survival rate was 66.3% in the IMFINZI® group and 55.6% in the placebo group, suggesting a significantly prolonged Overall Survival with IMFINZI® when compared with placebo and a 32% reduction in the risk of death (HR for death=0.68; P=0.0025). The Overall Survival benefit with IMFINZI®, was observed across all the prespecified subgroups. In this updated analysis, the PFS was similar to those previously reported, with a median duration of 17.2 months in the IMFINZI® group and 5.6 months in the placebo group (HR=0.51). The median time to death or distant metastasis was 28.3 months in the IMFINZI® group and 16.2 months in the placebo group (HR=0.53). Approximately 30% of the patients in the IMFINZI® group and 26% of those in the placebo group had grade 3 or 4 adverse events of any cause, and 15% and 10% of the patients respectively, discontinued the trial regimen because of adverse events.

The authors concluded that in this updated analysis of the PACIFIC trial, the Primary end point of Overall Survival was significantly longer with IMFINZI® than with placebo, among patients with unresectable stage III NSCLC, in all the prespecified subgroups. The updated results for Secondary end points, including the time to death or distant metastasis, the incidence of new lesions, and the Objective Response Rate, were similar to those that were previously reported. The authors commented that PACIFIC trial is the first study to demonstrate a survival advantage for unresectable Stage III NSCLC, supporting this regimen as the standard of care. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. Antonia SJ, Villegas A, Daniel D, et al. [published online ahead of print September 25, 2018]. N Eng J Med. doi: 10.1056/NEJMoa1809697.

First line treatment with KEYTRUDA® and INLYTA® Combination Significantly Improves Survival in advanced Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 63,340 new cases of kidney cancer will be diagnosed in the United States in 2018 and about 14,970 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is significant unmet need for improved therapies for this disease. SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/ smooth vessel cell wall and is capable of specifically binding to tyrosine kinases, inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® is the standard first-line intervention for treatment naïve patients with advanced RCC. In a large, multi-center, randomized, phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. INLYTA® (Axitinib) is a kinase inhibitor and inhibits Receptor Tyrosine Kinases including Vascular Endothelial Growth Factor Receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors have been implicated in pathologic angiogenesis, tumor growth, and cancer progression. Previously published data from a Phase I clinical trial showed that antitumor activity with a combination of KEYTRUDA® and INLYTA® was superior to monotherapy with either PD-1/PD-L1 inhibitor or INLYTA®, in treatment-naïve patients with advanced RCC. Further unlike excess toxicities associated with a combination of VEGF and PD-1 checkpoint inhibitors, a combination of INLYTA® and PD-1 inhibitor was associated with fewer liver function test abnormalities and less fatigue. The excess toxicities have been attributed to off-target effects of multitargeted Tyrosine Kinase Inhibitors.

KEYNOTE-426 is a pivotal, open label, randomized, double-arm, Phase III trial in which the safety and efficacy of KEYTRUDA® in combination with INLYTA® as first-line treatment for advanced or metastatic, clear cell RCC, was compared to SUTENT®. In this study, 861 patients treatment naïve patients who had prior nephrectomy were randomly assigned to receive KEYTRUDA 200 mg IV every three weeks along with INLYTA® 5 mg orally twice daily for up to 24 months, or SUTENT® 50 mg orally once daily for four weeks followed by no treatment for two weeks, given continuously. The dual Primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS). The Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), and Duration of Response (DOR). PFS and OS were assessed at 12, 18 and 24 months.

Merck, the manufacturer of KEYTRUDA® in a press release on October 18, 2018 announced that based on the first interim analysis by the independent Data Monitoring Committee (DMC), the study had met the coprimary endpoints and the combination of KEYTRUDA® and INLYTA® resulted in statistically significant and clinically meaningful improvements in Overall Survival and Progression Free Survival, compared to SUTENT® monotherapy. The study also met the key Secondary endpoint of Objective Response Rate, with significant improvements for the KEYTRUDA® and INLYTA® combination, compared with SUTENT® monotherapy. Results for OS, PFS and ORR were consistent regardless of PD-L1 expression and across all risk groups. It was noted that the safety profile of KEYTRUDA® and INLYTA® in this trial was generally consistent with that observed in previously reported studies for each therapy.

According to the manufacturer, this is the first time that combination treatment with an anti PD-1 inhibitor achieved the dual Primary endpoints of Overall Survival and Progression Free Survival, as first line therapy in advanced RCC. Merck’s KEYTRUDA® (pembrolizumab) in Combination with Pfizer’s Inlyta® (axitinib) Significantly Improved Overall Survival (OS) and Progression-free Survival (PFS) as First-Line Therapy for Advanced or Metastatic Renal Cell Carcinoma. Merck. Published October 18, 2018.

TECENTRIQ® and ABRAXANE® Significantly Prolonged Survival in Advanced Triple Negative Breast Cancer

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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. It is estimated that 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and 40,920 women are expected to die from the disease. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. Those who do not achieve a pathological Complete Response tend to have a poor prognosis. It therefore appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway.

Previously published studies have shown that tumor-infiltrating lymphocytes were associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC. 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. Single-agent TECENTRIQ® is presently approved for the treatment of metastatic Urothelial carcinoma and Non Small Cell Lung Cancer (NSCLC). TECENTRIQ® has also been shown to have clinical activity with acceptable safety profile in patients with other solid tumors including Triple Negative Breast Cancer. The premise for combining chemotherapy with immune checkpoint inhibitors is that chemotherapy may enhance release of tumor antigens and antitumor responses to immune checkpoint inhibition. Taxanes in particular may additionally activate toll-like receptor activity and promote dendritic-cell activity. ABRAXANE® (Nanoparticle Albumin-Bound – nab Paclitaxel) was selected as a chemotherapy partner in the present study because at the time that this trial was designed, the glucocorticoid premedication that is required with solvent-based Paclitaxel (TAXOL®), had been hypothesized to affect immunotherapy activity.

IMpassion130 is an international, randomized, double-blind, placebo-controlled phase III trial in which first-line treatment with TECENTRIQ® plus ABRAXANE®, was compared with placebo ABRAXANE®, in patients with locally advanced or metastatic Triple Negative Breast Cancer. Patients with untreated metastatic Triple Negative Breast Cancer (N=902) were randomly assigned in a 1:1 ratio and received TECENTRIQ® 840 mg IV or placebo on days 1 and 15 and ABRAXANE® 100 mg/m2 IV on days 1, 8, and 15 of every 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Stratification factors included presence or absence of liver metastases, use or non-use of neoadjuvant or adjuvant taxane treatment, and PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area (less than 1% was considered PD-L1 negative versus1% or more considered PD-L1 positive) according to ImmunoHistochemical testing (IHC). Both treatment groups were well balanced. Approximately 40% of the patients were PD-L1 positive. The two Primary end points were Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 12.9 months, the median PFS in the intent-to-treat population was 7.2 months with TECENTRIQ® plus ABRAXANE®, as compared with 5.5 months with placebo plus ABRAXANE® (HR=0.80; P=0.002). This suggested a 20% improvement in PFS with the TECENTRIQ® combination. Among patients with PD-L1–positive tumors, the addition of TECENTRIQ® improved PFS by 38% (HR=0.62; P<0.001) and similar benefit was noted in the OS, with a median OS of 25 months with the TECENTRIQ® combination and 15.5 months with placebo plus ABRAXANE® (HR=0.62). Grade 3 or 4 adverse events were 48.7% in the TECENTRIQ® and ABRAXANE® and 42.2% in the placebo plus ABRAXANE® group.

It was concluded that TECENTRIQ® plus ABRAXANE® significantly prolonged Progression Free Survival among patients with metastatic Triple Negative Breast Cancer in both the intent-to-treat population and the PD-L1 positive subgroup, and could potentially change how we manage patients with Triple Negative Breast Cancer. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. Schmid P, Adams S, Rugo HS, et al. October 20, 2018. DOI: 10.1056/NEJMoa1809615

Evaluation of Urine May Aid in the Diagnosis of Lambda Light Chain 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, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma (MM) in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma evolves from a precursor stage called Monoclonal Gammopathy of Undetermined Significance (MGUS) to MM. Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution.

Monoclonal gammopathies are often diagnosed by electrophoretic examination of the serum and urine proteins. They include Serum Protein ElectroPhoresis (SPEP), Serum Protein Immunofixation electrophoresis (SIFE), Urine Protein ElectroPhoresis (UPEP), Urine Protein Immunofixation electrophoresis (UIFE), and Bone Marrow evaluation. In addition, quantitative assessment of Serum Free Light Chains has been recommended for diagnosis and monitoring of neoplastic monoclonal gammopathies. Normal-Immunoglobulin

The Y-shaped Immunoglobulins are heterodimeric proteins composed of two heavy (H) and two light (L) chains. The two different types of light chains include Kappa and Lambda, which are distinctive in their amino acid sequence, with normally twice as many Kappa light chains. Malignancy can affect both types of light chains and in Multiple Myeloma. The relevant light chain production can increase, but the increase is more often in the Kappa light chains. Immunoglobulin light chains are produced in excess of the corresponding heavy chains and the excess free light chains can be quantified in serum and can also be detected in the urine, as they, by virtue of their size, are freely filtered through the glomerulus (Bence Jones protein). Excess amounts of free monoclonal light chains in patients with monoclonal gammopathy can produce nephropathy due to precipitation of these proteins in renal tubules.

Serum free Kappa and Lambda light chains are normally present in a ratio of about 0.26 to 1.65 and this ratio is increased in patients with Kappa light chain monoclonal gammopathy and decreased in patients with Lambda chain producing monoclonal gammopathies. Even though alteration in the serum K/L ratio is an important diagnostic criterion for plasma cell neoplasms, there is a high rate of positive results in patients receiving tertiary care, with abnormal K/L ratio noted in 36% of patients and about 90% of these are Kappa light chain dominant.

The serum K/L ratio is however less frequently abnormal and stays normal in patients with Lambda chain lesions even when an abnormal Lambda immunoglobulin is detected in the urine. These variabilities can result in the less-common Lambda chain-associated lesions going undiagnosed. There is a high false negative rate for Lambda dominant K/L ratio in Lambda chain associated monoclonal gammopathy (89% for MGUS, 60% for SMM and 51% for MM). It is estimated that the overall excess false negative K/L ratio rate for Lambda chain lesions, compared to Kappa chain lesions, is approximately 30%. The high false negative rate for the Lambda dominant K/L ratio, in patients with Lambda chain neoplastic monoclonal gammopathies, may be due to under-detection of Lambda light chains, Lambda chains are not produced in as much excess as are Kappa chains resulting in lower rates of Lambda dominant K/L ratio in patient with Lambda light chain neoplastic monoclonal gammopathy, and overproduction of polyclonal Kappa light chains in Lambda chain monoclonal gammopathies, as is usually noted in patients receiving tertiary care.

This study was undertaken by comparing the results of Serum and Urine Protein Electrophoreses with the results of Serum Free Light Chain Assay (SFLCA), to ascertain if the levels of overproduction of the Kappa and Lambda light chain types and their detection rates are different in patients with neoplastic monoclonal gammopathies. The authors performed a retrospective review of SPEP/SIFE, UPEP/UIFE, and SFLCA results from January 2010 through September 2017 from a total of 482 patients. Among these patients, 175 patients had a diagnosis of Neoplastic Monoclonal Gammopathy (MGUS, SMM or MM). , and evaluable results were available to address the questions of this study. Patients with Lymphomas and CLL were excluded.

The authors noted that the serum K/L ratios were appropriately abnormal more often in Kappa light chain disease. In contrast, in those with Lambda light chain disease, the K/L ratios were normal in about 25% of patients but free homogenous Lambda light chains were detectable in urine.

It was concluded that the serum Kappa/Lambda ratio in patients with Lambda light chain disease can be normal in a 25% of patients with Neoplastic Monoclonal Gammopathy and can be missed if not further evaluated with UPEP/UIFE. The authors comment that UPEP/UIFE is under- utilized and the study results question the medical necessity and clinical usefulness of the serum free light chain assay. Serum Free Light Chains in Neoplastic Monoclonal Gammopathies: Relative Under-Detection of Lambda Dominant Kappa/Lambda Ratio, and Underproduction of Free Lambda Light Chains, as Compared to Kappa Light Chains, in Patients With Neoplastic Monoclonal Gammopathies. Lee WS and Singh G. J Clin Med Res. 2018;10:562-569.

First Line KEYTRUDA® plus Chemotherapy Improves Overall Survival in Advanced Squamous NSCLC

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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), approximately 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.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. The FDA approved KEYTRUDA® for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), as well as in combination with Pemetrexed and Carboplatin, as first-line treatment of patients with metastatic nonsquamous NSCLC and for previously treated advanced NSCLC with a PD-L1 Tumor Proportion Score of 1% or more. Currently, KEYTRUDA® currently is the only FDA approved immunotherapy for initial treatment of NSCLC as monotherapy (KEYNOTE-024) or in combination with chemotherapy (KEYNOTE-189).Unleashing-T-Cell-Function-with-Combination-Immunotherapy

KEYNOTE-407 is a global, double-blind, placebo-controlled, phase 3 trial which compared KEYTRUDA® plus chemotherapy with placebo plus chemotherapy in patients with squamous NSCLC of any level of PD-L1 expression. In this study, 559 patients with untreated metastatic, squamous NSCLC were randomly assigned, in a 1:1 ratio to receive KEYTRUDA® 200 mg IV along with Carboplatin AUC 6 and either TAXOL® (Paclitaxel) 200 mg/m2 IV or ABRAXANE® (nab-paclitaxel) 100 mg/m2 IV days 1, 8 and 15. every 3 weeks for 4 cycles (N=278) or placebo with the same chemotherapy regimen for 4 cycles (N=281). Patients in the experimental arm following the first 4 cycles continued KEYTRUDA® every 3 weeks, for an additional 31 cycles, whereas the control group received placebo. Patients in the placebo-combination group were eligible to cross over to receive KEYTRUDA® monotherapy and 42.8% of patients assigned to the placebo plus chemotherapy group who discontinued chemotherapy went on to receive subsequent anti PD-1 or anti PD-L1 therapy and 75 patients received KEYTRUDA® monotherapy as part of in-study crossover. Patients were stratified according to the PD-L1 Tumor Proportion Score (1% or less versus more than 1%), choice of Taxane (Paclitaxel versus nab-Paclitaxel), and geographic region of enrollment. Tumor Proportion Score is the percentage of tumor cells with membranous PD-L1 staining, with less than 1% indicating PD-L1 negative score. Both treatment groups were well balanced. The co-Primary end points were Overall Survival and Progression Free Survival and the Secondary end points included Response Rate, Duration of Response and Safety. The effects of PD-L1 expression on Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR) were prespecified exploratory end points.

At the second interim analysis, after a median follow-up of 7.8 months, the median Overall Survival was 15.9 months in the KEYTRUDA® combination group and 11.3 months in the placebo combination group (HR=0.64; P<0.001). This meant that there was a 36% reduction in the risk of death with the addition of KEYTRUDA® to chemotherapy. This OS benefit was consistently seen regardless of the level of PD-L1 expression. The median PFS was 6.4 months in the KEYTRUDA® combination group and 4.8 months in the placebo combination group (HR=0.56; P<0.001) and this suggested that the risk of disease progression or death was 44% lower with the addition of KEYTRUDA® to chemotherapy. The PFS benefit with the addition of KEYTRUDA® to chemotherapy was observed in all prespecified subgroups with incremental improvements noted with increasing PD-L1 Tumor Proportion Score. The Objective Response Rate was also significantly higher in the KEYTRUDA® chemotherapy group compared to the placebo chemotherapy group (59.4% versus 38%; P=0.0004), with a median time to response of 1.4 months and median Duration of Response of 7.7 months versus 4.8 months, respectively. Grade 3 or higher adverse events were similar in both treatment groups. Treatment discontinuation due to adverse events was more frequent in the KEYTRUDA® combination group (13.3% versus 6.4%).

It was concluded that inpatients with previously untreated metastatic, squamous NSCLC, the addition of KEYTRUDA® to chemotherapy resulted in significantly longer Overall Survival and Progression Free Survival than chemotherapy alone, and should become a new standard of care for squamous NSCLC. Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer. Paz-Ares L, Luft A, Vicente D, et al. for the KEYNOTE-407 Investigators. September 25, 2018. DOI: 10.1056/NEJMoa1810865

FDA Approves COPIKTRA® for Chronic Lymphocytic Leukemia and Follicular Lymphoma

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SUMMARY: The FDA on Sept. 24, 2018 granted regular approval to COPIKTRA® (Duvelisib), for adult patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL), after at least two prior therapies. In addition, COPIKTRA® received accelerated approval for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after at least two prior systemic therapies.

COPIKTRA® is a first-in-class novel, oral, dual inhibitor of PhosphoInositide 3-Kinase (PI3K)-delta and PI3K-gamma, two enzymes/isoforms known to help support the growth and survival of malignant B-cells and T-cells. PI3K-delta is constitutively expressed in hematologic malignancies and its inhibition has been shown to reduce the proliferation and survival of malignant leukemia and lymphoma cells, while allowing normal immune cell survival. Inhibiting PI3K-gamma impairs the function of cancer-supportive macrophages and T cells, which sustain leukemia and lymphoma cells in a protective tumor microenvironment. This broader dual inhibition may provide greater benefit than inhibiting just one isoform alone, by significantly inhibiting chemokines from both cancer cells and the tumor microenvironment. BCR-Signal-Pathways-and-MOA-of-New-Agents

DUO Trial is a randomized, multicenter, open-label, Phase III study in which COPIKTRA® was compared to ARZERRA® (Ofatumumab), in patients with Relapsed or Refractory CLL or SLL. This study randomized 319 patients in a 1:1 ratio to receive either COPIKTRA® 25 mg orally twice daily or ARZERRA®. ARZERRA® was administered at an initial dose of 300 mg IV, followed one week later by 2000 mg once weekly for 7 doses, and then 2000 mg once every 4 weeks for 4 additional doses. The median age was 69 years and 23% of patients had tumors with 17p deletion. All patients received Pneumocystis prophylaxis while on treatment. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Response Rate (ORR), Duration of Response (DOR) and Overall Survival (OS). The FDA approval of COPIKTRA® for CLL and SLL was based on a subset of these 319 patients (N=196), with CLL or SLL, who had received at least 2 prior therapies. In this subset, 95 patients were randomized to the COPIKTRA® group and 101 patients to ARZERRA® group. The estimated median PFS as assessed by an Independent Review Committee (IRC), was 16.4 months in the COPIKTRA® group and 9.1 months in the ARZERRA® group (HR=0.40). The Overall Response Rate (ORR) per IRC was 78% and 39% for the COPIKTRA® and ARZERRA® arms, respectively.

The accelerated approval for Follicular Lymphoma was based on a single-arm, multicenter, Phase II monotherapy study (DYNAMO Trial), in patients with refractory, indolent Non-Hodgkin Lymphoma. In this study, 83 patients with Follicular Lymphoma who were refractory to RITUXAN® (Rituximab) and to either chemotherapy or radioimmunotherapy, were enrolled. The median age was 64 years, 37% had bulky disease with lesions 5 cm or more and 81% were refractory to 2 or more prior lines of therapy. The ORR determined by an IRC, was 42%, with 41% of patients experiencing Partial Responses and one patient having a Complete Response. Of the 35 responding patients, 43% maintained responses for at least 6 months and 17% maintained responses for at least 12 months. The most common adverse reactions were nausea, diarrhea or colitis, anemia, neutropenia, rash, fatigue, fever, cough, upper respiratory infection, pneumonia and musculoskeletal pain.

It was concluded that monotherapy with COPIKTRA® is an effective oral treatment option for patients with Relapsed or Refractory CLL/SLL and Follicular Lymphoma and addresses an unmet need for patients who have limited options, once they have progressed after two prior therapies. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm621503.htm

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer ASCO Clinical Practice Guideline Focused Update

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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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer.

ASCO published an adaptation of the Cancer Care Ontario guideline, on optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for HER2 (Human Epidermal Growth Factor receptor 2) positive breast cancers, in 2016. The recent publication of phase III studies relevant to the clinical care of breast cancer patients prompted the ASCO Update Steering Group of the original Expert Panel, to provide a focused update of the 2016 guideline. With the exception of this focused update, the remaining recommendations from the 2016 ASCO guideline are unchanged.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update

Questions Addressed in Focused Update

1) Should adjuvant Capecitabine be given following completion of standard preoperative Anthracycline- and Taxane-based combination chemotherapy in patients with early-stage HER2-negative breast cancer with residual invasive disease at surgery?

2) Should 1 year of adjuvant Pertuzumab be added to Trastuzumab-based combination chemotherapy in patients with early stage HER2-positive breast cancer?

3) Should Neratinib be offered as extended adjuvant therapy for patients after combination chemotherapy and Trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer?

Target Population

Patients who are being considered for, or who are receiving, systemic therapy following definitive surgery for early-stage invasive breast cancer, defined largely as invasive cancer anatomic Stages I to IIIC

Target Audience

Medical oncologists, Pathologists, Surgeons, Oncology nurses, Patients, and Caregivers.

Focused Update Recommendations

Patients with early-stage HER2-negative breast cancer with pathologic invasive residual disease at surgery following standard Anthracycline and Taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant Capecitabine (XELODA®).

Qualifying statements: If clinicians decide to use Capecitabine, then the Expert Panel preferentially supports the use of adjuvant Capecitabine in the subgroup of patients with Hormone Receptor negative, HER2-negative disease. The Capecitabine dosage used in the CREATE-X study (1,250 mg/m2 PO twice daily) is associated with higher toxicity in patients 65 years or older.

Clinicians may add 1 year of adjuvant Pertuzumab (PERJETA® ) to Trastuzumab (HERCEPTIN®)-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer.

Qualifying statements: The Expert Panel preferentially supports Pertuzumab in patients with node-positive, HER2-positive breast cancer in view of the clinically insignificant absolute benefit observed among node-negative patients. After a median follow up of 3.8 years, Pertuzumab offered a modest Disease Free Survival (DFS) benefit. The first planned interim analysis did not show an Overall Survival (OS) benefit in the trial population. There are no data to guide the duration of Pertuzumab in patients who received neoadjuvant Pertuzumab and achieved a pathologic Complete Response.

Clinicians may use extended adjuvant therapy with Neratinib (NERLYNX®) to follow Trastuzumab in patients with early stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea and diarrhea prophylaxis must be used.

Qualifying statements: The Expert Panel preferentially favors use of Neratinib in patients with HER2-positive, Hormone Receptor positive, and node-positive disease. At a median follow-up of 5.2 years, no OS benefit has been observed. Patients who began Neratinib within 1 year of Trastuzumab completion appeared to derive the greatest benefit. There are no data on the added benefit of Neratinib in patients who also received Pertuzumab in the neoadjuvant or adjuvant setting.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update. Denduluri N, Chavez-MacGregor M, Telli ML, et al. J Clin Oncol. 2018;36:2433-2443.

MicroRNA-31-3p Expression is a Predictive Biomarker of Anti-EGFR Efficacy in Patients with RAS Wild-type Metastatic Colorectal Cancer

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Advanced ColoRectal Cancer (CRC) is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor RAS mutations. It is now becoming clear that among these pan RAS wild type tumors, a predictive biomarker, MiR-31-3p expression in tumors, may further determine who would benefit from Anti-EGFR targeted therapy.
In a recently published study (Clin Cancer Res 2018), tumors with Low MiR-31-3p expression benefited from ERBITUX® combination compared to AVASTIN® for PFS (HR=0.74;P=0.05), OS (HR=0.61;P<0.01) and Objective Response Rate (P<0.01). There was however no difference in outcomes among High MiR-31-3p expressors between the two treatment groups. This study suggested that only low MiR-31-3p expressing tumors among the pan RAS wild type CRC patients benefit from Anti-EGFR targeted therapies.

MicroRNA-31-3p Expression is a Predictive Biomarker of Anti-EGFR Efficacy in Patients with RAS Wild-type Metastatic Colorectal Cancer

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SUMMARY: 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%). Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patients, about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents.

MicroRNAs (MiRNA) are small non-coding RNA molecules that play a key role in the regulation of intracellular processes through post-transcriptional regulation of gene expression. It has been shown that MicroRNAs controlling expression of oncogenes and tumor suppressor genes are frequently deregulated in cancer cells. One MiRNA which is frequently deregulated in a variety of cancers is MiR-31, which is frequently overexpressed in colorectal cancer, with high expression correlating with advanced disease. A mature sequence of MiR-31, MiR-31-3p, has been shown to predict outcomes among for colorectal cancer patients treated with anti-EGFR therapy such as ERBITUX® and VECTIBIX®.

FIRE-3 is an open-label, randomized Phase III trial in which FOLFIRI plus ERBITUX® was compared with FOLFIRI plus AVASTIN®, as first line treatment in patients with metastatic ColoRectal Cancer (CRC). This study suggested that patients with KRAS exon 2 wild-type metastatic CRC had a longer Overall Survival (OS) when treated with FOLFIRI plus ERBITUX® compared with FOLFIRI plus AVASTIN®.

Based on the premise that MiR-31-3p expression has been shown to be associated with response to anti-EGFR therapy, in previously published studies, the authors investigated the predictive role of this biomarker in the FIRE-3 study patient population, in its ability to differentiate outcomes between patients receiving anti-EGFR and anti-VEGF therapy. In this study, MiR-31-3p expression was measured in primary tumors obtained from 340 RAS wild-type mCRC patients enrolled in the FIRE-3 Trial. The study population included 164 patients randomized to receive FOLFIRI plus ERBITUX® and 176 patients to FOLFIRI plus AVASTIN®. Patients were divided into subgroups, defined by Low or High MiR-31-3p expression.

It was noted that patients with Low MiR-31-3p expression benefited from ERBITUX® combination compared to AVASTIN® for PFS (HR=0.74;P=0.05), OS (HR=0.61;P<0.01) and Objective Response Rate (P<0.01). There was however no difference in outcomes among High MiR-31-3p expressors between the two treatment groups.

It was concluded that MiR-31-3p expression level is a validated predictive biomarker of anti EGFR therapy efficacy for RAS wild-type mCRC patients, and can enable clinicians to identify patients who would benefit from first-line anti-EGFR treatment. MiRNAs are well preserved in Formalin-Fixed Paraffin-Embedded (FFPE) tissues and MiR-31- 3p expression levels can be measured using RT qPCR. Validation of miR-31-3p Expression to Predict Cetuximab Efficacy When Used as First-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer. Laurent-Puig P, Grisoni ML, Heinemann V, et al. Clin Cancer Res. 2018 Aug 14. pii: clincanres.1324.2018. doi: 10.1158/1078-0432.CCR-18-1324. [Epub ahead of print]