Category: Meeting Updates

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

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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 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 Adding ZYTIGA® to Androgen Deprivation Therapy Improves Overall Survival in Newly Diagnosed Advanced Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 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

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

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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)

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

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 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. Traditionally, clinical risk assessment has been based on Tumor stage, Gleason score and PSA level, in patients who had Radical Prostatectomy for Prostate cancer. However, new validated biomarkers can improve risk stratification for men with Prostate cancer.

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 IMFINZI® for Advanced Bladder Cancer

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SUMMARY: The FDA on May 1, 2017, granted accelerated approval to IMFINZI® (Durvalumab) for the treatment of patients with locally advanced or metastatic Urothelial Carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The FDA also approved the VENTANA PD-L1 (SP263) Assay as a complementary diagnostic for the assessment of the PD-L1 protein in Formalin-Fixed, Paraffin-Embedded Urothelial Carcinoma tissue. Urothelial Carcinoma accounts for 90% of all bladder cancers and can originate in the renal pelvis, ureter and urethra. The American Cancer Society estimates that in 2017, approximately 79,030 new cases of Bladder Cancer will be diagnosed and 16,870 patients will die of the disease. Treatment options for patients who progress after platinum based chemotherapy are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.

The treatment paradigm for solid tumors has been rapidly evolving, with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), as well as Programmed cell Death Ligands (PD-L1) that are expressed by cells in the tumor micro environment. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. It has been noted that PD-L1 is widely expressed in tumor and immune cells of patients with Urothelial Carcinoma. This in turn helps cancer cells to evade detection from the immune system by binding to the PD-1 receptor on cytotoxic T lymphocytes.

IMFINZI® is a selective, high-affinity human IgG1 monoclonal antibody directed against PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80. The accelerated FDA approval of IMFINZI® was based on evaluation of 182 patients in the bladder cancer cohort of Study 1108, which is a single-arm Phase I/II trial. This study evaluated the safety and efficacy of IMFINZI® in patients with locally-advanced or metastatic Urothelial Carcinoma of the bladder, who had progressed while on or after a platinum-containing chemotherapy regimen. This study included patients who had progressed within 12 months of receiving therapy, in a neoadjuvant or adjuvant setting. Treatment consisted of IMFINZI® 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. Tumor PD-L1 expression was assessed using the validated VENTANA SP263 Assay, in Formalin-Fixed, Paraffin-Embedded Urothelial Carcinoma tissue. High PD-L1 expression was defined as 25% or more expression on tumor and immune cells. The Primary endpoints were Objective Response Rate and Safety. Secondary endpoints included Duration of Response (DoR) and Overall Survival (OS).

The confirmed Objective Response Rate as assessed by blinded Independent Central Review was 17% and the median response duration was not reached. Objective Response Rate was also analyzed by PD-L1 expression status. In the 182 patients, the confirmed Objective Response Rate was 26.3% in patients with a high PD-L1 score and 4.1% in patients with a low or negative PD-L1 score. The most common adverse reactions were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection.

The authors concluded that IMFINZI® has significant clinical activity and an excellent safety profile in patients with locally advanced or metastatic Urothelial Carcinoma. Clinical trials are underway, evaluating IMFINZI® as monotherapy and in combination with other checkpoint inhibitors, in the first line treatment of patients with advanced bladder cancer. Updated Efficacy and Tolerability of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma. Powles T, O’Donnell PH, Massard C, et al. J Clin Oncol. 2017;35 (suppl 6S; abstract 286).

RITUXAN® Maintenance Prolongs Survival in Mantle Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Mantle Cell Lymphomas (MCL) account for approximately 6% of all Non Hodgkin Lymphomas in adults and have a high relapse rate following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease. Maintenance therapy with RITUXAN® (Rituximab) following induction chemotherapy with R-CHOP, prolonged remission and significantly improved Overall Survival in elderly patients with MCL (N Engl J Med. 2012;367:520-531). The role of maintenance RITUXAN® and its impact on Overall Survival in young patients following Autologous Stem Cell Transplant (ASCT) has however not been investigated.

The LyMa trial is a prospective, international, randomized, phase III study that evaluated the benefit of RITUXAN® maintenance following ASCT, in young previously untreated MCL patients. This study enrolled 299 treatment-naïve MCL patients, diagnosed according to WHO 2008 classification, with a median age of 57 years, of whom 277 patients (N=277) were included in the study. Induction chemotherapy consisted of 4 cycles of R-DHAP (RITUXAN®, Dexamethasone, High dose Ara-C, Cisplatin) given every 3 weeks followed by ASCT. Patients who did not respond to R-DHAP received 4 additional courses of R-CHOP-14 before undergoing ASCT (N=20). The conditioning regimen for ASCT was R-BEAM (RITUXAN® BiCNU, Etoposide, Ara-C, and Melphalan). Following ASCT, 240 patients who responded, were randomized in a 1:1 ratio to receive RITUXAN® maintenance at 375 mg/m2 every 2 months for 3 years or no maintenance treatment. The Primary endpoint was Event Free Survival (EFS) calculated from time of randomization and these events included disease progression, relapse, death, severe infection or allergy to RITUXAN®. Secondary endpoints included Progression Free Survival and Overall Survival from time of diagnosis and time of randomization.

In the final analysis, the 4-year Event Free Survival (EFS) was 78.9% with RITUXAN® maintenance compared with 61.4% for those who did not get maintenance therapy (P=0.0012). The EFS duration was significantly superior in the RITUXAN® maintenance arm with a 54% reduction in the risk of events (HR=0.46; P=0.0016). The 4-year Progression Free Survival was 82.2% versus 64.6% with and without RITUXAN® maintenance, respectively (P=0.0005). The Overall Survival at 4 years was 88.7% and 81.4%, for RITUXAN® maintenance and no maintenance respectively (P=0.04). Patients in the RITUXAN® maintenance group had a 60% reduction in the risk of progression (HR=0.40; P=0.0007) and a 50% reduction in the risk of death (HR=0.50; P=0.05).

The authors concluded that RITUXAN® maintenance after ASCT prolongs Event Free Survival, Progression Free Survival and Overall Survival and is a new standard of care for young Mantle Cell Lymphoma patients. Rituximab Maintenance after Autologous Stem Cell Transplantation Prolongs Survival in Younger Patients with Mantle Cell Lymphoma: Final Results of the Randomized Phase 3 LyMa Trial of the Lysa/Goelams Group. Le Gouill S, Thieblemont C, Oberic L, et al. Presented at: 58th American Society of Hematology Annual Meeting & Exposition; December 3, 2016; San Diego, CA. Abstract 145.

Sequencing Therapies in Metastatic Castrate Resistant Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 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. Chemotherapy is usually considered for patients who progress on hormone therapy (Castrate Resistant Prostate Cancer-CRPC) and TAXOTERE® (Docetaxel) has been shown to improve Overall Survival (OS) of metastatic prostate cancer patients, who had progressed on Androgen Deprivation Therapy. Tumors in patients with CRPC are not androgen independent and continue to rely on Androgen Receptor signaling. Two oral Androgen Receptor Targeted Agents (ARTA) are presently available for metastatic CRPC. They include ZYTIGA® (Abiraterone) and XTANDI® (Enzalutamide). ZYTIGA® inhibits CYP 17A1 enzyme thus decreasing androgen biosynthesis and depletes adrenal and intratumoral androgens. XTANDI® competes with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor (AR), thereby inhibiting AR signaling and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR. There is presently very little guidance with regards to the sequencing of these two oral agents.

It has remained unclear when a patient should receive chemotherapy following progression on AR-targeted therapies. To determine the ideal second line therapy in this patient population, the authors conducted a retrospective study, to assess if second line chemotherapy was associated with improved outcomes, compared with second line alternative AR Targeted Agents, in patients with a very short duration of response to first line Androgen Receptor Targeted Agents, in the US community oncology setting.

Using Altos electronic medical records, the authors identified 345 patients with metastatic CRPC who did not respond to first-line AR Targeted Agents (ZYTIGA® or XTANDI®) who then went on to receive second-line TAXOTERE® – Docetaxel or JEVTANA® – Cabazitaxel (chemotherapy cohort, N=147), or an alternative AR Targeted Agent (ARTA cohort, N=198), from May 2011 to Oct 2014. Patients receiving chemotherapy as second-line treatment, compared to those receiving second-line ARTA, were younger (median age, 74 vs 79 years) and had several poor prognostic factors including a higher mean PSA, LDH and Alkaline Phosphatase, as well as lower mean hemoglobin and increased opioid use. Treatment outcomes were evaluated from start of second-line treatment and second-line chemotherapy was compared to second-line ARTA. The primary endpoints included Prostate Specific Antigen (PSA) response (50% or more reduction) and Overall Survival (OS).

It was noted that more patients in the chemotherapy group had a PSA response compared to the AR Targeted Agent group (P=0.005), and there was a non-statistically significant trend toward improved Overall Survival for second-line chemotherapy versus AR Targeted Agent (adjusted HR=0.81; P=0.15). Among patients with poor prognostic features, those in the chemotherapy cohort had significantly improved Overall Survival (adjusted HR=0.55; P=0.009) compared with those in the AR Targeted Agent cohort.

The authors concluded that patients who do not respond well to first-line Androgen Receptor Targeted Agent and have poor prognostic features, should not receive a second AR-targeted agent but instead receive second-line chemotherapy, as this may confer a survival benefit. Real-world outcomes in patients with metastatic castration-resistant prostate cancer receiving second-line chemotherapy vs alternative androgen receptor-target agents (ARTA) after lack of response to first-line ARTA in US community oncology practices. Oh WK, Cheng WY, Miao R, et al. J Clin Oncol. 2017;35 (suppl 6S; abstr 214).

CABOMETYX® Superior to SUTENT® in Metastatic Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that about 63,990 new cases of kidney cancer will be diagnosed in the United States in 2017 and about 14,400 patients will die from this disease. The VHL (Von Hippel-Lindau) protein is a tumor suppressor gene which is frequently mutated and inactivated in approximately 90% of clear cell Renal Cell Carcinomas (RCC). The VHL gene under normal conditions binds to Hypoxia-Inducible Factor (HIF-1 alpha) and facilitates degradation of this factor. Under hypoxic conditions and in patients having biallelic loss of function and mutation of VHL genes, HIF-1alpha is not degraded. Build up of HIF-1 alpha results in increased angiogenesis, increased tumor cell proliferation and survival, as well as metastasis.

SUTENT® (Sunitinib) is the standard first-line intervention for treatment naïve patients with advanced Renal Cell Carcinoma. VOTRIENT® (Pazopanib) another VEGFR-targeted therapy, is an alternative choice, as it was found to be non-inferior to SUTENT® in the COMPARZ trial. CABOMETYX® (Cabozantinib) is an oral, small-molecule Tyrosine Kinase Inhibitor (TKI) but, unlike SUTENT® which targets the Vascular Endothelial Growth Factor Receptors (VEGFR), CABOMETYX® additionally inhibits the action of tyrosine kinases MET and AXL. Both MET and AXL are up-regulated in Renal Cell Carcinoma as a consequence of VHL inactivation and increased expression of MET and AXL is associated with tumor progression and development of resistance to VEGFR inhibitors. CABOMETYX® was approved by the FDA in 2016 for the treatment of advanced Renal Cell Carcinoma (RCC), in patients who have received prior anti-angiogenic therapy.

The Alliance for Clinical Trials in Oncology reported the results of a randomized, multicenter, open-label phase II CABOSUN trial, which compared CABOMETYX® with standard-of-care SUTENT®, in IMDC intermediate and poor-risk untreated patients with locally advanced or metastatic clear-cell RCC. The study population had a high rate of bone metastases, a known negative prognostic factor in RCC. This study enrolled 157 patients who were randomized in a 1:1 ratio to receive CABOMETYX® 60 mg orally daily (N=79) or SUTENT® 50 mg orally 4 weeks on, 2 weeks off (N=78). A treatment cycle was defined as 6 weeks in both study groups and treatment was continued until disease progression or intolerance to therapy. Patients were stratified by IMDC risk category (intermediate or poor) and presence of bone metastases. Crossover between treatment groups was not allowed. The median age was 63 years and 81% of the enrolled patients were classified as IMDC intermediate risk and 19% as poor risk, 36% of patients had bone metastases and 75% of the patients had prior nephrectomy. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Objective Response Rate (ORR), Overall Survival (OS) and safety.

It was noted that the treatment with CABOMETYX® significantly increased median PFS compared with SUTENT® (8.2 versus 5.6 months) and was associated with a 34% reduction in rate of disease progression or death (HR=0.66; P=0.012). The ORR was 46% in the CABOMETYXreg; group compared with 18% in the SUTENT® group. The median OS with CABOMETYX® was 30.3 months versus 21.8 months with SUTENT® (HR=0.80), with this preliminary data showing a 20% decrease in the risk of death with CABOMETYX®. Grade 3 or 4 adverse events were similar in both treatment groups with more hypertension and Palmar-Plantar Erythrodysesthesia in the CABOMETYX® group whereas the SUTENT® group experienced more fatigue and hematologic toxicities. Discontinuation rates related to adverse events were similar in both treatment groups.

The authors concluded that CABOMETYX® significantly improved PFS and ORR compared to SUTENT®, in the initial treatment of patients with intermediate or poor-risk clear cell metastatic Renal Cell Carcinoma. CABOMETYX® is the first agent to demonstrate clinical superiority over SUTENT®, which has been the established standard of care for more than 10 years. The authors attributed the superiority of CABOMETYX® over SUTENT® due to its mechanism of action, which targets MET and AXL, in addition to VEGFR. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Choueiri TK, Halabi S, Sanford BL, et al. DOI: 10.1200/JCO.2016.70.7398 Journal of Clinical Oncology 35, no. 6 (February 2017) 591-597.

Location of Primary Tumor in the Colon Predicts Survival and Choice of Treatment in 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 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. Several published studies have demonstrated a nearly 20% reduced risk of death for patients diagnosed with left sided colon cancer compared with those who had right sided tumors. Venook and colleagues had previously presented their findings from a retrospective evaluation of the phase III 80405 clinical trial which included data from 1,025 metastatic ColoRectal Cancer patients with KRAS wild-type disease. The researchers assessed the impact of tumor location on Overall and Progression Free Survival in this group of patients. The median age was 59 yrs and 293 patients had a right-sided primary tumor (location in the cecum to hepatic flexure) and 732 patients had a left-sided primary tumor (location in the splenic flexure to rectum). It was noted that patients with tumors originating in the right side of the colon had much shorter median Overall Survival (19.4 months) compared to patients with left-sided tumors (33.3 months), (HR=1.60; P<0.001), with a 14 month survival improvement in the left versus right-sided primary tumors, for patients with metastatic disease. Tumor location in the colon also had a bearing on response to ERBITUX® (Cetuximab) and AVASTIN® (Bevacizumab). For the patient group who received ERBITUX®, the median Overall Survival (OS) was 36 months for patients with left-sided tumors but only 16.7 months for patients with right-sided tumors. For those who received AVASTIN®, the median OS was 31.4 months for patients with left-sided tumors and 24.2 months for those with right-sided tumors. The median Progression Free Survival was also influenced by the site of the primary tumor and was 11.5 months for left-sided tumors versus 8.9 months for right-sided tumors in the overall cohort of patients (HR = 1.26; P = 0.002). It was concluded that the biology of tumors originating in the right colon may be different from those originating in the left colon and regardless of KRAS mutational status, AVASTIN® based, first line chemotherapy regimen should be considered, for all patients with metastatic colorectal cancer, with a right-sided colon primary tumor and ERBITUX® should be avoided in this patient group.

Understanding that there is a difference in outcomes with biologic therapy, based on tumor location in the colon, the authors in this study evaluated the molecular variations of tumors arising in different parts of the left colon. Using protein expression, gene amplification and NextGen sequencing, 1,457 primary tumors (125 from splenic flexure to descending colon, 460 in the sigmoid colon and 872 in the rectum) were examined. MicroSatellite Instability (MSI) was measured by PCR and tumor mutational load was calculated using somatic nonsynonymous missense mutations.

They noted that the incidence of  to MSI significantly decreased from right colon (22%), to descending colon (7%),sigmoid colon (4%) to rectum (1%) and this was statistically significant (P=0.01). Rectal tumors had a higher frequency of TP53 and APC gene mutations and higher expression of TOPO1, ERCC1 and MGMT, compared to tumors in the descending colon. Compared to sigmoid colon tumors, rectal tumors had a higher expression of TOPO1, MGMT, TLE3 and TUBB3.

The authors concluded that tumors arising in the rectum have a distinct set of genetic alterations compared with other left colon tumors, and these distinct biologic entities may need to be addressed with individually tailored therapy. Molecular variances between rectal and left-sided colon cancers. Marshall J, Lenz H, Xiu J, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 522)

FDA Approves KEYTRUDA® for Hodgkin Lymphoma

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SUMMARY: The FDA on March 14, 2017 granted an accelerated approval to KEYTRUDA® (Pembrolizumab) for the treatment of adult and pediatric patients with classical Hodgkin Lymphoma (cHL) who are Refractory, or have Relapsed, after 3 or more lines of therapy. This approved indication is based on tumor response rate and durability of response. The American Cancer Society estimates that in the United States for 2017, about 8,260 new cases of Hodgkin lymphoma will be diagnosed and about 1,070 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 and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS). The HRS cells in turn recruit an abundance of ineffective inflammatory cells and infiltrates of immune cells. Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-L. Classical Hodgkin Lymphoma is an excellent example of how the tumor microenvironment influences cancer cells to proliferate and survive.

The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2 with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin’s lymphomas. It would therefore seem logical to block or inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Under normal circumstances, Immune checkpoints or gate keepers inhibit intense immune responses by switching off the T cells of the immune system. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. 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.

The approval of KEYTRUDA® was based on data from the non-randomized, open-label KEYNOTE-087 trial, which included 210 adult patients with Relapsed/Refractory classical Hodgkin Lymphoma. Approximately 58% of patients were refractory to their last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior treatment regimens. Patients received a median number of four prior therapies and prior therapies included Autologous Hematopoietic Stem Cell Transplantation (61%), ADCETRIS® -Brentuximab vedotin (83%), and radiation therapy (36%). The median age was 35 years and 9% of patients were older than 65 years. KEYTRUDA® was administered at 200 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years, in patients who did not have disease progression. Patients were assessed every 12 weeks to determine their disease status. The Primary end point was Overall Response Rate (ORR). Secondary end points included Complete Response Rate (CRR), Duration of Response, Progression Free Survival, and Overall Survival. The median follow-up was 9.4 months.

It was noted that the Overall Response Rate was 69% and this included Complete Responses in 22% of patients and Partial Responses in 47% of patients. The median Duration of Response was 11.1 months. The most common adverse events were fatigue, pyrexia, cough, musculoskeletal pain, diarrhea, and skin rash. Serious adverse reactions occurred in 16% of patients and the most common grade 3/4 treatment-related adverse events were neutropenia, thrombocytopenia and diarrhea. Adverse reactions led to treatment discontinuation in 5% of the patients.

The authors concluded that PD-1 blockade with KEYTRUDA® has significant clinical activity in subsets of heavily pretreated patients with classical Hodgkin Lymphoma, with high Overall Response Rates and Duration of Response. This important study gives a fighting chance for these generally young patients with poor prognosis. Pembrolizumab in Relapsed/Refractory Classical Hodgkin Lymphoma: Primary End Point Analysis of the Phase 2 Keynote-087 Study. Moskowitz CH, Zinzani PL, Fanale MA, et al. Presented at the ASH 58th Annual Meeting & Exposition, San Diego, CA. December 3-6, 2016. Abstract #1107