Author: RR

Late Breaking Abstract – ASH 2016 Superior Efficacy Data with Pacritinib in Myelofibrosis

RR

SUMMARY: Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.

Pacritinib is a potent JAK2 inhibitor, without significant JAK1 inhibition. It additionally targets FLT3, IRAK1, and CSF1R. Preliminary studies have shown minimal myelosuppression with Pacritinib. JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor approved by the FDA in 2011 to treat intermediate or high-risk Myelofibrosis. It is however not indicated for patients with platelet counts under 50,000/μl, and this group represents approximately one third of Myelofibrosis patients and have limited or no treatment options. Previously published PERSIST-1 trial showed that Pacritinib significantly reduced Spleen Volume and Myelofibrosis associated symptoms, in patients with low platelet count, when compared to Best Available Therapy (excluding JAKAFI®).

PERSIST-2 is an open label, phase III study in which the safety and efficacy of Pacritinib was compared with currently available therapies, including JAKAFI®, thus expanding the definition of Best Available Therapy (BAT). A total of 311 patients with platelet counts 100,000/μl or less were randomly assigned in a 1:1:1 ratio to receive Pacritinib 200 mg BID (N=107), 400 mg QD (N=104) or Best Available Therapy (N=100). The efficacy population in the Intent To Treat group included a total of 221 patients. Approximately half of the study population had platelet counts of less than 50,000/μl. Over 40% of the patients in both the treatment groups had prior therapy with JAKAFI®. About 60-70% of the patients had a diagnoses of Primary Myelofibrosis, and half of the patients fell in the International Prognostic Scoring System (IPSS) Intermediate-2 risk category. The two coprimary endpoints were the proportion of patients achieving 35% or greater reduction in Spleen Volume (SVR) as measured by MRI or CT scan and the proportion achieving a 50% or more improvement in symptoms such as fatigue, bone pain, itching, and abdominal pain after 24 weeks of follow up. The secondary objectives were to compare Pacritinib BID and Pacritinib QD, individually to BAT.

It was noted that 18% of patients who received Pacritinib achieved a 35% or greater reduction in Spleen Volume from baseline to week 24, compared to 3% of those in the BAT group (P=0.001). In the patient group who received Pacritinib twice daily, 32% reported a 50% or more reduction in symptoms compared with 14% in the BAT group (P=0.01). Further, patients treated with Pacritinib required fewer red blood cell transfusions and additionally, patients who received Pacritinib twice daily had substantially greater improvement in platelet count among those who had platelets counts 50,000/μl or less at enrollment. The most common adverse events related to Pacritinib included nausea, vomiting, diarrhea, anemia, and low platelets.

The authors concluded that this is the only randomized trial to date in patients with Myelofibrosis and thrombocytopenia that enrolled patients who had prior therapy with a JAK2 inhibitor. Regardless, Pacritinib was more effective at Spleen Volume Reduction than BAT and Pacritinib given BID was even more effective than QD dosing. Results of the Persist-2 Phase 3 Study of Pacritinib (PAC) Versus Best Available Therapy (BAT), Including Ruxolitinib (RUX), in Patients (pts) with Myelofibrosis (MF) and Platelet Counts <100,000/µl. Hoffman R, Talpaz M, Gerds AT, et al. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract LBA-5.

Late Breaking Abstract – ESMO 2016 FASLODEX® Superior to ARIMIDEX® as Initial Therapy in Advanced Breast Cancer

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 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 60-65% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol, in extragonadal/peripheral tissues. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. FASLODEX® (Fulvestrant) is an estrogen antagonist and like NOLVADEX®, binds to estrogen receptors (ERs) competitively, but unlike NOLVADEX® causes rapid degradation and loss of ER protein (ER downregulator), and is devoid of ER agonist activity.

The superiority of ARIMIDEX® over NOLVADEX® was first established in the year 2000 following the publication of the results of a North American Multicenter Randomized Trial. In this study, ARIMIDEX® as first-line treatment in postmenopausal women with advanced breast cancer resulted in a significant increase in Time To Progression and a lower incidence of thromboembolic events and vaginal bleeding, compared to NOLVADEX®. In a previously reported phase II study (FIRST trial), first-line treatment with FASLODEX® significantly improved Time To disease Progression and Overall Survival compared with ARIMIDEX®, in patients with hormone receptor (HR) positive advanced breast cancer.

The FALCON trial is a phase III study conducted to confirm findings from the FIRST trial. This study included 462 postmenopausal women, with locally advanced or metastatic hormone receptor positive, HER2-negative, endocrine-therapy naive breast cancer. Patients were randomized to receive FASLODEX® IM at 500 mg on days 0, 1, and 28 and then every 28 days (N=230) or ARIMIDEX® 1 mg PO daily (N=232). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was Progression Free Survival (PFS), and secondary endpoints included Overall Survival, Objective Response Rate, Clinical Benefit Rate, Duration of Response, health-related Quality of Life, and safety.

It was noted that FASLODEX® provided better disease control with a median PFS of 16.6 months compared to 13.8 months with ARIMIDEX® (P=0.048). Subgroup analysis showed that FASLODEX® was markedly superior to ARIMIDEX® in patients with non-visceral disease with a median Progression Free Survival of 22.3 months compared with 13.8 months for ARIMIDEX®. There was no significant improvement in the Overall Response Rate between the treatment groups. However, the median Duration of Response was 20.0 months with FASLODEX® compared to 13.2 months with ARIMIDEX®. Expected Duration of response and expected Duration of Clinical Benefit were in favor of FASLODEX® (11.4 vs 7.5 months; P=0.001) and (21.9 vs 17.5 months; P=0.001), respectively. There was no difference in Overall Survival at the time of this analysis. Rates of adverse events were similar in both treatment groups.

The authors concluded that FASLODEX® was superior to ARIMIDEX® as initial treatment of hormone receptor positive, endocrine therapy naive, advanced breast cancer. Patients with non-visceral and low volume disease, as well as elderly patients, may benefit the most with FASLODEX®, as this therapy is well tolerated with a low toxicity profile. FALCON: a phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer. Ellis MJ, Bondarenko I, Trishkina E, et al. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA14.

ASH – 2016 Discontinuing Tyrosine Kinase Inhibitors is Feasible in Some Patients with CML

RR

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,220 new CML cases will be diagnosed in the United States in 2016 and about 1,070 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC® (Imatinib), share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected, using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that Deep Molecular Response (BCR-ABL <0.01% on the International Scale – MR4) is a new molecular predictor of long term survival in CML patients and this was achieved in a majority of patients treated with optimized dose of GLEEVEC®. It has been hypothesized based on previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, stopping CML therapy is currently not a clinical recommendation and should only be considered in the context of a clinical trial.

The European Stop TKI (EURO-SKI) trial was conducted to assess the safety of stopping Tyrosine Kinase Inhibitor therapy in patients with CML, whose leukemia was in Deep Molecular Response (DMR). This trial enrolled 821 patients with chronic phase CML without prior TKI failure, in DMR (BCR-ABL <0.01% on the International Scale – MR4) for at least one year, following treatment with either Imatinib, Nilotinib or Dasatinib. Following cessation of treatment with TKIs, patients were followed up testing by RQ-PCR (Real-time Quantitative Polymerase Chain Reaction) every 4 weeks for the first 6 months followed by every 6 weeks, the first year and every 3 months thereafter. Molecular recurrence was defined by the loss of the Major Molecular Response (BCR-ABL <0.1% IS – MR3) at any one point.

It was noted that after stopping TKI therapy, 62% showed no evidence of molecular recurrence at 6 months, and 52% showed no recurrence at 24 months. Patients who had taken a TKI for more than 5.8 years before stopping, were significantly less likely to experience relapse within the first 6 months and had a Molecular Relapse Free Survival at 6 months of 65.5% compared with 42.6% for those on treatment for 5.8 years or less. Further, each additional year of TKI therapy increased a patient’s chances of maintaining Major Molecular Response successfully at 6 months by 16%, after TKI therapy was discontinued. Most of the patients who experienced molecular recurrence were able to regain their previous remission level, after resuming TKI therapy and none of the patients in the study had progression to advanced stage.

The authors concluded that stopping TKI therapy of CML patients appeared safe and feasible in over 50% of the patients and longer duration of therapy with TKIs (5.8 years or more) prior to stopping therapy with TKIs, was associated with a higher probability of Molecular Recurrence Free Survival. Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial. Mahon F-X, Richter J, Guilhot J, et al. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 787.

Immediate Androgen Deprivation Therapy Confers Survival Benefit in Prostate Cancer Patients with Biochemical Recurrence

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 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease. The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. The American Urological Association suggested that a PSA of 0.2 ng/mL or higher after Radical Prostatectomy, defines PSA failure or relapse. A PSA rise 2 ng/ml or more above post Radiation Therapy nadir is considered PSA failure or relapse. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent 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. The appropriate time (immediate versus delayed) to start Androgen Deprivation Therapy in patients with prostate cancer with rising PSA, as the only sign of relapse, has remained unclear. This has been partly due to lack of patient accruals and patient reluctance to be randomized, in these clinical trials.

The authors conducted a randomized, prospective, phase III trial, to determine if immediate intervention with Androgen Deprivation Therapy (ADT) would improve Overall Survival (OS), compared with delayed ADT, in prostate cancer patients with PSA relapse, following previous attempted curative therapy (radiotherapy or surgery with or without postoperative radiotherapy) or in those considered not suitable for curative treatment (because of age, comorbidity or locally advanced disease). This analysis combined prostate cancer patients with PSA relapse enrolled in two separate studies. Two hundred and ninety three (N=293) eligible patients were randomly assigned 1:1 to immediate Androgen Deprivation Therapy (N= 142) or delayed ADT (N=151). The primary endpoint was Overall Survival. Secondary endpoints included Cancer-Specific Survival and Time to Clinical Progression. The median follow up was 5 years.

There was a statistically significant improvement in the Overall Survival, with a 45% reduction in the risk for death, for those receiving immediate ADT compared with the delayed treatment group (HR=0.55; P=0.05). Further, with immediate ADT, there was a statistically significant delay in the time to first local progression (HR= 0.51; P=0.001).

The authors concluded that immediate Androgen Deprivation Therapy significantly improved Overall Survival and Time to Clinical Progression for prostate cancer patients with PSA relapse, following immediate intervention with Androgen Deprivation Therapy. This benefit however must be weighed against the risks associated with long term Androgen Deprivation Therapy. Immediate ADT may be appropriate for patients with high risk features at the time of initial diagnosis, who present with early biochemical relapse after initial treatment and have a rapid PSA doubling time (less than 6 months). Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Duchesne GM, Woo HH, Bassett JK, et al. Lancet Oncol 2016;17:727-737

Prolonged Survival with FOLFIRINOX Regimen in Locally Advanced Pancreatic Cancer

RR

SUMMARY: The American Cancer Society estimates that in 2016, over 53,000 people will be diagnosed with Pancreatic cancer in the United States and close to 42,000 patients will die of the disease. Some important risk factors for Pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Approximately 35% of patients with Pancreatic cancer have unresectable, locally advanced disease at diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the Pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease.

In a previously published study (N Engl J Med 2011; 364:1817-1825), FOLFIRINOX regimen, a combination of Fluorouracil, Leucovorin, Irinotecan (CAMPTOSAR®) and Oxaliplatin (ELOXATIN®) was significantly superior to single agent Gemcitabine (GEMZAR®), as first-line therapy, in patients with metastatic Pancreatic cancer. FOLFIRINOX resulted in a significantly improved median Overall Survival (OS), median Progression Free Survival (PFS) and Objective Response Rate (ORR).

The researchers in this study evaluated the effectiveness of FOLFIRINOX as first-line treatment in patients with newly diagnosed, locally advanced, unresectable Pancreatic cancer. The authors searched large databases for studies which involved treatment-naive patients of any age, who had received FOLFIRINOX as first-line treatment for locally advanced Pancreatic cancer. They were able to include 689 patients from 13 studies, of whom 355 (52%) patients had locally advanced Pancreatic cancer. FOLFIRINOX regimen consisted of Oxaliplatin 85mg/m2 IV over 2 hours, followed by Leucovorin 400mg/m2 IV over 2 hours given concomitantly with Irinotecan 180mg/m2 IV over 90 minutes, followed by 5-FU 400 mg/m2 IV bolus and 5-FU 2400 mg/m2 given as a 46 hour continuous infusion, with this cycle repeated every 2 weeks. The median number of administered cycles ranged from 3-11 cycles. In his retrospective review, the authors looked at Overall Survival as the Primary outcome. Secondary outcomes were Progression Free Survival, rates of Grade 3 or 4 toxicities, proportion of patients who underwent Radiotherapy or Chemoradiotherapy, surgical resection after FOLFIRINOX and R0 resection (margin-negative resection microscopically, with no gross or microscopic tumor present in the primary tumor bed).

It was noted that across studies, the pooled median OS was 24.2 months, median PFS was 15 months, Grade 3 or 4 adverse events were 60 events per 100 patients and no deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent Radiotherapy or Chemoradiation after FOLFIRINOX ranged from 31% to 100% across studies and the pooled proportion of patients who received any Radiotherapy treatment was 63.5%. The pooled proportion of patients who had surgical resection was 25.9% and the pooled proportion of patients who had R0 resection was 78.4%. There was no significant correlation found across studies, between the median number of FOLFIRINOX cycles administered and median Overall Survival.

The authors concluded that patients with locally advanced Pancreatic cancer treated with FOLFIRINOX had a longer median Overall Survival (24.2 months), compared with single agent GEMZAR® (6-13 months) and future studies should establish which patients might benefit from Radiotherapy or Chemoradiotherapy or Surgical resection, following treatment with FOLFIRINOX. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Suker M, Beumer BR, Sadot, F, et al. Lancet Oncol 2016;17:801-810.

IBRANCE® plus FEMARA® – A New Standard for Previously Untreated Advanced Breast Cancer

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 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 60-65% 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 cancels it 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. IBRANCE® (Palbociclib) is a reversible, oral, selective, small molecule inhibitor of Cyclin Dependent Kinases, CDK4 and CDK6, and prevents RB1 phosphorylation. IBRANCE® is the first CDK inhibitor approved by the FDA. It exhibits synergy when combined with endocrine therapies. The FDA in February 2016, approved IBRANCE® in combination with FASLODEX® (Fulvestrant), for the treatment of women with Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2) negative advanced or metastatic breast cancer, with disease progression following endocrine therapy. In a phase II study, a combination of IBRANCE® plus FEMARA® showed improved Progression Free Survival compared with FEMARA® alone, in the initial treatment of postmenopausal women with Estrogen-Receptor (ER) positive, HER2 negative advanced breast cancer. Based on this encouraging data, a phase III study was conducted, to confirm the efficacy and safety of IBRANCE® plus FEMARA® for this patient group.

In this double blind study (PALOMA-2), 666 postmenopausal women with ER positive, HER2 negative breast cancer, who had no prior therapy for advanced disease, were randomly assigned, in a 2:1 ratio to receive IBRANCE® plus FEMARA® (N=444) or placebo plus FEMARA® (N=222). IBRANCE® was administered at 125 mg PO daily, 3 weeks on and 1 week off, every 4 weeks and all patients received FEMARA® 2.5 mg PO daily . The median age was 62 years, 48% had visceral disease and 63% had prior systemic therapy for breast cancer. The primary end point was Progression Free Survival and secondary end points included Overall Survival, Objective Response Rate, Clinical Benefit Response and safety.

The median PFS was 24.8 months in the IBRANCE® plus FEMARA® group compared with 14.5 months in the placebo plus FEMARA® group (HR=0.58; P<0.001). This benefit was seen across all patient subgroups. The Objective Response Rate was 42% with the IBRANCE® plus FEMARA® combination and 35% with the placebo plus FEMARA® combination. The Clinical Benefit Response (complete response, partial response or stable disease for 24 weeks or more) was 84% in the IBRANCE® plus FEMARA® group and 71% in the placebo plus FEMARA® group (P<0.001). The most common grade 3 or 4 adverse events were neutropenia noted in 66% of the patients in the IBRANCE® group versus 1.4% in the placebo plus FEMARA® group. Approximately 10% of the patients in the IBRANCE® group permanently discontinued study treatment due to toxicities and 6% did so in the placebo plus FEMARA® group.

The authors concluded that a combination of IBRANCE® and FEMARA® significantly prolonged Progression Free Survival compared with FEMARA® alone, among patients with previously untreated ER-positive, HER2 negative advanced breast cancer and this combination should be the new standard of care for this patient group. Palbociclib and Letrozole in Advanced Breast Cancer. Finn RS, Martin M, Rugo HS, et al. N Engl J Med 2016; 375:1925-1936

Superior Outcomes with REVLIMID® and Dexamethasone in Elderly Patients with Multiple Myeloma

RR

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, about 30,330 new cases will be diagnosed in 2016 and 12,650 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Nonetheless, patients 75 years or older, are often under-represented in clinical trials because of increased comorbidities and altered pharmacodynamics. This group of elderly, newly diagnosed Multiple Myeloma patients, who are ineligible for Stem Cell Transplantation (SCT), are often treated with combination therapies such as Melphalan, Prednisone, and Thalidomide (MPT), VELCADE® (Bortezomib), Melphalan, and Prednisone (VMP) or REVLIMID® (Lenalidomide) and low dose Dexamethasone (Rd). However there is limited data regarding the efficacy and safety of front line use of REVLIMID® in this patient group.

The FIRST (Frontline Investigation of REVLIMID® Plus Dexamethasone Versus Standard Thalidomide) trial is a randomized, global, phase III trial, in which the efficacy and safety of REVLIMID® and Dexamethasone, given until disease progression or for a fixed number of cycles, was compared with MPT given for a fixed number of cycles, in patients with newly diagnosed Multiple Myeloma, who were ineligible for Stem Cell Transplantation. A total of 1,623 patients were randomly assigned patients in a 1:1:1 ratio to receive REVLIMID® and Dexamethasone (Rd continuous) in 28 day cycles until disease progression, REVLIMID® and Dexamethasone (Rd18) in 28 day cycles for 72 weeks (18 cycles), or MPT in 42 day cycles for 72 weeks (12 cycles). In both REVLIMID® groups, patients received REVLIMID® 25 mg orally daily on days 1 – 21 of each 28 day cycle, and Dexamethasone 40 mg orally on days 1, 8, 15, and 22. Patients in the MPT group received Melphalan 0.25 mg/kg/day orally on days 1- 4, Prednisone 2 mg/kg/day orally on days 1- 4 and Thalidomide 200 mg orally daily, administered in 42 day cycles. The median patient age was 73 years and 35% of the patients were older than 75 years. Patients were stratified by age (75 years or less versus more than 75 years) and disease stage. The Primary end point was Progression Free Survival (PFS) and Secondary end point included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), time to first response and Time to Treatment Failure. The primary objective was to compare the efficacy of Rd continuous with MPT.

In this updated analysis after a median follow up of 45.5 months, Rd continuous reduced the risk of progression or death by 31% compared with MPT (HR=0.69; P<0.001) overall. In patients 75 years or younger, Rd continuous reduced the risk of progression or death by 36% (HR=0.64; P<0.001) and by 20% (HR=0.80; P=0.08) in those older than 75 years. Patients in the Rd continuous group also had a longer median Overall Survival than those in the MPT group regardless of age, and there was a 14 month Overall Survival advantage for the group of patients 75 years or older. In the Rd continuous group, grade 3-4 adverse events were similar across age groups although older patients had more frequent REVLIMID® dose reductions.

The authors concluded that the FIRST study results, with the largest cohort of patients 75 years or older, support Rd continuous treatment as a new standard of care for Stem Cell Transplantation-ineligible patients with newly diagnosed Multiple Myeloma. Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan, Prednisone, and Thalidomide in the Randomized, Phase III FIRST Trial Hulin C, Belch A, Shustik C, et al. J Clin Oncol 2016;34:3609-3617

FDA Approves OPDIVO® for Head and Neck Cancer

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SUMMARY: The FDA on November 10, 2016, approved OPDIVO® (Nivolumab) for the treatment of patients with recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), with disease progression on or after a Platinum-based therapy. The American Cancer Society estimates that 61,760 people will be diagnosed with Head and Neck cancer in 2016 and 13,190 patients will die of the disease. Patients with recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck have a poor prognosis with a median Overall Survival (OS) of about 13 months with first line therapy and about 6 months or less with later lines of therapy. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of immune evasion and the role of 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. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. 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 blocking the Immune checkpoints, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody that has demonstrated antitumor efficacy in multiple tumor types. The FDA approval of OPDIVO® for the treatment of recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), was based on the results of CheckMate-141 study which is a randomized, open label, phase III trial. In this study, 361 patients with recurrent Squamous Cell Carcinoma of the Head and Neck (cancer of the oral cavity, pharynx, or larynx), whose disease had progressed within 6 months after Platinum-based chemotherapy, were randomly assigned, in a 2:1 ratio to receive OPDIVO® (N=240) or investigator’s choice of a standard, single agent therapy (N=121). OPDIVO® was administered at a dose of 3 mg/kg every 2 weeks, whereas standard therapy consisted of either weekly Methotrexate at a dose of 40-60 mg/m2 IV, weekly Docetaxel at a dose of 30-40 mg/m2 IV or Cetuximab administered at a loading dose of 400 mg/m2 followed by 250 mg/m2 IV weekly. The median age was 60 years, over 90% had received prior radiation therapy and 54.5% of the patients had received 2 or more lines of prior systemic therapies. The primary end point was Overall Survival and secondary end points included Progression Free Survival, Objective Response Rate, safety, and patient-reported quality of life measures. Prespecified analysis of Overall Survival according to tumor PD-L1 expression and p16 status was also performed.

The median Overall Survival was 7.5 months in the OPDIVO® group versus 5.1 months for the group that received standard therapy and this improvement was statistically significant (HR=0.70; P=0.01). The estimated 1-year survival rate was 36% in the OPDIVO® group and 16.6% with standard therapy. The median Progression Free Survival was 2.0 months with OPDIVO® versus 2.3 months with standard therapy and the rate of Progression Free Survival at 6 months was 19.7% with OPDIVO® versus 9.9% with standard therapy. The Objective Response Rate was 13.3% in the OPDIVO® group versus 5.8% in the standard therapy group. Even though preliminary biomarker analysis suggested that patients with a tumor PD-L1 expression level of 1% or more, or p16-positive tumors, or both, benefited more from OPDIVO® therapy than those whose PD-L1 level was less than 1% or who had p16-negative tumors, these interactions were not statistically significant. Treatment-related grade 3 or 4 adverse events were more common in the standard therapy group (35%) versus OPDIVO® group (13%) and quality of life measures were stable in the OPDIVO® group and were worse for those who received standard therapy.

The authors concluded that OPDIVO® prolonged survival, as compared with standard therapy, among patients with Platinum-refractory Squamous Cell Carcinoma of the Head and Neck and this benefit was accomplished with fewer toxicities, compared with standard therapy. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. Ferris RL, Blumenschein G, Fayette J, et al. N Engl J Med 2016; 375:1856-1867

Neoadjuvant Chemotherapy in Advanced Ovarian Cancer – ASCO Clinical Practice Guideline

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SUMMARY: The American Cancer Society estimates that over 22,280 women will be diagnosed with ovarian cancer in the United States for 2016 and over 14,240 will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. For the past 40 years, primary cytoreductive surgery followed by chemotherapy has been the standard approach, for women with advanced epithelial ovarian cancer. The benefit of neoadjuvant chemotherapy followed by interval debulking surgery was recognized in the early 1990’s, especially when treating those with advanced age, stage and associated comorbidities. An Expert Panel from the Society of Gynecologic Oncology and the American Society of Clinical Oncology conducted a systematic review of the literature and the primary evidence for these recommendations is based on four phase III clinical trials. The following recommendations are meant to provide guidance to Health Care Providers regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer. The following clinical questions were addressed:

What clinical evaluations should be performed in all women with suspected or newly diagnosed stage IIIC or IV epithelial ovarian cancer?

Recommendation 1.1. All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy to determine whether they are candidates for primary cytoreductive surgery.

Recommendation 1.2. A primary clinical evaluation should include a CT scan of the abdomen and pelvis with Oral and IV contrast and chest imaging (CT preferred), to evaluate the extent of disease and feasibility of surgical resection. The use of other tools to refine this assessment may include laparoscopic evaluation or additional radiographic imaging such as PET scan or MRI.

Which patient and disease factors should be used as criteria for identifying patients who are not suitable for primary cytoreductive surgery?

Recommendation 2.1. Women who have a high perioperative risk profile, or a low likelihood of achieving cytoreduction to less than 1 cm, ideally to no visible disease, should receive neoadjuvant chemotherapy.

Recommendation 2.2. Decisions that women are not eligible for medical or surgical cancer treatment, should be made after consultation with a gynecologic oncologist and/or a medical oncologist with gynecologic expertise.

How do neoadjuvant chemotherapy and primary cytoreductive surgery compare with respect to progression-free survival, overall survival, and perioperative morbidity and mortality in women who are fit for primary cytoreduction and have potentially resectable disease, and how should this information be used to select initial treatment?

Recommendation 3.1. For women who are fit for primary cytoreductive surgery, with potentially resectable disease, either neoadjuvant chemotherapy or primary cytoreductive surgery may be offered, based on data from phase III randomized, controlled trials that demonstrate neoadjuvant chemotherapy is noninferior to primary cytoreductive surgery with respect to Progression Free and Overall Survival. Neoadjuvant chemotherapy is associated with less peri- and postoperative morbidity and mortality and shorter hospitalizations, but primary cytoreductive surgery may offer superior survival in selected patients.

Recommendation 3.2. For women with a high likelihood of achieving cytoreduction to less than 1 cm (ideally to no visible disease) and with acceptable morbidity, primary cytoreductive surgery is recommended over neoadjuvant chemotherapy.

Recommendation 3.3. For women who are fit for primary cytoreductive surgery but are deemed unlikely to have cytoreduction to less than 1 cm (ideally to no visible disease) by a gynecologic oncologist, neoadjuvant chemotherapy is recommended over primary cytoreductive surgery. Neoadjuvant chemotherapy is associated with less peri and postoperative morbidity and mortality and shorter hospitalizations.

What additional clinical evaluations should be performed in women with suspected or newly diagnosed stage IIIC or IV epithelial ovarian cancer before neoadjuvant chemotherapy is delivered?

Recommendation 4. Before neoadjuvant chemotherapy is delivered, all patients should have histologic confirmation (core biopsy preferred) of an invasive ovarian, fallopian tube, or peritoneal cancer. In exceptional cases, when a biopsy cannot be performed, cytologic evaluation combined with a serum CA-125 to carcinoembryonic antigen (CEA) ratio more than 25 is acceptable, to confirm the primary diagnosis and exclude a non-gynecologic cancer.

What is the preferred chemotherapy regimen for women with stage IIIC or IV epithelial ovarian cancer who will receive neoadjuvant chemotherapy?

Recommendation 5. For neoadjuvant chemotherapy, a Platinum-Taxane doublet is recommended. However, alternative regimens, containing a Platinum agent, may be selected based on individual patient factors.

Among women treated with neoadjuvant chemotherapy, does the timing of interval cytoreduction or the number of chemotherapy cycles after interval cytoreduction affect the safety or efficacy of treatment?

Recommendation 6. Randomized, controlled trials tested surgery following three or four cycles of chemotherapy in women who had a response to neoadjuvant chemotherapy or stable disease. Interval cytoreductive surgery should be performed after up to four cycles of neoadjuvant chemotherapy for women with a response to chemotherapy or stable disease. Alternative timing of surgery has not been prospectively evaluated but may be considered based on patient-centered factors.

What are the treatment options for patients with progressive disease on neoadjuvant chemotherapy?

Recommendation 7. Patients with progressive disease on neoadjuvant chemotherapy have a poor prognosis. Options include alternative chemotherapy regimens, clinical trials, and/or discontinuation of active cancer therapy and initiation of end-of-life care. In general, there is little role for surgery, and it is not typically advised, unless for palliation such as relief of bowel obstruction. Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline. Wright AA, Bohlke K, Armstrong DK, et al. Journal of Clinical Oncology 2016;34:3460-3473

FDA Approves PDGFRα Antagonist LARTRUVO® for Soft Tissue Sarcoma

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SUMMARY: The FDA on October 19, 2016 granted accelerated approval to LARTRUVO® (Olaratumab) for the treatment of patients with Soft Tissue Sarcoma (STS), not amenable to curative treatment with radiotherapy or surgery, and with a histologic subtype for which an anthracycline containing regimen is appropriate. The American Cancer Society estimates that in 2016, about 12,310 new soft tissue sarcomas will be diagnosed in the United States and 4,990 patients will die of the disease. The most common types of Soft Tissue Sarcomas in adults are undifferentiated pleomorphic sarcoma (previously called Malignant Fibrous Histiocytoma), Liposarcoma, and Leiomyosarcoma. Patients with advanced Soft Tissue Sarcomas are often treated with a Doxorubicin based chemotherapy regimen and the median Overall Survival (OS) for those treated is 12-16 months.

LARTRUVO® is a human IgG1 monoclonal antibody that binds to human PDGFRα with high affinity and blocks PDGFs (Platelet Derived Growth Factors) such as PDGF-AA, PDGF-BB, and PDGF-CC ligands, from binding to the receptor. Coexpression of PDGFRα and PDGFs, with associated autocrine-mediated cell growth, has been implicated in Sarcomas and Glioblastomas. Platelet Derived Growth Factor Receptor α (PDGFRα) is expressed in multiple tumor types and its aberrant activation may facilitate cancer development and spread.

The approval of LARTRUVO® was based on data from a randomized phase II study of Doxorubicin plus LARTRUVO® treatment, in patients with unresectable (locally advanced) or metastatic Soft Tissue Sarcoma (STS). In this pivotal trial, 133 patients with metastatic STS were randomized in a 1:1 ratio to receive LARTRUVO® plus Doxorubicin (N=66) or Doxorubicin alone (N=67). Enrolled patients had metastatic STS not amenable to curative treatment with surgery or radiotherapy, and a histologic type of sarcoma for which an anthracycline-containing regimen was appropriate, but had not been administered. LARTRUVO® was administered at 15 mg/kg as an IV infusion on days 1 and 8 of each 21-day cycle. All patients received doxorubicin 75 mg/m2 as an IV infusion on day 1 of each 21-day cycle for maximum of eight cycles. Single-agent LARTRUVO® was offered to patients in the Doxorubicin alone arm at the time of disease progression. The median patient age in the combination arm was 58.5 years and 88% of patients were positive for PDGFRα. Over a third of the enrolled patients had Leiomyosarcoma and over 25 different STS histologies were included in this study.

It was noted that there was a statistically significant improvement in Overall Survival (OS) for the combination treatment group with a median OS of 26.5 months compared to 14.7 months for those receiving Doxorubicin alone (HR=0.52; P<0.05). The median Progression Free Survival (independent review) was 8.2 months for patients in the combination group and 4.4 months for those receiving Doxorubicin alone (HR=0.74) and the Overall Response Rate (independent review) was 18% in the combination group and 8% in the Doxorubicin alone group. The most common (greater than or equal to 20%) side effects of treatment with LARTRUVO® were nausea, fatigue, neutropenia, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache. Infusion related reactions were seen in 13% of patients.

It was concluded that the combination of LARTRUVO® with Doxorubicin reduced the risk of death by 48% compared with Doxorubicin alone, for patients with advanced STS and is the first new therapy approved by the FDA for the initial treatment of Soft Tissue Sarcoma since the approval of Doxorubicin, more than 4 decades ago. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Tap WD, Jones RL, Van Tine BA, et al. Lancet. 2016;388:488-497