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

November 25th, 2016

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


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

November 25th, 2016

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


Neoadjuvant Chemotherapy in Advanced Ovarian Cancer – ASCO Clinical Practice Guideline

November 18th, 2016

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 OPDIVO® for Head and Neck Cancer

November 18th, 2016

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


VYXEOS® – A Novel First Line Treatment for High Risk Acute Myeloid Leukemia

November 11th, 2016

SUMMARY: The American Cancer Society estimates that in 2016, 19,950 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,430 patients will die of the disease. Acute Myeloid Leukemia in general is a disease of the elderly and the average age of a patient with AML is about 66 years. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. In general, only 40% of patients younger than 60 years of age survive more than 5 years and 5 year survival for those who relapse after achieving a complete remission (CR) is dismal. Treatment with conventional chemotherapy regimens in elderly patients with secondary AML (sAML) have resulted in poor outcomes. Even though rapid development of new agents against genetic and epigenetic targets is underway, modifications and reformulations of conventional chemotherapy have demonstrated improved outcomes in patients with AML.

CPX-351 (VYXEOS®) is a liposomal formulation of a fixed combination of Cytarabine and Daunorubicin in a 5:1 molar ratio, developed using a platform known as “CombiPlex”. In vitro studies have demonstrated that this ratio maximizes synergy with the lowest level of antagonism and results in preferential uptake of the drug into leukemic cells. In a randomized, open label phase II trial involving patients with or without secondary AML (sAML), CPX-351 improved the composite CR (CRc) rate (Complete Remission and CR with incomplete blood count recovery – CRi) when compared to conventional induction chemotherapy with Daunorubicin and Cytarabine. Those patients with a higher rate of CRc (CR + CRi) had a statistically significant 6 month survival benefit. In another study of AML patients in first relapse, CPX-351 improved median Overall Survival (OS) in poor-risk patients when compared to investigator’s choice of salvage regimens.

On the basis of these studies, the authors conducted a randomized, open-label, phase III trial of first-line CPX-351 in patients with high-risk sAML. Enrolled patients (N=309) were stratified based on AML type (therapy-related AML, AML with a history of MDS with and without prior Hypo Methylating Agent therapy, AML with a history of CMML, or de novo AML with MDS karyotype) and age (60-69 yrs or 70-75yrs). Patients were randomized in a 1:1 ratio to receive either CPX-351 (N=153) 100 units/m2, days 1, 3, 5 or the standard 7+3 (Cytarabine 100 mg/m2/day x 7 days, Daunorubicin 60 mg/m2 days 1, 2, 3) induction therapy (N=156). Both treatment groups were well balanced. The primary end point was Overall Survival (OS) and secondary endpoints included Event Free Survival (EFS), independent blinded assessment of CR+CRi, and 60-day mortality.

The final analysis began after a minimum follow up of 13.7 months. Patients in the CPX-351 group had a significant improvement in Overall Survival compared with standard treatment (HR=0.69; P=0.005; median OS, 9.56 versus 5.95 months). Additionally, there was a significant improvement in Event Free Survival for the CPX-351 group compared to standard therapy (HR=0.74; P=0.021), as well as CR+CRi response (47.7% versus 33.3%; P=0.016) and 60-day mortality (13.7% versus 21.2%). The Complete Remission rates alone were 37.3% and 25.6%, in favor of CPX-351 (P=0.04). Grade 3-5 Adverse Events were similar in frequency and severity in both arms (92% versus 91%) and similar numbers of patients underwent transplantation in both treatment groups.

The authors concluded that treatment with CPX-351 (VYXEOS®) significantly improved Overall Survival, Event Free Survival and Response Rates, without an increase in 60-day mortality or Adverse Events, in elderly patients with high risk secondary AML, when compared with standard induction therapy. CPX-351 reduced the risk of death by 31%. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. Lancet JE, Uy GL, Cortes JE, et al. J Clin Oncol 34, 2016 (suppl; abstr 7000).


FDA Approves PDGFRα Antagonist LARTRUVO® for Soft Tissue Sarcoma

November 11th, 2016

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


Adjuvant Therapy with SUTENT® in High-Risk Renal Cell Carcinoma after Nephrectomy

November 4th, 2016

SUMMARY: The American Cancer Society estimates that about 62,700 new cases of kidney cancer will be diagnosed in the United States in 2016 and over 14,000 patients will die from this disease. The prognosis for patients with Renal Cell Carcinoma (RCC) is dependent on the stage of disease and risk factors. Two validated models, the University of California Los Angeles Integrated Staging System (UISS) and the Stage, Size, Grade, and Necrosis (SSIGN) score were developed, to assess the risk for relapse. UISS is based on ECOG Performance Status, Fuhrman nuclear grading and TNM pathological stage, whereas the SSIGN score takes Stage, Size, Grade and Necrosis into consideration. Approximately 16% of patients with RCC present with Locoregional disease, and up to 40% of these patients relapse with metastatic disease, following nephrectomy. The 5-year survival for locoregional (stage III) disease is 53%, and 8% for metastatic disease. The standard management of high risk patients following nephrectomy has been surveillance, as there has been limited data demonstrating the benefit of adjuvant therapy in reducing the risk of relapse.

SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/ smooth vessel cell wall and is capable of specifically binding to tyrosine kinases, inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® is indicated for the treatment of advanced renal cell carcinoma and in a multi-center, randomized study, demonstrated superior Progression Free Survival and Objective Response Rate, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. The authors in this study examined the efficacy and safety of SUTENT® in patients with locally advanced RCC, at high risk for tumor recurrence, following nephrectomy.

Sunitinib as Adjuvant Treatment for Patients at High Risk of Recurrence of Renal Cell Carcinoma Following Nephrectomy (S-TRAC) is a randomized, double blind, phase III trial in which 615 patients with locoregional, high risk, clear cell Renal Cell Carcinoma were randomly assigned to receive SUTENT® (N=309) or placebo (N=306). Treatment consisted of either SUTENT® 50 mg PO daily or placebo, on a 4-weeks-on, 2-weeks-off schedule, for 1 year or until disease recurrence or unacceptable toxicity. Eligible patients had tumor Stage III or higher, regional lymph node metastasis, or both and were required to have absence of macroscopic residual or metastatic disease after nephrectomy, as confirmed by a CT scan. The primary end point was Disease Free Survival and secondary end points included Overall Survival, and Safety.

It was noted that the median duration of Disease Free Survival was 6.8 years in the SUTENT® group and 5.6 years in the placebo group (HR=0.76; P=0.03). Overall Survival data were not mature at the time of this analysis. Grade 3 or 4 adverse events were more frequent in the SUTENT® group compared to the placebo group and dose reductions, dose interruptions and discontinuations were more frequent in the SUTENT® group as well. The most commonly reported adverse events were skin toxicity (palmar-plantar erythrodysesthesia), hypertension, and fatigue, with declines in quality of life while on active therapy. In a previously published adjuvant trial (ASSURE trial), there was no improvement in Disease Free Survival in patients receiving Sunitinib or Sorafenib as compared with placebo. This has been attributed to the ASSURE trial including many patients with early (Stage 1) tumors as well as those with non-clear cell histology. Additionally, the dosing schedule in the ASSURE trial was lower than this present study.

It was concluded that adjuvant treatment with SUTENT® following nephrectomy in patients with high risk disease, results in significantly improved Disease Free Survival but this benefit may be associated with higher rate of toxicities during treatment. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. Ravaud A, Motzer RJ, Pandha HS, et al. for the S-TRAC Investigators. October 10, 2016DOI: 10.1056/NEJMoa1611406


FDA Approves KEYTRUDA® for Treatment Naïve Patients with Advanced NSCLC

November 4th, 2016

SUMMARY: The FDA on October 24, 2016 approved KEYTRUDA® (Pembrolizumab) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have high PD-L1 expression (Tumor Proportion Score greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC. Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2016 about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Non Small Cell Lung Cancer accounts for approximately 85% of all lung cancers.

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. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced Non Small Cell Lung Cancer (NSCLC) have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is a open-label, randomized, phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for 35 cycles or the investigator’s choice of platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. The primary end point was Progression Free Survival and secondary end points included Overall Survival, Objective Response Rate and safety.

The median PFS was 10.3 months in the KEYTRUDA® group versus 6.0 months in the chemotherapy group (HR=0.50; P<0.001). This benefit was observed across all patient subgroups including tumor histologic type and chemotherapy regimen administered. The estimated Overall Survival at 6 months was 80.2% in the KEYTRUDA® group versus 72.4% in the chemotherapy group (HR=0.60; P=0.005). Patients in the KEYTRUDA® group experienced higher Response Rates than in the chemotherapy group (44.8% vs. 27.8%) as well as longer median duration of response (Not Reached versus 6.3 months). These benefits were realized even after 43.7% of the patients in the chemotherapy group following progression, had crossed over to receive KEYTRUDA®. Adverse events of any grade were less frequent in the KEYTRUDA® group compared to the chemotherapy group, with diarrhea, fatigue and pyrexia being more common in the KEYTRUDA® group whereas anemia, nausea and fatigue were more often noted in the chemotherapy group. As expected, immune-mediated adverse events (including pneumonitis) occurred more frequently with KEYTRUDA® whereas cytopenias occurred more frequently with chemotherapy.

It was concluded that in treatment naïve patients with advanced NSCLC and a PD-L1 tumor proportion score of 50% or greater, KEYTRUDA® was associated with significantly longer Progression Free and Overall Survival and with fewer adverse events, compared with platinum-based chemotherapy. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. Reck M, Rodríguez-Abreu D, Robinson AG, et al. for the KEYNOTE-024 Investigators. October 9, 2016DOI: 10.1056/NEJMoa1606774


KEYTRUDA® (Pembrolizumab)

November 2nd, 2016

The FDA on October 24, 2016 approved KEYTRUDA&reg; for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors express PD-L1, as determined by an FDA-approved test. This is the first FDA approval of a checkpoint inhibitor for first-line treatment of Lung cancer. This approval also expands the indication in second-line treatment of Lung cancer to include all patients with PD-L1-expressing NSCLC. KEYTRUDA&reg; is a product of Merck & Co., Inc.


LARTRUVO® (Olaratumab)

November 2nd, 2016

The FDA on October 19, 2016 granted accelerated approval to LARTRUVO® 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. LARTRUVO® is a product of Eli Lilly and Company.