Hem/Onc Updates – Page 98

Adjuvant Therapy with XELODA® Improves Overall Survival in Biliary Tract Cancer

June 23, 2017April 6, 2020 RR

SUMMARY: Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. About 8,000 people in the US are diagnosed with bile duct cancer each year. The average age of an individual in the US diagnosed with bile duct cancer is 71 years and approximately 20% of the cases are suitable for surgical resection. The 5-year survival is less than 10%. There is no standard adjuvant therapy for patients with resectable bile duct cancer, although adjuvant intervention in a previously reported meta-analysis showed improved Overall Survival (Horgan AM, Amir E, Walter T, et al. JCO 2012;30:1934-1940).

The BILCAP trial is a phase III study conducted to determine whether XELODA® (Capecitabine) improved Overall Survival (OS) compared to Observation, following radical surgery. In this trial, 447 patients were randomized to receive XELODA® (N=223) or Observation (N=224). Eligible patients had completely resected, cholangiocarcinoma or gallbladder cancer (including liver and pancreatic resection, as appropriate), with a R0 resection (microscopically negative margin resection) for 62% and R1 resection (removal of all macroscopic disease, but microscopic margins are positive for tumor) for 38% and with negative lymph nodes in 46% of the patients. The primary disease sites were extrahepatic cholangiocarcinoma (35%), hilar (28%), intrahepatic (19%), and muscle-invasive gallbladder cancers (18%). Patients were randomized in a 1:1 ratio to receive XELODA® 1250 mg/m2, D1-14 every 21 days, for 8 cycles or Observation. The median age was 63 years and the follow up was at least 36 months in more than 80% of the surviving patients. The primary end point was Overall Survival in the Intent to Treat population and the primary analysis was performed with at least 24 months of follow up.

The median Overall Survival with XELODA® was 51 months compared with 36 months for Observation, and this was not statistically significant (P=0.097). In the sensitivity analyses however, with adjustment for nodal status, gender and grade of the disease, there was a 29% reduction in the risk of death with adjuvant XELODA®, when compared with Observation (HR=0.71; P < 0.01). In the per-protocol analysis which included 430 patients, the median Overall Survival was 53 months with adjuvant XELODA® versus 36 months with Observation, resulting in a 25% reduction in the risk of death with XELODA®, and these results were statistically significant (HR=0.75; P=0.028). The most common adverse events related to XELODA® as anticipated were, palmar plantar erythema, fatigue and diarrhea.

The authors concluded that single agent XELODA® improves Overall Survival in Biliary Tract Cancer, when used as adjuvant therapy, without a negative impact on Quality of Life. They added that this is the first phase III study to show a survival benefit in the adjuvant setting, and should become standard of care. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study. Primrose JN, Fox R, Palmer DH, et al. J Clin Oncol 35, 2017 (suppl; abstr 4006)

Late Breaking Abstract – ASCO 2017 Three Months of Adjuvant Therapy Adequate for Stage III Colon Cancer Patients with T1-3, N1 Disease

June 15, 2017April 5, 2020 RR

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 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (stage III) colon cancer, has been the standard of care since 1990s. Adjuvant treatment with an ELOXATIN® (Oxaliplatin) based chemotherapy regimen has been considered standard intervention since 2004, for patients with stage III colon cancer following surgical resection and has been proven to decrease the chance of recurrent disease. Chemotherapy regimens have included (FOLFOX – Leucovorin, 5-FluoroUracil, ELOXATIN®) or CAPOX/XELOX (XELODA®/Capecitabine and ELOXATIN®/Oxaliplatin), given over a period of 6 months. ELOXATIN® can however be associated with neuropathy which can be long lasting or permanent, depending on the duration of therapy. Additional toxicities with longer duration of chemotherapy include diarrhea, fatigue as well as more office visits.

The IDEA Collaboration is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials which included 12,834 patients from 12 countries. The goal of this study was to determine if 3 months of adjuvant chemotherapy would be as effective as 6 months of therapy and would be Non Inferior. Of the enrolled patients with Stage III disease, 13% had T1-2 disease, 66% had T3 disease, and 21% had T4 tumors. Twenty eight percent (28%) of the patients had N2 disease and 40% of the patients received XELOX chemotherapy. Approximately 60% had low-risk disease (T1-3, N1) and 40% had high-risk (T4 or N2). The primary endpoint was Disease Free Survival (DFS). The median follow up was 39 months.

It was noted that a shorter 3 month course of adjuvant chemotherapy was associated with a less than 1% lower risk of recurrence at 3 years compared to the standard 6 month course of therapy (74.6% versus 75.5%). In the subset of patients considered to be at low risk of cancer recurrence (1-3 positive lymph nodes and tumor not completely penetrating through the bowel wall), there was almost no difference in the DFS between a 3-month versus 6-month course of therapy (83.1% vs 83.3%). Even though Non Inferiority was not established for the overall cohort of patients, patients with stage T1-3 N1 disease showed Non Inferiority for 3 months versus 6 month course of adjuvant therapy. Further, 3 months of XELOX adjuvant therapy was Non Inferior to 6 months of ELOXATIN® based adjuvant therapy. Grade 2 or more neurotoxicity was significantly lower for patients who received 3 months of adjuvant therapy versus 6 months (P <0.0001), regardless of the treatment regimen (17% vs 48% for FOLFOX and 15% vs 45% for XELOX, respectively).

It was concluded by the IDEA collaboration that, a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with stage III colon cancer. Three months of adjuvant chemotherapy is adequate for patients with T1-3, N1 disease. For patients with T4 and/or N2 disease or other high risk factors, the duration of adjuvant therapy has to be determined based on patient preference, assessment of recurrent risk and tolerability. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration. Shi Q, Sobrero AF, Shields AF, et al. J Clin Oncol 35, 2017 (suppl; abstr LBA1)

Late Breaking Abstract – ASCO 2017 LYNPARZA® Improves Progression Free Survival in BRCA Positive Breast Cancer

June 15, 2017November 9, 2018 RR

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, 255,180 new cases of invasive breast cancer will be diagnosed in 2017 and over 41,070 women will die of the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.

The PARP (Poly ADP Ribose Polymerase) family of enzymes which include PARP1 and PARP2, repair damaged DNA. LYNPARZA® (Olaparib) is a PARP enzyme inhibitor that causes cell death in tumors that already have a DNA repair defect, such as those with BRCA1 and BRCA2 mutations. The FDA approved LYNPARZA® (Olaparib) in 2014 as monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated advanced ovarian cancer.

OlympiAD is a randomized, open-label, phase III study that evaluated the efficacy and safety of LYNPARZA® (Olaparib) compared with physician’s choice of standard single agent chemotherapy (TPC), in patients with HER2-negative metastatic breast cancer, with inherited, germline BRCA mutations. In this study, 302 patients were randomized in a 2:1 ratio to receive LYNPARZA® tablets 300 mg PO BID (N=205) or physician’s choice of standard chemotherapy (N=97). The later included 21-day cycles of either XELODA® (Capecitabine) 2500 mg/m2 orally on days 1-14, NAVELBINE® (Vinorelbine) 30 mg/m2 IV days 1 and 8 or HALAVEN® (Eribulin)1.4 mg/m2 IV days 1 and 8. Treatment was continued until disease progression or unacceptable toxicity. The median age was 44 years, 50% of the patients had triple negative disease, 71% of the patients had prior chemotherapy for metastatic breast cancer, 28% had prior platinum based chemotherapy regimen and those with hormone receptor positive breast cancer had received hormonal therapy. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival, time to second progression or death, Objective Response Rate and effect on health-related Quality of Life.

At a median follow up of about 14 months, the median PFS was 7 months in the LYNPARZA® group versus 4.2 months with standard chemotherapy (HR=0.58; P=0.0009), suggesting a 42% reduced risk of cancer progression in the LYNPARZA® group compared to those who received chemotherapy. Following disease progression, the time to second progression (which meant duration of time before the cancer worsened again), was also longer in the LYNPARZA® group (HR 0.57), suggesting that recurrent disease was not more aggressive following progression on LYNPARZA®. The Objective Response Rate was 60% and 29% in LYNPARZA® and chemotherapy group respectively. Severe side effects were more common in chemotherapy treated patients (50%) compared with LYNPARZA® group (37%). The most common side effects in the LYNPARZA® group included nausea, fatigue and cytopenias, where as rash on hands and feet were most common in the chemotherapy group.

The authors concluded that LYNPARZA® monotherapy significantly improved Progression Free Survival in HER2-negative metastatic breast cancer patients, with inherited germline BRCA mutations, compared to standard chemotherapy. This “proof of the principle” study demonstrated that breast cancers with defects in a specific DNA damage repair pathway are sensitive to targeted therapy and this is the first of several phase III studies with PARP inhibitors that are underway. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). Robson ME, Im S-A, Senkus E, et al. J Clin Oncol 35, 2017 (suppl; abstr LBA4).

Late Breaking Abstract – ASCO 2017 Targeted Therapy Based on Genomic Profiling Improves Overall Survival

June 9, 2017May 6, 2020 RR

SUMMARY: Tumor genomic profiling enables the identification of specific genomic alterations and thereby can provide personalized treatment options with targeted therapies that are specific for those molecular targets. A genomic test can be performed on a tumor specimen or on cell-free DNA in plasma (“liquid biopsy”) or an ImmunoHistoChemistry (IHC) test can be performed on tumor tissue for protein expression that demonstrates a genomic variant known to be a drug target, or to predict sensitivity to a chemotherapeutic drug. Next-generation sequencing (NGS) platforms or second-generation sequencing unlike the first-generation sequencing, known as Sanger sequencing, perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. With this high-throughput sequencing, the entire genome can be sequenced in less than 24 hours. Recently reported genomic profiling studies performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors.

ProfiLER is an ongoing, molecular profiling clinical trial, developed to guide treatment by exploring genomic alterations in cancer cells of patients with advanced malignancy. DNA extracted from either archival or fresh tumor tissue was analyzed by next-generation sequencing of 60 cancer-related genes and whole-genome comparative genomic hybridization, a methodology for rapidly comparing DNA samples. A multidisciplinary board of experts in genomic profiling analyzed the genomic test results data and recommended molecular targeted therapies, when actionable mutations were found. These therapies were either commercially available drugs or those being tested in early clinical trials.

This study enrolled 2,676 patients to date and 1,944 tumors were analyzed. They included colorectal, gynecologic, breast, brain, and head and neck cancers, as well as sarcomas. Actionable mutations were found in 1,004 tumor samples (52%), 609 patients had only 1 actionable mutation, and 394 patients had 2-6 actionable mutations. The most common actionable mutation involved the PI3K/mTOR pathway. The molecular tumor board recommended molecularly targeted treatments to 676 patients (35% of 1,944 patients tested). Of these 676 patients, 143 received the recommended treatment, mostly through enrollment in a clinical trial. The rest of the 533 patients were unable to receive the recommended treatment because of poor health, rapid tumor progression, not meeting eligibility criteria for a clinical trial, or difficulty obtaining off-label commercially available drugs.

The Overall Survival rates for the 143 patients who received targeted therapies based on genomic testing was then compared with the 533 patients who did not. The Overall Survival rate at 3 years for those patients who received the recommended molecular targeted therapy was 53.7% compared with 46.1% for those patients who did not. The 5-year Overall Survival rate was also higher for patients who received molecular targeted therapy compared to those who did not (34.8% versus 28.1%).

This study validated that comprehensive genomic profiling can be performed in routine clinical practice, to select patients for targeted cancer therapies. The TAPUR (Targeted Agent and Profiling Utilization Registry) study conducted by ASCO is underway and is aimed at collecting “real-world” data on clinical outcomes, to help learn additional uses of molecularly-targeted cancer drugs, outside of indications approved by the FDA. Routine molecular screening of advanced refractory cancer patients: An analysis of the first 2490 patients of the ProfilER Study. Tredan O, Corset V, Wang Q, et al. J Clin Oncol 35, 2017 (suppl; abstr LBA100)

Late Breaking Abstract – ASCO 2017 Adding ZYTIGA® to Androgen Deprivation Therapy Improves Overall Survival in Newly Diagnosed Advanced Prostate Cancer

June 9, 2017April 5, 2020 RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 161,360 new cases of Prostate cancer will be diagnosed in 2017 and 26,730 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. For patients with Castrate Resistant Prostate Carcinoma (CRPC), several agents have been proven to improve Overall Survival and they include, TAXOTERE® (Docetaxel), JEVTANA® (Cabazitaxel), ZYTIGA® (Abiraterone acetate), XTANDI® (Enzalutamide), XOFIGO® (Radium-223), and PROVENGE® (Sipuleucel-T).

The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial is an ongoing study and uses a novel multiarm, multistage (MAMS) platform design, to test whether the addition of further treatments to ADT improves Overall Survival, when used in first-line setting, for patients with hormone sensitive, locally advanced or metastatic prostate cancer. This group previously reported that there was a significantly improved Overall Survival with the addition of TAXOTERE® to initial ADT. This is presently the standard of care for appropriate patients with prostate cancer, who had not received prior hormone therapy. The barriers to chemo-hormonal therapy with TAXOTERE® include advanced patient age, poor Performance Status, comorbidities, patient preferences, as well as potential life threatening toxicities associated with TAXOTERE®.

ZYTIGA® is a selective, irreversible inhibitor of CYP 17A1 enzyme and decreases androgen biosynthesis in the testes, adrenal glands, and prostate-tumor tissue. Combining a CYP17A1 inhibitor such as ZYTIGA® with Androgen Deprivation Therapy is a more effective way of androgen depletion than with Orchiectomy or GnRH analogues alone. In this analysis, the STAMPEDE trial evaluated Overall Survival outcomes, with the earlier use of ZYTIGA®, in men with high risk, hormone sensitive prostate cancer, who were initiating long-term Androgen Deprivation Therapy.

A total of 1917 patients were randomly assigned patients in a 1:1 ratio to receive Androgen Deprivation Therapy (ADT) alone (N=957) or ADT plus ZYTIGA® (N=960), administered at 1000 mg PO daily and prednisolone 5 mg PO daily (combination therapy). ADT was given for at least 2 years. Eligible patients had prostate cancer that was newly diagnosed and metastatic, node-positive, or high-risk locally advanced disease or prostate cancer that was previously treated with radical surgery or radiotherapy and was now relapsing with high-risk features. Patients with locally advanced disease could also receive radiation therapy in addition to ADT. Radiotherapy was mandated for patients with N0M0 disease and encouraged for those with stage N+M0 disease. The median age was 67 years, and the median PSA level was 53 ng/ml. Approximately 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate, non-metastatic disease, and 28% had node-negative, non-metastatic disease. Majority of the patients (95%) had newly diagnosed disease. The median follow up was 40 months.

There was a significant survival advantage with combination therapy with a 3-year Overall Survival of 83% with ADT plus ZYTIGA® compared with 76% with ADT alone group (HR=0.63; P<0.001). This meant a 37% reduction in the risk of death with the ZYTIGA® combination treatment. Further, the combination treatment reduced the risk of relapse by 71% (HR=0.29; P<0.001), and also reduced the risk of symptomatic skeletal events by 54% (HR=0.46; P<0.001), compared with ADT alone. Treatment overall was well tolerated.

It was concluded that ADT plus ZYTIGA® and prednisolone results in significantly higher rates of Overall Survival as well as Failure-Free Survival, compared with ADT alone, among men with hormone sensitive, locally advanced or metastatic prostate cancer. Interestingly, the LATITUDE trial showed similar findings in newly diagnosed, metastatic, hormone sensitive prostate cancer patients (June 4, 2017DOI: 10.1056/NEJMoa1704174). The results of both STAMPEDE and LATITUDE trials will very likely change practice patterns and will become the new standard of care for this patient group. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. James ND, de Bono JS, Spears MR, et al. for the STAMPEDE Investigators. June 3, 2017DOI: 10.1056/NEJMoa1702900

FDA Approves KEYTRUDA® for MicroSatellite Instability-High (MSI-H) or MisMatch Repair Deficient (dMMR) Solid Tumors

June 2, 2017May 6, 2020 RR

SUMMARY: The FDA on May 23, 2017, granted accelerated approval to KEYTRUDA® (Pembrolizumab) for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair Deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR ColoRectal cancer that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan.

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 (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI colon 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 increased immunogenicity. These tumors are susceptible to PD-1 blockade and respond to treatment with checkpoint inhibitors such as KEYTRUDA® (N Engl J Med 372:2509-2520, 2015). Other MSH-H and dMMR tumors include, Endometrial and GastroIntestinal tumors and to a lesser extent Breast, Prostate, Bladder and Thyroid tumors.

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.

KEYTRUDA® 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, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. This unique FDA approval was based on data from 149 patients with MSI-H or dMMR tumors (15 cancer types), enrolled across five uncontrolled, multi-cohort, multi-center, single-arm clinical trials. Ninety patients had colorectal cancer and 59 patients were diagnosed with one of 14 other cancer types. KEYTRUDA® was administered at 200 mg IV every 3 weeks or 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity, for a maximum period of 24 months. The median age was 55 years and over a third of the patients were 65 yrs or older. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response. The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, Polymerase Chain Reaction (PCR) tests for MSI-H status or ImmunoHistoChemistry (IHC) tests for MMR deficiency.

The Objective Response Rate (ORR) with KEYTRUDA® was 39.6% with 7.4% Complete Responses and 32.2% Partial Responses. The ORR was 36% in patients diagnosed with ColoRectal Cancer and 46% in patients with any of the other cancer types. Responses lasted six months or more for 78% of those patients, who responded to KEYTRUDA®.

The most common toxicities included fatigue, rash, pruritus, nausea, diarrhea, decreased appetite, cough and dyspnea. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. The Prescribing Information for KEYTRUDA® includes a “Limitation of Use” stating that the safety and effectiveness of KEYTRUDA® in pediatric patients with MSI-H Central Nervous System cancers have not been established.

This is the first FDA approval of a cancer treatment, based on specific genetic biomarker, rather than location in the body where the tumor originated.

Pembrolizumab for patients with previously treated, mismatch repair-deficient microsatellite instability-high advanced colorectal carcinoma: phase 2 KEYNOTE-164 study. Dung L, Thierry A, Won KT, et al. Ann Oncol (2016) 27 (suppl_2): ii79.

First-line pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient or microsatellite instability–high metastatic colorectal Carcinoma. Luis D, Dung L, Takayuki Y, et al. Annals of Oncology (2016) 27 (2): 1-85. 10.1093/annonc/mdw199

Final Overall Survival Results with KADCYLA® in Metastatic Breast Cancer

June 2, 2017October 19, 2018 RR

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, 255,180 new cases of invasive breast cancer will be diagnosed in 2017 and over 41,070 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. 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. It binds to the extracellular domain of the receptor and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). HERCEPTIN® in combination with chemotherapy has been proven to significantly improve Progression Free Survival and Overall Survival in patients with advanced breast cancer. Despite this benefit, majority of these patients develop progressive disease within 18 months. The tumors in these patients continue to express HER2 although the lower sensitivity to HER2 targeted agents has been attributed to HER2 independent escape mechanisms. Treatment strategies for this patient population have included switching chemotherapy in subsequent lines of treatment and continuing HERCEPTIN®, combining another HER2 targeted agent, Lapatinib (TYKERB®) with Capecitabine (XELODA®) and dual HER2 inhibition with a combination of HERCEPTIN® and TYKERB®.

KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival when compared with TYKERB® plus XELODA®, in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a taxane.

TH3RESA is an open label randomized phase III trial in which KADCYLA® was compared with treatment of physician’s choice, in patients with unresectable locally advanced, recurrent or metastatic breast cancer. Eligible patients had a left ventricular ejection fraction of 50% or more and had HER2-positive advanced breast cancer and had received two or more HER2-directed regimens in the advanced setting, and had progressed on both HERCEPTIN® and TYKERB® containing regimens in metastatic setting, and also had disease progression on a taxane, in any setting. Patients were randomized in a 2:1 ratio to receive either KADCYLA® 3.6 mg/kg IV every 21 days (N=404) or treatment of physician’s choice (N=198), which included HER2 directed therapy for the majority of patients. Treatment was continued until disease progression or unmanageable toxicity. The Co-primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included Response Rates, Duration of Response, Safety and Quality of Life. The authors had previously reported a significant improvement in PFS with KADCYLA® compared with physician's treatment choice (6.2 months vs 3.3 months, HR= 0.528, P<0.0001) and an OS trend favoring KADCYLA®.

The authors now reported the results from the final Overall Survival analysis of the TH3RESA trial. At data cutoff, 47% of the patients in the physician's choice group had crossed over to KADCYLA®. The Overall Survival was significantly longer with KADCYLA® compared with treatment of physician's choice (median 22.7 months versus 15.8 months, HR=0.68, P=0.0007). This benefit was seen in all pre-specified subgroups. Patients in the KADCYLA® group had a lower incidence of grade 3 toxicities compared to the patients in the physician’s treatment choice group (40% vs 47%). Grade 3 thrombocytopenia however was more common in the KADCYLA® group compared to the physician’s choice group (6% vs 3%) and this has been attributed to the inhibition of megakaryocyte differentiation by KADCYLA®.

The authors concluded that for patients who had progressed on two or more HER2-directed regimens, treatment with KADCYLA® significantly improved Overall Survival, compared with treatment of physician's choice, thereby validating HER2 as a therapeutic target, even after multiple lines of previous therapy. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Krop IE, Kim SB, González-Martín A, et al. Lancet Oncol. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30313-3

Genomic Prostate Score® (GPS) can Predict Prostate Cancer Mortality and Risk of Metastases in Early Stage Prostate Cancer

May 26, 2017April 5, 2020 RR

The Oncotype DX® Prostate Cancer Assay is a multi-gene RT-PCR expression assay that was developed for use with Fixed Paraffin-Embedded (FPE) Prostate needle biopsy specimens. This 17 gene assay measures expression of 12 cancer related genes representing four biological pathways with a known role in Prostate cancer development (androgen pathway, cellular organization, proliferation and stromal response), and 5 reference genes used to control for sources of pre-analytical and analytical variability. Combined together algorithmically, the Genomic Prostate Score (GPS, scale 0-100) is calculated, with a higher GPS score representing a more aggressive tumor phenotype. Genomic Prostate Score has been shown to predict unfavorable outcomes beyond conventional clinical and pathologic factors and has been validated as an independent predictor of adverse surgical pathology and BioChemical Recurence after Radical Prostatectomy, in men with low-risk and low-volume intermediate-risk Prostate cancer.

The authors conducted a large community based study, to confirm that Genomic Prostate Score (GPS) is a predictor of BioChemical Recurrence in all clinical risk groups (low, intermediate and high), in a large cohort of Prostate cancer patients, followed up at Kaiser Permanente medical groups in Northern California. A retrospective study was performed from the Kaiser Permanente clinical database of 6,184 Prostate cancer patients, between 1995- 2010, with NCCN very low, low, intermediate and high-risk disease, who were treated with Radical Prostatectomy. BioChemical Recurrence was defined as either 2 successive post-Radical Prostatectomy PSAs of 0.2 ng/mL or more, or initiation of salvage therapy after a rising PSA of 0.1 ng/mL or more. Genomic Prostate Score was derived from the archival biopsy tissue. The researchers were able to retrieve the biopsy tissue of 334 patients of whom 279 patients met all eligibility criteria and a valid GPS score was available in 259 (93%) patients.

It was noted that Genomic Prostate Score was strongly associated with BioChemical Recurrence after adjusting for PSA, clinical T stage and tumor Gleason Score (P=0.002). Genomic Prostate Score was a strong independent predictor of Prostate cancer-specific death and disease progression (metastases) at 10 years, across all NCCN clinical risk groups. Further, the association between GPS and BioChemical Recurrence was similar within the different racial groups.

It was concluded that for patients with Prostate cancer treated with Radical Prostatectomy, a higher Genomic Prostate Score was associated with BioChemical Recurrence, independent of other clinical factors. Genomic Prostate Score can hence improve risk stratification beyond clinical risk assessment, by predicting both near term adverse pathology and long term clinical outcomes Validation of a 17-Gene Genomic Prostate Score (GPS) as a predictor of biochemical recurrence (BCR) in men with prostate cancer treated with radical prostatectomy (RP) in a community setting. VanDenEeden SK, Zhang N, Quesenberry CP, et al. J Clin Oncol 35, 2017 (suppl 6S; abstract 41)

FDA Approves BAVENCIO® for Merkel Cell Carcinoma

May 26, 2017October 11, 2018 RR

SUMMARY: The FDA on March 23, 2017, granted accelerated approval to BAVENCIO® (Avelumab) for the treatment of patients 12 years and older with metastatic Merkel Cell Carcinoma (MCC). Even though skin cancer is by far the most common type of cancer in the US, Merkel Cell Carcinoma (MCC) is not common. The American Cancer Society estimates that about 1,500 cases of MCC are diagnosed in the United States each year and over 90% of those diagnosed with MCC are older than 50yrs of age. The incidence of MCC in the US has tripled between 1986 and 2001. Merkel Cell Carcinoma, also known as Trabecular Cancer of the Skin, is much more common in Caucasians than in people of other races, and occurs at increased frequency in individuals who are immunodeficient including patients who are transplant recipients. Other risk factors include exposure to ultraviolet light.

Merkel cells are often found at the base of the epidermis and are responsible for fine touch and pressure sensation. Merkel Cell Carcinoma (MCC) is a very aggressive neuroendocrine carcinoma of the skin. Merkel Cell PolyomaVirus (MCPyV) has been identified in over 80% of Merkel Cell tumors and a majority of MCCs contain clonally integrated viral DNA and express viral T antigen transcripts and protein. The presence of the virus in tumor cells can be confirmed by FISH analysis. This along with ultraviolet radiation-induced mutations provides the rationale for the treatment of MCC, with antibodies that target the PD-L1/PD-1 pathway. BAVENCIO® is a human IgG1 lambda monoclonal antibody, directed against Programmed cell Death Ligand1 (PD-L1) and blocks the interaction of PD-L1 with PD-1. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. BAVENCIO® is the first FDA-approved product to treat Merkel Cell Carcinoma.

The approval of BAVENCIO® was based on data from the JAVELIN study which is a multicentre, international, prospective, open-label, phase II trial. This study enrolled 88 previously treated patients with metastatic Merkel Cell Carcinoma. The median age was 72 years. Visceral disease was present in over 50% of patients. Overall, 66% of patients were PD-L1-positive and 52% were positive for the Merkel Cell PolyomaVirus (MCPyV). BAVENCIO® was given intravenously at 10 mg/kg IV every 2 weeks. The Primary endpoint was Objective Response Rate (Complete Response or Partial Response), assessed by an Independent Review Committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug.

The Objective Response Rate was 33% with 11% Complete Response and 22% Partial Response. Among the responding patients, the response duration ranged from 3 months to 23 months with 86% of responses durable for 6 months or longer. Responses were ongoing in 82% of the patients at the time of analysis. Responses were observed in patients regardless of PD-L1 tumor expression or presence of Merkel Cell PolyomaVirus. The most common adverse reactions were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.

The authors concluded that BAVENCIO® is associated with durable response rates and represents a new therapeutic option for advanced Merkel Cell Carcinoma. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Kaufman H, Russell JS, Hamid O, et al. Lancet Oncol. 2016;17:1374-1385

FDA Approves KEYTRUDA® in Combination with Chemotherapy as First-Line Treatment for Metastatic NSCLC

May 19, 2017October 11, 2018 RR

SUMMARY: The FDA on May 10, 2017 granted accelerated approval to KEYTRUDA® (Pembrolizumab) in combination with ALIMTA® (Pemetrexed) and Carboplatin, for the treatment of patients with previously untreated metastatic non-squamous Non Small Cell Lung Cancer (NSCLC). Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Non Small Cell Lung Cancer accounts for approximately 85% of all lung cancers. The FDA in October 2016, approved KEYTRUDA® for the treatment of patients with metastatic NSCLC, whose tumors have high PD-L1 expression (Tumor Proportion Score greater than or equal to 50%), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC.

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