Author: RR

FDA Approves AndexXa®, The First Antidote for Factor Xa Inhibitors

RR

SUMMARY: The FDA on May 3, 2018 approved AndexXa® (Andexanet Alfa), a recombinant coagulation Factor Xa, inactivated-zhzo), for patients treated with XARELTO® (Rivaroxaban) and ELIQUIS® (Apixaban), when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. It is estimated that 4 million individuals are presently on Factor Xa inhibitors, and in the US there were approximately 117,000 hospital admissions attributable to Factor Xa inhibitor-related bleeding and nearly 2000 bleeding related deaths per month. There are presently five New Oral Anticoagulants approved in the US for the treatment of Venous ThromboEmbolism (VTE). They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® (Warfarin), the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. The half-life of these agents can however be prolonged in those with renal insufficiency and may be unsafe and direct oral anticoagulants are ineffective in patients with mechanical heart valves. In several clinical studies, these New Oral Anticoagulants have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN®. Unlike bleeding caused by COUMADIN®, which can be reversed using Vitamin K or Fresh Frozen Plasma, until now, there were no specific agents available, for reversing bleeding caused by the New Oral Anticoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent surgical intervention. The FDA in 2015, granted accelerated approval to PRAXBIND® (Idarucizumab), for the treatment of patients treated with PRADAXA®, a direct thrombin inhibitor, when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. However, the Factor Xa inhibitors approved in the US for the treatment of VTE did not have an antidote until this new approval. As such, some Health Care Providers discouraged their patients from taking these direct oral anticoagulants until an antidote became available, should their patients need urgent surgical intervention.MOA-of-New-Oral-Anticoagulants

AndexXa® (Andexanet alfa) is a recombinant, modified human Factor Xa decoy protein without intrinsic catalytic activity, that binds Factor Xa inhibitors. The approval of AndexXa® was based on data from two Phase III ANNEXA studies (ANNEXA-A and ANNEXA-R) as well as interim data from the ongoing ANNEXA-4 study. ANNEXA-A and ANNEXA-R are randomized, double-blind, placebo-controlled, Phase III studies which evaluated the safety and efficacy of AndexXa® in reversing the anticoagulant effect of ELIQUIS® and XARELTO® respectively, in healthy volunteers aged 50-68 years. A two-part randomized placebo-controlled study was conducted for each Factor Xa inhibitor, to evaluate AndexXa® administered as a bolus or as a bolus plus a 2-hour infusion. The Primary endpoint was reduction in anti-Factor Xa activity levels, a measure of Factor Xa inhibition by the anticoagulant. Secondary endpoints included reduction in plasma levels of free unbound XARELTO® or ELIQUIS® and restoration of the endogenous thrombin potential (ETP), a measure of thrombin generation.

ANNEXA-A Study: In Part 1, 33 healthy participants were given ELIQUIS® 5 mg twice daily for 3.5 days and then randomized in a 3:1 ratio to receive either AndexXa® administered as a 400 mg IV bolus or placebo. Within 2-5 minutes of completion of the bolus dose, AndexXa® rapidly reduced the anticoagulant activity of ELIQUIS® by 94% compared with placebo (P<0.001), as measured by anti-Factor Xa activity. The reversal of anti-factor Xa activity persisted for 2 hours. Further, AndexXa® significantly reduced the level of free (unbound) ELIQUIS® in the plasma compared with placebo (P<0.001) and fully restored thrombin generation in 100 percent of subjects (P<0.001 vs. placebo). In Part 2, 31 healthy participants received ELIQUIS® 5 mg twice daily for four days and then randomized in a 3:1 ratio to receive either AndexXa® administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes or placebo. AndexXa® significantly reduced anti-Factor Xa activity by 92% compared with placebo (P<0.001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound ELIQUIS® was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound ELIQUIS® compared with placebo (P<0.001). AndexXa® also restored thrombin generation to normal in all participants who received the compound (p<0.001 vs. placebo).

ANNEXA-R Study: In Part 1, 41 healthy volunteer participants were given XARELTO® 20 mg once daily for four days and then randomized in a 2:1 ratio to receive either AndexXa® administered as an 800 mg IV bolus or placebo. Within 2-5 five minutes of completion of the bolus dose, AndexXa® significantly reversed the anticoagulant activity of XARELTO® by 92% compared with placebo (P<0.001), as measured by anti-Factor Xa activity. Further, AndexXa® significantly reduced the level of free (unbound) XARELTO® in the plasma compared with placebo (P<0.001) and fully restored thrombin generation in 96% of participants (P<0.001 versus placebo). In Part 2, 39 healthy volunteers were given XARELTO® 20 mg once daily for four days and then randomized in a 2:1 ratio to receive either AndexXa® administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes or placebo. AndexXa® significantly reduced anti-Factor Xa activity by 97% compared with placebo (P<0.001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound XARELTO® was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound XARELTO® compared with placebo (P<0.001). AndexXa® also restored thrombin generation to normal in all participants who received this agent (P<0.001 versus placebo).

ANNEXA-4 Study: This is an ongoing, multicenter, prospective, open-label, single-group study designed to evaluate the use of AndexXa® in patients with acute potentially life-threatening major bleeding, within 18 hours after the administration of one of four Factor Xa inhibitors – ELIQUIS®, XARELTO®, SAVAYSA®, or LOVENOX® (Enoxaparin). . All patients received a bolus dose of AndexXa® within 3-6 hours following presentation to the ER followed by a 2-hour infusion of the drug. The two co-primary outcomes were the percent change in the anti-Factor Xa activity and the rate of excellent or good hemostatic efficacy, 12 hours after the AndexXa® infusion. Anti-Factor Xa activity was measured by means of a validated chromogenic assay of Factor Xa enzymatic activity. Among the 185 evaluable high-risk patients in this open-label study, hemostatic efficacy was adjudicated as excellent or good by the independent committee, 12 hours after the AndexXa® infusion in 83% of patients. It was noted that following the bolus dose of AndexXa®, the median anti-Factor Xa activity decreased by 90% from baseline, among patients receiving XARELTO® and by 93% among patients receiving ELIQUIS® and these levels remained the same during the 2-hour infusion.

In conclusion, AndexXa® is the first and only antidote indicated for patients treated with XARELTO® and ELIQUIS® when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. The availability of this antidote assures both patients and health care providers to consider Factor Xa inhibitors with greater confidence. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. Siegal DM, Curnutte JT, Connolly SJ, et al. N Engl J Med 2015; 373:2413-242. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. Connolly SJ, Milling TJ, Eikelboom JW, et al. N Engl J Med 2016; 375:1131-1141

TAFINLAR® and MEKINIST®

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The FDA on May 4, 2018 approved TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) for Anaplastic Thyroid Cancer with BRAF V600E mutation. TAFINLAR® and MEKINIST® are products of Novartis Pharmaceuticals Corp.

AndexXa® (Andexanet Alfa)

RR

The FDA on May 3, 2018 approved AndexXa®, a recombinant coagulation Factor Xa, inactivated-zhzo), for patients treated with XARELTO® (Rivaroxaban) and ELIQUIS® (Apixaban), when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. AndexXa® is a product of Portola Pharmaceuticals.

KYMRIAH® (Tisagenlecleucel)

RR

The FDA on May 1, 2018 approved KYMRIAH®, a CD19-directed genetically modified autologous T-cell immunotherapy, for adult patients with relapsed or refractory large B-cell lymphoma, after two or more lines of systemic therapy including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from Follicular Lymphoma. KYMRIAH® is a product of Novartis Pharmaceuticals Corp.

KYPROLIS® along with REVLIMID® and Dexamethasone Improves Overall Survival in Relapsed or Refractory 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, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Overall Survival (OS) in the relapsed setting.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone proteasome inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. Most of the recent phase III trials in Relapsed or Refractory Myeloma have used Progression Free Survival (PFS) as the Primary end point, with the exception of the phase III trial ENDEAVOR trial in which patients treated with KYPROLIS® and Dexamethasone achieved a statistically significant 7.6-month improvement in median Overall Survival (OS) compared to those patients treated with VELCADE® and Dexamethasone (HR=0.79; P=0.01). REVLIMID® (Lenalidomide) given along with weekly Dexamethasone, was associated with significantly improved Progression Free Survival (PFS) when administered until disease progression, in patients with newly diagnosed Multiple Myeloma. The combination of REVLIMID® and weekly Dexamethasone is considered a reference regimen for both newly diagnosed and relapsed Multiple Myeloma. VELCADE® in combination with REVLIMID® and Dexamethasone showed an overall response rate of 64% and a median PFS of 9.5 months in patients with Relapsed or Refractory Multiple Myeloma.

Based on this background, a randomized, open label, multicenter, phase III study (ASPIRE) was conducted, in which the safety and efficacy of a combination of KYPROLIS® (Carfilzomib), REVLIMID® and weekly Dexamethasone (KRd) was compared with a combination of REVLIMID® and weekly Dexamethasone (Rd), in patients with Relapsed or Refractory Multiple Myeloma. Seven hundred and ninety two (N=792) patients were randomly assigned in a 1:1 ratio to KRd (N=396) and Rd (N=396). Eligible patients included those with Multiple Myeloma who had received one to three prior treatments which included VELCADE® or REVLIMID® and Dexamethasone combination, provided that they did not have disease progression during treatment with these agents. The 28 day treatment cycle consisted of KYPROLIS® IV given on days 1, 2, 8, 9, 15, and 16 (starting dose, 20 mg/m2 on days 1 and 2 of cycle 1 with a target dose of 27 mg/m2 thereafter) during cycles 1 through 12 and on days 1, 2, 15, and 16 during cycles 13 through 18, following which KYPROLIS® was discontinued. REVLIMID® 25 mg PO was given on days 1 through 21 and Dexamethasone 40 mg PO was administered on days 1, 8, 15, and 22. Patients in both treatment groups received only REVLIMID® and Dexamethasone after cycle 18 until disease progression. Antiviral and antithrombotic prophylaxis was administered to patients in both treatment groups. The Primary end point was Progression Free Survival (PFS) and secondary end points included Overall Survival (OS), the rate of overall response (partial response or better), response duration, health-related quality of life, and safety.

The study met its Primary endpoint at the time of the pre-specified interim analysis with a significant improvement in the median PFS for those patients in the KRd group compared to the Rd (26.3 months versus 17.6 months; HR=0.69; P=0.0001). This benefit in the PFS was demonstrated across all predefined subgroups. The overall response rates (partial response or better) were 87.1% and 66.7% in the KYPROLIS® and control groups, respectively (P<0.001). Further, patients in the KYPROLIS® group reported superior health-related quality of life.

The authors in this prespecified analysis reported the final Overall Survival (OS) data and updated safety results. The median follow up was 67.1 months. The median OS was 48.3 months in the KRd group and 40.4 months in the Rd group (HR=0.79; P=0.0045). This represented a 7.9 month prolongation of OS and 21% decrease in the risk of death with KRd. Among patients who had received one prior line of therapy, KRd improved median OS by 11.4 months and among those who had received 2 or more prior lines of therapy, KRd improved median OS by 6.5 months, compared to Rd. Among patients who had received one prior line of VELCADE® based therapy, the median OS was improved by 12 months with KRd versus Rd, with a 18% reduction in the risk of death, and among patients with prior transplantation at first relapse, the median OS was improved by 18.6 months with KRd versus Rd, with a 29% reduction in the risk of death. The OS benefit with KRd was noted across all age, Creatinine Clearance (CrCL) and ECOG PS subgroups, including those 75 years or older, patients with impaired renal function (CrCL 30 to less than 60 mL/min), and patients with decreased Performance Status (ECOG PS, 2). The median time to next treatment from time of randomization was 39.0 months for patients who received KRd and 24.4 months for those who received Rd (HR=0.65; P<0.001).

An updated median PFS with longer follow up (median , 48.4 months) was 26.1 months in the KRd group versus 16.6 months in the Rd group (HR=0.66; P<0.001). Grade 3 or higher adverse events were reported in 87% and 83.3% of patients in the KRd and Rd groups, respectively.

It was concluded that treatment with KRd resulted in a statistically significant and clinically meaningful reduction in the risk of death, compared to Rd, among patients with Relapsed or Refractory Myeloma. This analysis supports the early use of KYPROLIS® at first relapse, regardless of prior treatment with VELCADE® or transplantation. Because each subsequent line of therapy can result in shorter response duration and increased treatment resistance, the authors suggested that early treatment with an effective regimen is important to maximize Overall Survival and KRd regimen should be considered a preferred treatment option in Relapsed or Refractory Multiple Myeloma. Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. Siegel DS, Dimopoulos MA, Ludwig H, et al. J Clin Oncol. 2018;36:728-734

Dual HER2 Blockade Along with an Aromatase Inhibitor is an Effective Chemotherapy-Sparing Alternative Treatment 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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. The HER or erbB family of receptors consist of HER1 (EGFR), HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Approximately 50% of HER2-positive breast cancers are Hormone Receptor positive.

Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine).

Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival. The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Not all HER2-positive, Hormone Receptor positive metastatic breast cancer patients, are candidates for chemotherapy. These patients however may benefit from anti-HER2 targeted therapy given along with endocrine therapy.

Preclinical evidence suggested that endocrine resistance may be related to cross talk between HER2- and Hormone Receptor-signaling pathways. HER2 inhibition may in turn enable the Estrogen Receptor (ER) to become the primary driver of cell proliferation, resulting in relative resistance to anti-HER2 therapy. Therefore, targeting both HER2 and ER simultaneously may be essential to derive optimal benefit among patients with HER2-positive Hormone Receptor positive metastatic breast cancer. Previously published studies demonstrated improved median PFS when single HER2 blockade combined with endocrine therapy was compared with endocrine therapy alone, among treatment naïve patients with HER2-positive and Hormone Receptor positive metastatic breast cancer.

Based on the improved outcomes with dual anti-HER2 blockade compared with single HER2 blockade in both neoadjuvant as well as metastatic settings, this present study was designed to evaluate the superiority of dual HER2 blockade with TYKERB® and HERCEPTIN® given along with an Aromatase Inhibitor (AI), over single HER2 blockade with HERCEPTIN® given along with an AI, in patients with HER2-positive, Hormone Receptor positive metastatic breast cancer, who experienced disease progression after prior neo(adjuvant)/first-line HERCEPTIN® based chemotherapy. This study also included a third treatment arm of TYKERB® plus an AI, which was compared with the other two treatment groups.

The ALTERNATIVE study is an open-label, phase III trial, in which 355 patients were randomly assigned in a 1:1:1 ratio to receive either TYKERB® along with HERCEPTIN® plus an AI (N=120), HERCEPTIN® plus an AI (N=117) or TYKERB® plus an AI. TYKERB® was administered at 1000 mg orally daily in the dual HER2 blockade group and at 1500 mg orally daily in the TYKERB® plus AI group. Patients receiving TYKERB® were urged to initiate treatment with Loperamide at the onset of diarrhea. HERCEPTIN® was administered IV at a loading dose of 8 mg/kg, followed by the maintenance dose of 6 mg/kg IV every 3 weeks. Physician’s choice of AIs included either Letrozole 2.5 mg, Anastrozole 1 mg or Exemestane 25 mg, orally daily. Enrolled patients were postmenopausal women, with histologically or cytologically confirmed ER-positive and/or Progesterone Receptor-positive, HER2-positive metastatic breast Cancer, as determined in a local laboratory. Prior treatment with endocrine therapy and disease progression during or after a prior HERCEPTIN® based chemotherapy regimen in the neo(adjuvant) setting and/or in the first-line metastatic setting, was a requirement for enrollment in this study. Only one prior regimen in the metastatic setting was allowed. Patients for whom chemotherapy was felt appropriate per treating physician’s judgement, were excluded from the study. Two thirds of the patients had received HERCEPTIN® based regimens in adjuvant setting and approximately one third in metastatic setting. The Primary end point was Progression Free Survival (PFS) with dual HER2 blockade plus AI compared with HERCEPTIN® plus AI. Secondary end points included PFS comparison of other treatment groups, Overall Survival, Overall Response Rate (ORR), Clinical Benefit Rate and Safety.

The study met its Primary end point and the median PFS utilizing dual HER2 blockade with a combination of TYKERB® along with HERCEPTIN® plus an AI was 11 months, compared with 5.7 months for HERCEPTIN® plus an AI (HR=0.62, P=0.0064). This represented a 38% reduction in the risk of disease progression. The PFS benefit was consistently observed in various predefined subgroups of patients. Further, the ORR and Clinical Benefit Rate were superior in the TYKERB® along with HERCEPTIN® plus AI group compared to HERCEPTIN® plus AI group ((31.7% versus 13.7% and 41% versus 31%, respectively). Although survival data were immature, there was also a trend favoring treatment with dual HER2 (median 46 months versus 40 months). When other treatment groups were compared, the median PFS with TYKERB® plus an AI was 8.3 months compared to 5.7 months with HERCEPTIN® plus an AI (HR=0.71, P=0.036), suggesting that among HER2-positive, Hormone Receptor positive metastatic breast cancer patients, who had progressed after prior treatment with HERCEPTIN®, anti-HER2 treatment with TYKERB® along with an AI may be a reasonable alternative, although this hypothesis will need to be confirmed. Common adverse events included higher incidence of diarrhea and rash in the groups treated with TYKERB® and serious adverse events were similar across the three treatment groups. Treatment discontinuation due to adverse events was lower in the dual HER2 blockade group.

The authors concluded that dual HER2 blockade with a combination of TYKERB®, HERCEPTIN® and an Aromatase Inhibitor (AI) resulted in improved PFS compared with HERCEPTIN® plus an AI, among HER2-positive and Hormone Receptor positive metastatic breast cancer patients, who had prior HERCEPTIN® based chemotherapy and endocrine therapy in the neo(adjuvant) and/or first line metastatic setting. This dual HER2 blockade combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor–Positive Metastatic Breast Cancer: ALTERNATIVE. Johnston SR, Hegg R, Im S, et al. J Clin Oncol 2017;36:741-748

TAFINLAR® and MEKINIST®

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The FDA on April 30, 2018 granted regular approval to TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib), in combination, for the adjuvant treatment of patients with Melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. TAFINLAR® and MEKINIST® are products of Novartis Pharmaceuticals Corp.

TAGRISSO® (Osimertinib)

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The FDA on April 19, 2018 approved TAGRISSO® for the first-line treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. TAGRISSO® is a product of AstraZeneca Pharmaceuticals LP.