YERVOY® (Ipilimumab)

The FDA on October 28, 2015 approved YERVOY® injection for the additional indication of adjuvant treatment of patients with Cutaneous Melanoma, with pathologic involvement of regional lymph nodes of more than 1 mm, who have undergone complete resection, including total lymphadenectomy. YERVOY® is a product of Bristol-Myers Squibb Company.

YONDELIS® (Trabectedin)

The FDA on October 23, 2015 approved YONDELIS®) for the treatment of patients with unresectable or metastatic Liposarcoma or Leiomyosarcoma who have received a prior Anthracycline-containing regimen. YONDELIS® injection is a product of Janssen Biotech, Inc.

ONIVYDE® (Irinotecan liposome injection)

The FDA on October 22, 2015 approved ONIVYDE® injection, administered in combination with Fluorouracil (5-FU) and Leucovorin, for the treatment of patients with metastatic Adenocarcinoma of the Pancreas, whose disease has progressed following Gemcitabine-based therapy. ONIVYDE® injection is a product of Merrimack Pharmaceuticals, Inc

PRAXBIND® (Idarucizumab)

The FDA on October 16, 2015 granted accelerated approval to PRAXBIND® for the treatment of patients treated with PRADAXA® (Dabigatran), when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. PRAXBIND® injection is a product of Boehringer Ingelheim Pharmaceuticals, Inc.

FDA Approves OPDIVO® for Renal Cell Carcinoma

SUMMARY: The FDA on November 23, 2015 approved OPDIVO® (Nivolumab) for the treatment of advanced Renal Cell Carcinoma in patients who have received prior anti-angiogenic therapy. The American Cancer Society estimates that about 61,560 new cases of kidney cancer will be diagnosed in the United States in 2015 and over 14,000 patients will die from this disease. The understanding of the Immune checkpoints has lead to the development of novel immunotherapies. Immune checkpoints or gate keepers 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 may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. 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 PD-1(Programmed cell Death-1), etc. Following inhibition of PD-1 by specific antibodies, T cells are unleashed, resulting in T cell proliferation and activation with subsequent therapeutic responses. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® in previously reported studies demonstrated an Objective Response Rate (ORR) of 20-22% and an Overall Survival (OS) of 18-25 months in previously treated patient with metastatic Renal Cell Carcinoma. AFINITOR® (Everolimus) is an inhibitor of mTOR (Mammalian Target of Rapamycin), which is a serine/threonine kinase. With the inhibition of mTOR, protein synthesis is down regulated resulting in decreased angiogenesis, cell proliferation and survival. AFINITOR® is presently indicated for the treatment of patients with advanced Renal Cell Carcinoma after failure, following treatment with SUTENT® (Sunitinib) or NEXAVAR® (Sorafenib) and has demonstrated improved median Progression Free Survival compared to placebo.

The FDA approval of OPDIVO® for Renal Cell Carcinoma (RCC), was based on a randomized, open-label, phase III study, in which 821 previously treated patients with advanced clear cell RCC, were randomly assigned in a 1:1 ratio to receive either OPDIVO® (N=410) or AFINITOR® (N=411). Treatment consisted of OPDIVO® 3 mg/kg IV every 2 weeks or AFINITOR® 10 mg PO daily. Enrolled patients had received prior treatment with one or two regimens of anti-angiogenic therapy which included SUTENT® (Sunitinib), VOTRIENT® (Pazopanib) and INLYTA® (Axitinib). The median age was 62 years. The primary end point was Overall Survival and secondary end points included Objective Response Rate and safety.

It was noted that the median Overall Survival in the OPDIVO® group was 25 months and 19.6 months in the AFINITOR® group, and this meant a 27% reduction in the risk of death with OPDIVO® (HR=0.73; P=0.002). This survival benefit was noted regardless of the PD-L1 expression level of the patient’s kidney tumors. The Objective Response Rate was greater with OPDIVO® compared with AFINITOR® (25% vs 5%; P<0.001) and the median Progression Free Survival was 4.6 months with OPDIVO® and 4.4 months with AFINITOR® (HR=0.88; P=0.11). Treatment related grade 3 or 4 adverse events occurred in 19% of the patients receiving OPDIVO® and in 37% of the patients receiving AFINITOR®.

The authors concluded that OPDIVO® significantly improved Overall Survival in patients with previously treated metastatic Renal Cell Carcinoma and is one of the few therapies with survival benefit, in this patient population. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. Motzer RJ, Escudier B, Dermott DF, et al. for the CheckMate 025 Investigators. N Engl J Med 2015; 373:1803-1813

FDA Approves First Oral Triplet Combination (NINLARO®, REVLIMID® and Dexamethasone) for Multiple Myeloma

SUMMARY: The FDA on November 20, 2015, approved NINLARO® (Ixazomib) in combination with REVLIMID® (Lenalidomide) and Dexamethasone for the treatment of patients with Multiple Myeloma who have received at least one prior therapy. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, close to 27,000 new cases will be diagnosed in 2015 and 11,240 will die of the disease. Proteasomes are enzymes found in cells and they enable the breakdown of abnormal or mutant proteins. The amino acids from these proteins are recycled to make new proteins. Myeloma cells depend on the proteasomes to facilitate this metabolic function, to regulate their growth and survival. NINLARO® (Ixazomib) unlike VELCADE® (Bortezomib), is a second generation, oral, proteasome inhibitor, which disrupts protein metabolism in Myeloma cells, by inhibiting proteasomes and has an antiproliferative and pro-apoptotic effect.

The approval of NINLARO® was based a pivotal, multicenter, randomized, double-blind, placebo-controlled, phase III trial (TOURMALINE-MM1 study), in which 722 patients with Multiple Myeloma were randomized in a 1:1 ratio to receive either a combination of NINLARO®, REVLIMID® and Dexamethasone (N=360) or a combination of Placebo, REVLIMID® and Dexamethasone (n=362). NINLARO® was administered at 4 mg PO on days 1, 8, and 15 in combination with REVLIMID® 25 mg PO on days 1 thru 21 and Dexamethasone 40 mg PO on days 1, 8, 15, and 22 of a 28 day treatment cycle. Treatment was continued until disease progression or unacceptable toxicity. Enrolled patients had received 1 to 3 prior lines of therapy, which included VELCADE® (69%), THALOMID® (45%), and REVLIMID® (12%) and 77% of the patients had relapsed Multiple Myeloma. The median age of patients was 66 years. The primary end point of the study was Progression Free survival (PFS) and secondary endpoints included Objective Response Rate (ORR), safety, and Overall Survival.

At a prespecified interim analysis, the median PFS with the combination arm of NINLARO®, REVLIMID® and Dexamethasone was 20.6 months compared with 14.7 months for the combination group of Placebo, REVLIMID® and Dexamethasone (HR= 0.74, P=0.012).Secondary end points data was not mature at the time of this analysis. Patients in the NINLARO® group experienced more adverse events which included cytopenias, vomiting, diarrhea, peripheral neuropathy and skin rash.

The authors concluded that NINLARO® based oral triplet therapy significantly prolonged Progression Free Survival compared with REVLIMID® and Dexamethasone, with acceptable toxicities. Studies are underway, evaluating NINLARO® in newly diagnosed Myeloma patients as well as maintenance therapy in non-transplant patients. Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (NCT01564537). Moreau P, Masszi T, Grzasko N, et al. 2015 ASH Annual Meeting; Orlando, FL; December 5-8, 2015. Abstract 727.

OPDIVO® (Nivolumab)

The FDA on October 9, 2015 approved OPDIVO® for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), with progression on or after Platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations, prior to receiving OPDIVO®. OPDIVO® Injection is a product of Bristol-Myers Squibb Company.

FDA Approves TAGRISSO®, a Third Generation TKI, for EGFR T790M-Positive Non Small Cell Lung Cancer

SUMMARY: The U.S. FDA granted accelerated approval to TAGRISSO® (Osimertinib), for the treatment of patients with metastatic Epidermal Growth Factor Receptor (EGFR) T790M mutation-positive Non Small Cell Lung Cancer (NSCLC), as detected by an FDA-approved test, who had progressed on or after EGFR Tyrosine Kinase Inhibitor (TKI) therapy. 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. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 221,200 new cases of lung cancer will be diagnosed in the United States in 2015 and over 158,000 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Approximately 10% to 15% of Caucasian patients and 50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R point mutations in Exon 21. EGFR Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60% to 70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9 to 14 months. This resistance to frontline EGFR TKI therapy has been attributed to acquired T790M “gatekeeper” point mutation in EGFR, identified in 50% – 60% of patients. The approval of TAGRISSO® was based on two multicenter, single arm, open label clinical trials (AURA and AURA2), in patients with metastatic EGFR T790M mutation-positive NSCLC, who had progressed on prior systemic therapy, including an EGFR TKI.

In the AURA dose escalation/expansion study (Study 1), 201 patients with EGFR mutation-positive advanced NSCLC received TAGRISSO® 80 mg PO daily until disease progression. Tumor samples were taken from all patients after disease progression on the most recent line of therapy, for prospective confirmation of T790M positive status by central laboratory testing, before enrollment. The median age was 62 years. The primary endpoint was Objective Response Rate (ORR) and secondary endpoints included Disease Control Rate (DCR), duration of response (DoR) and Progression Free Survival (PFS). The ORR in an updated analysis at the 2015 WCLC was 61% and DCR was 92%. The ORRs were similar across all lines of therapy, ie. Second line vs third line or more. The median DoR and median PFS have not been reached.

In the AURA2 Phase II study, 210 patients with locally advanced or metastatic NSCLC received TAGRISSO® 80 mg PO daily until disease progression. All eligible patients progressed on a previous EGFR TKI treatment and had a mandatory tumor sample taken after disease progression on the most recent line of therapy, for confirmation of T790M positive status by central laboratory testing. The median age was 64 years. The primary endpoint was Objective Response Rate (ORR) and secondary end points included Disease Control Rate (DCR), Duration of Response (DoR), Progression Free Survival (PFS), and safety. The ORR in an updated analysis presented at the 2015 WCLC was 71%, with 2 complete responses. The stable disease rate at 6 weeks or more was 21%, for a Disease Control Rate of 92%. The median Duration of Response was 7.8 months. The median Progression Free Survival (PFS) was 8.6 months.

Grade 1-2 toxicities from these two trials, which included a total of 411 patients included diarrhea, rash, dry skin, nail toxicity, eye disorders, nausea, decreased appetite and constipation. From these two studies it was concluded that TAGRISSO® is a new treatment option for patients who test positive for the EGFR resistance mutation, T790M, with significant response rates noted in over 50% of the treated patients. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. Mitsudomi T, Tsai C, Shepherd F, et al. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1406.

FDA Approves YONDELIS® for Soft Tissue Sarcomas

SUMMARY: The U.S. FDA approved YONDELIS® (Trabectedin) for the treatment of patients with unresectable or metastatic Liposarcoma or Leiomyosarcoma, who have received a prior Anthracycline-containing regimen. Soft Tissue Sarcomas are a heterogeneous group of tumors of mesenchymal origin with over 50 different histological variants. The American Cancer Society estimates that in 2015, about 11,930 new soft tissue sarcomas will be diagnosed in the United States and 4,870 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. Chemotherapy is the standard of care for advanced Soft Tissue Sarcomas. Following first line therapy with Anthracycline or Ifosfamide based chemotherapy regimens, Response Rates are low and second line treatment options are limited. YONDELIS® (Trabectedin) originally isolated from the Caribbean sea sponge (Ecteinascidia turbinate) is a synthetic alkaloid that binds to the minor groove of DNA and induces apoptosis by damaging the DNA.

Based on promising phase II trials, a randomized, open-label, multicenter, phase III trial was conducted, in which 518 patients with unresectable, locally advanced or metastatic Liposarcoma or Leiomyosarcomas were randomly assigned in a 2:1 to receive either YONDELIS® or Dacarbazine. YONDELIS® was dosed at 1.5 mg/m2, administered as an intravenous infusion over 24 hours (N=345) and Dacarbazine was dosed at 1000 mg/m2 administered as an intravenous infusion over 20 to 120 minutes (N=173) and the treatment was given once every 3 weeks. The median age was 56 years and enrolled patients were heavily pretreated and had received prior Anthracycline containing chemotherapy regimens. Close to 90% of the patients had received at least two prior lines of chemotherapy. Patients were stratified by Soft Tissue Sarcoma subtype (Leiomyosarcoma vs Liposarcoma), ECOG performance status, and number of prior chemotherapy regimens. The primary end point was Overall Survival (OS) and secondary end points included Progression Free Survival (PFS), Time To Progression, Objective Response Rate, Duration of Response, as well as safety.

This study demonstrated a statistically significant improvement in PFS in the YONDELIS® group with a 45% reduction in the risk of disease progression or death compared with Dacarbazine (HR= 0.55; P<0.001). The median PFS was 4.2 and 1.5 months in the YONDELIS® and Dacarbazine groups, respectively. This benefit was noted in patients with both Leiomyosarcoma and Liposarcoma. The greatest benefit in median PFS (5.6 months vs 1.5 months with YONDELIS® vs Dacarbazine, respectively) was noted in the myxoid or round cell Liposarcomas, which are considered as translocation-related sarcomas. This additional benefit can be explained based on the direct inhibition by YONDELIS®, of the chimeric FUS-CHOP translocation-generated oncoprotein, which regulates transcriptional activity in myxoid or round cell Liposarcomas. There was however no significant difference in the median Overall Survival between YONDELIS® and Dacarbazine (12.9 months vs 12.4 months, P=0.37). This may be due to crossover of close to 30% of patients who progressed on Dacarbazine to Receptor Tyrosine Kinase Inhibitor, VOTRIENT® (Pazopanib), which was approved in the U.S. during the course of this study. Most of patients who benefited from YONDELIS®, experienced stable disease as their best response for longer durations, compared to those with Dacarbazine (51% vs 35%).

The most common adverse reactions (20% or more) with YONDELIS® were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. The most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases. The authors concluded that YONDELIS® significantly improves Progression Free Survival with superior disease control compared to Dacarbazine, in patients with heavily pretreated, advanced Liposarcoma and Leiomyosarcoma. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. Demetri GD, von Mehren M, Jones RL, et al. J Clin Oncol, doi: 10.1200/JCO.2015.62.4734.

ONIVYDE® in Combination with 5-FU and Leucovorin Improves Overall Survival in Metastatic Pancreatic Carcinoma

SUMMARY: The FDA on October 22, 2015 approved ONIVYDE® (Irinotecan liposome injection) administered in combination with Fluorouracil (5-FU) and Leucovorin , for the treatment of patients with metastatic adenocarcinoma of the Pancreas, whose disease has progressed following GEMZAR® (Gemcitabine) based therapy. The American Cancer Society estimates that in 2015, close to 49,000 people will be diagnosed with pancreatic cancer in the United States and over 40,000 people 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. 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.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

NAPOLI-1 is an open-label phase III study in which 417 patients with Gemcitabine-refractory metastatic Pancreatic adenocarcinoma were randomly assigned in a 1:1:1 ratio to receive either ONIVYDE® monotherapy, ONIVYDE® plus 5-FluoroUracil (5-FU) and Leucovorin or 5-FU with Leucovorin (control group). Sixty one percent (61%) of patients had cancer in the head of the Pancreas and 68% had liver metastases. Treatment consisted of ONIVYDE® 120 mg/m2 IV over 90 minutes every 3 weeks in Group A, ONIVYDE® 80 mg/m2 IV given over 90 minutes followed by 5-FU 2400 mg/m2 given over 46 hours and racemic Leucovorin 400 mg/m2 IV given over 30 minutes every 2 weeks in Group B and 5-FU 2000 mg/m2 IV given over 24 hours plus racemic Leucovorin 200 mg/m2 IV given over 30 minutes weekly for 4 weeks followed by 2 weeks of rest in Group C (Control group).

Each of the two ONIVYDE® containing groups was compared with the 5FU/Leucovorin control group. The primary study endpoint was Overall Survival and secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR). The combination of ONIVYDE®, 5-FU and Leucovorin resulted in a median OS of 6.1 months compared with 4.2 months with 5-FU and Leucovorin alone (HR = 0.67; P=0.012). The median PFS was 3.1 months for the ONIVYDE® combination compared with 1.5 months with 5-FU and Leucovorin alone (HR= 0.55; P=0.0001). The ORR was low in both treatment groups (7.7% vs 0.8%). ONIVYDE® montherapy was not superior, compared with 5-FU and Leucovorin and was associated with more side effects compared to the combination regimen. In an expanded, pre-specified analyses, patients who received at least 80% of the target dose in the first 6 weeks experienced an even greater Overall Survival benefit (43% improvement) with ONIVYDE® combination, compared with 5-FU and Leucovorin alone (8.9 months vs 5.1 months, HR=0.57, P=0.011).

The most common grade 3/4 adverse events with ONIVYDE® plus 5-FU and Leucovorin were neutropenia, fatigue, diarrhea and vomiting. The authors concluded that a combination of ONIVYDE® plus 5-FU and Leucovorin significantly improved Overall Survival compared to 5-FU and Leucovorin with manageable toxicities. Expanded analyses of Napoli-1: Phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. Chen L, Von Hoff DD, Li C, et al. J Clin Oncol 33, 2015 (suppl 3; abstr 234)