Category: Meeting Updates

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

FDA Approves KISQALI® for First-Line Treatment of Hormone Receptor Positive Advanced Breast cancer

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SUMMARY: The FDA on March 13, 2017 approved KISQALI® (Ribociclib), a cyclin-dependent kinase 4/6 inhibitor, in combination with an Aromatase Inhibitor, as initial endocrine-based therapy for the treatment of postmenopausal women with Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative advanced or metastatic breast cancer. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop breast cancer during their life time. Approximately, 255,180 new cases of breast cancer will be diagnosed in 2017 and 41,070 women will die of the disease. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6), phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.

KISQALI® is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. In a phase 1b study involving postmenopausal women with ER positive, HER2-negative advanced breast cancer, KISQALI® in combination with FEMARA® (Letrozole) demonstrated an Overall Response Rate (ORR) of 46% and a Clinical Benefit Rate of 79%, in treatment-naïve patients with advanced breast cancer.

MONALEESA-2 trial is a randomized, double-blind, placebo-controlled, phase III study in which 668 patients were randomly assigned in a 1:1 ratio to receive either KISQALI® plus FEMARA® (Letrozole) or placebo plus FEMARA®. Eligible patients included post-menopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer who had received no prior therapy for advanced disease. Treatment consisted of oral KISQALI® 600 mg daily on a 3-weeks on and 1-week off schedule, in 28-day treatment cycles plus FEMARA® 2.5 mg orally daily on a continuous schedule or placebo plus FEMARA®. Patients were stratified according to the presence or absence of liver or lung metastases and treatment was continued until disease progression or unacceptable toxicity. No treatment crossover was allowed. The median age was 62 years and close to 60% of the patients had visceral metastases. The primary end point was Progression Free Survival (PFS) and secondary end points included Overall Survival (OS), Overall Response Rate (ORR), Clinical Benefit Rate (Overall Response plus stable disease lasting 24 weeks or more), safety, and Quality of Life assessments.

A pre-planned interim efficacy analysis demonstrated a significant improvement in the PFS amongst the KISQALI® group compared to the placebo group (HR=0.56; P<0.0001). The median duration of follow-up was 15.3 months. The estimated median PFS had not been reached in the KISQALI® group and was 14.7 months in the placebo containing arm. The Overall Response Rate (ORR) in patients with measurable disease was 52.7% in the KISQALI® group and 37.1% in the placebo plus FEMARA® group (P<0.001). Overall Survival data was mature at the time of this analysis. The rates of discontinuation because of adverse events were 7.5% in the KISQALI® group and 2.1% in the placebo group. The most common adverse reactions observed in patients taking KISQALI® were myelosuppression, nausea, vomiting, diarrhea and fatigue, as well as abnormal liver function tests. KISQALI® has been shown to prolong the QT interval in a dose-dependent manner and prolongation of the QT interval occurred in 3.3% of patients treated at the 600 mg dose, with changes mostly occurring within the first 4 weeks of treatment.

The authors concluded that among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the addition of KISQALI® to FEMARA® significantly prolonged PFS compared to FEMARA® alone, with a higher rate of myelosuppression noted in the KISQALI® group. Ribociclib as First-Line Therapy for HR-positive, Advanced Breast Cancer. Hortobagyi GN, Stemmer SM, Burris HA, et al. N Engl J Med 375:1738-1748, 2016.

FDA Approves IMBRUVICA® for Marginal Zone Lymphoma

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SUMMARY: The FDA on January 18, 2017 granted accelerated approval to IMBRUVICA® (Ibrutinib) for the treatment of patients with Marginal Zone Lymphoma (MZL), who require systemic therapy and have received at least one prior anti-CD20 based therapy. 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. Indolent Non Hodgkin Lymphomas are mature B-cell lymphoproliferative disorders and include Follicular Lymphomas, Small Lymphocytic Lymphomas (SLL), LymphoPlasmacytic Lymphomas (LPL) and Marginal Zone Lymphoma subtypes such as Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL)/Mucosa-Associated Lymphoid Tissue (MALT) lymphoma and Splenic Marginal Zone Lymphoma (SMZL). Marginal Zone Lymphoma is an indolent B-cell lymphoma originating in the lymph nodes as well as in organs including the stomach, salivary glands, thyroid gland, lungs and spleen. It accounts for approximately 10% of all cases of Non Hodgkin Lymphomas (NHL) in adults and is often linked to chronic infection. When treatment is indicated, patients are often treated with a RITUXAN® (Rituximab) based regimens with improved outcomes. Relapses however are common and there is presently no therapy, specifically approved for the treatment of Marginal Zone Lymphoma.

Normal B-cell activation and proliferation is dependent on B-Cell Receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® is presently approved by the FDA for the treatment of patients with Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma including those with del-17p, patients with Mantle Cell Lymphoma who had received at least one prior therapy, and patients with Waldenstrom’s Macroglobulinemia.

The approval of IMBRUVICA®, in MZL was based on results from a multicenter, open-label, single-arm, phase II trial, in which the safety and efficacy of IMBRUVICA® was evaluated in 63 patients with Marginal Zone Lymphoma. Enrolled patients had previously received one or more prior therapies including at least one anti-CD20 targeted monoclonal antibody -containing regimen or monotherapy RITUXAN®. The subtypes of Marginal Zone Lymphomas included, Extra Nodal MZL (N=32), Nodal MZL (N=17) and Splenic MZL (N=14). The median number of prior systemic therapies was 2 and 35% of the enrolled patients had 3 or more prior therapies. Treatment consisted of IMBRUVICA® 560 mg orally once daily until progression or unacceptable toxicity. The primary study endpoint was Overall Response Rate (ORR). Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS), and safety.

The Overall Response Rate as assessed by an independent review committee was 46%,of whom with 3.2% of patients had a Complete Response and 42.9% achieved a Partial Response. This benefit was observed across all three subtypes of Marginal Zone Lymphomas (Overall Response Rate was 46.9%, 41.2%, and 50.0% for ENMZL/MALT, NMZL, and SMZL subtypes, respectively). The median time to response was 4.5 months and the median duration of response was not reached (range, 16.7 months – Not Reached). The most common adverse events were fatigue, diarrhea, cytopenias, nausea, peripheral edema, cough, arthralgia and dyspnea.

The authors concluded that single agent IMBRUVICA® achieved high Response Rates and durable responses in patients with Relapsed/Refractory Marginal Zone Lymphoma. IMBRUVICA® addresses an unmet need for previously treated Marginal Zone Lymphoma patients, who are in need of non-chemotherapy treatment options. Single-Agent Ibrutinib Demonstrates Efficacy and Safety in Patients with Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open-Label, Phase 2 Study. Noy A, de Vos S, Thieblemont C, et al. Presented at: ASH 2016 Annual Meeting and Exposition. Abstract 1213.

Chemoradiation Alone without Surgery does not Compromise Survival in Selected Patients with Rectal Cancer

RR

SUMMARY: The American Cancer Society estimates 39,910 new cases of Rectal Cancer will be diagnosed in the United States in 2017. Rectal cancer diagnosed at an early stage such as Stage II (T3-T4, N0) or Stage III (Node positive disease without distant metastases) is potentially curable and often treated with a combination of neoadjuvant (preoperative) chemoradiation and surgery and postoperative chemotherapy. Unlike colon cancer, the risk of locoregional recurrence is high in Rectal Cancer due to its close proximity to the surrounding pelvic organs and difficulty in obtaining a clear surgical margins. Further, there is no serosal tissue surrounding the rectum. For all these reasons, preoperative Radiation Therapy (RT) with concurrent Fluoropyrimidine based chemotherapy as a radiosensitizer, followed by postoperative chemotherapy, has been the standard intervention. Radiation consists of 45 Gy delivered in 25 fractions 5 days a week with a 5.4 Gy boost. Concurrent chemotherapy in the US has included 5-FU/Leucovorin, single agent 5-FU or single agent XELODA® (Capecitabine). Complete Response is seen in approximately 25% of the patients who receive chemoradiation. However, 15% to 25% of these patients develop local recurrence. Surgery following chemoradiation may result in long term complications and may necessitate temporary or permanent colostomy in addition to sexual and urinary dysfunction.

The International Watch & Wait Database Consortium was established in 2014 by EURECCA (the European Registration of Cancer Care) and the Champalimaud Foundation in Lisbon. This Consortium which includes 35 institutions in 11 countries was established mainly to collect all available data and expand knowledge on the benefits, risks and oncological safety of organ preserving strategies, in Rectal Cancer. This database as of August 2016 included 775 patients and majority of these patients had stage T2/3 disease (92%) with clinical N0/1 nodal status (75%). Ninety percent of these patients (N=679) had a clinical Complete Response following induction therapy with chemoradiation. These patients did not undergo surgery and were followed up for a median of 2.6 years.

It was noted that 25% of all patients had local recurrence and 84% of these occurred in the first 2 years of follow up. Local recurrence was endoluminal in 96% of the patients and in the loco-regional lymph nodes in 4%. Distant metastasis occurred in 7% of the patients. The 3-year Overall Survival rate was 91% among all patients, and was 87% for patients who experienced local recurrence. These findings are comparable to survival rates seen in patients with a Complete Response, who undergo standard surgery.

It was concluded that in this largest series of patients to date with Rectal Cancer, a “watch-and-wait” strategy to treating Rectal Cancer without surgery, following Complete Response to chemoradiation, resulted in outcomes comparable to historical controls. As more information is gathered, it is important that restaging be performed in all patients with Rectal Cancer who undergo chemoradiotherapy, to prevent unnecessary surgical procedures, and give patients the option for a watch-and-wait approach. The International Watch & Wait database (IWWD) for rectal cancer: An update. van der Valk M for the International Watch and Wait Database Consortium. J Clin Oncol 35, 2017 (suppl 4S; abstract 521)

Niraparib Maintenance Therapy Significantly Improves Progression Free Survival in Platinum-Sensitive Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 22,440 women will be diagnosed with ovarian cancer in 2017 and a little over 14,000 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease and the 5 year Overall Survival rate is about 20-30%. These patients are often treated with platinum based chemotherapy following primary surgical cytoreduction.

BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins that repair damaged DNA and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. 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. They also account for 15 percent of ovarian cancers in addition to other cancers such as colon and prostate.

Homologous Recombination (HR) is an important pathway that allows repair of double-stranded DNA breaks and operates during the S and G2 phases of the cell cycle, relying on several proteins including BRCA1 and BRCA2. Deficiency of BRCA1 and BRCA2 results in non-functioning HR pathway (HR Deficiency), and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Hereditary Epithelial Ovarian Cancer was thought to be caused almost exclusively by mutations in BRCA1 and BRCA2. It however now appears that about 50% of the high grade serous ovarian cancers have aberrations in HR repair pathway. BRCA mutations can either be inherited (germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations, and loss of BRCA function due to frequent somatic aberrations in ovarian cancers likely deregulates HR pathway and increases sensitivity to platinum drugs. Majority of the women with germline BRCA mutations (gBRCA) are positive for HR deficiency.

The PARP (Poly ADP Ribose Polymerase) family of enzymes which include PARP1 and PARP2, repair damaged DNA. PARP inhibitors kill tumors defective in the BRCA1 or BRCA2 genes through the concept of synthetic lethality. Epithelial Ovarian Cancers with Homologous Recombination Deficiency (HRD) have demonstrated sensitivity to PARP inhibitors. The two currently FDA approved PARP inhibitors include LYNPARZA® (Olaparib) for the treatment of ovarian cancer with gBRCA mutations after three lines of therapy and RUBRACA® (Rucaparib) for the treatment of ovarian cancer with gBRCA mutations and /or somatic mutations after two lines of therapy.

Niraparib is a highly selective PARP 1/2 inhibitor, that detects DNA damage and promotes its repair. Previously published studies demonstrated the antitumor activity of Niraparib in patients with ovarian cancer, at a maximum dose of 300 mg per day, with a low frequency of high grade adverse events. Based on this preliminary data, the authors conducted a randomized, placebo-controlled, phase III trial (ENGOT-OV16/NOVA) to evaluate the efficacy and safety of Niraparib versus placebo, as maintenance treatment in patients with platinum-sensitive, recurrent ovarian cancer.

This study enrolled two independent cohort of patients based on the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort), as determined on BRACAnalysis® testing (Myriad Genetics). All enrolled patients had tumors sensitive to platinum-based therapy and had received at least 2 lines of therapy. Enrolled patients (N=553) were randomly assigned in a 2:1 ratio to receive Niraparib 300 mg or placebo once daily. The gBRCA cohort included 203 patients (138 assigned to Niraparib and 65 to placebo) and the non-gBRCA cohort included 350 patients (234 assigned to Niraparib and 116 to placebo). The Primary end point was Progression Free Survival (PFS) and Secondary end points included chemotherapy-free interval, time to first subsequent therapy, Overall Survival and safety.

It was noted that patients in the Niraparib group had a significantly longer Progression Free Survival compared to those in the placebo group. In the gBRCA cohort, the PFS with Niraparib compared to placebo was 21.0 vs. 5.5 months (HR=0.27), in the non-gBRCA cohort for patients who had tumors with Homologous Recombination Deficiency (HRD), the PFS was 12.9 months vs. 3.8 months (HR=0.38) and for the overall non-gBRCA cohort, the PFS was 9.3 months vs. 3.9 months (HR=0.45). The P value was significant for all three comparisons (P<0.001). The most common grade 3 or 4 toxicities in the Niraparib group were thrombocytopenia (34%), anemia (25%), and neutropenia (20%), and this was managed with dose modifications.

The authors concluded that among patients with platinum-sensitive, recurrent ovarian cancer, Niraparib significantly prolonged Progression Free Survival compared to placebo and this benefit was achieved regardless of the presence or absence of gBRCA mutations or HRD status, with acceptable toxicities. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. Mirza MR, Monk BJ, Herrstedt J, et al. N Engl J Med 375:2154-2164, 2016