Category: Hem/Onc Updates

FDA Approves Adjuvant TAFINLAR® plus MEKINIST® for Stage III BRAF-Mutated Melanoma

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SUMMARY: 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. It is estimated that in the US, approximately 91,270 new cases of melanoma will be diagnosed in 2018 and about 9,320 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for stage I disease and 90% for stage II disease. Stage III malignant melanoma however is a heterogeneous disease, and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with stage IIIA disease have a disease-specific survival rate of 78% whereas those patients with stage IIIB and stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas and result in constitutive activation of the MAPK pathway.

TAFINLAR®,is a selective oral BRAF inhibitor and MEKINIST® is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. In patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, a combination of TAFINLAR® and MEKINIST® resulted in a median Overall Survival (OS) of more than 2 years, with approximately 20% of the patients remaining progression free at 3 years. These encouraging results led to the study of this combination in patients with stage III melanoma, with BRAFV600E or V600K mutations, after complete surgical resection.

This FDA approval was based on COMBI-AD, an international, multi-center, randomized, double-blind, placebo-controlled, phase III trial, in which 870 patients with completely resected, stage III melanoma and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. Eligible patients had undergone completion lymphadenectomy, with no clinical or radiographic evidence of residual regional node disease. None of the patients had received previous systemic anticancer treatment or radiotherapy for melanoma. BRAF V600 mutation status was confirmed in primary tumor tissue or lymph node tissue by a central reference laboratory. The median age was 50 years. Both treatment groups were well balanced and 18% had stage IIIA disease, 41% had stage IIIB disease, and 40% had stage IIIC disease. Of the enrolled patients, 91% had a BRAF V600E mutation, and 9% had a BRAF V600K mutation. The Primary end point was Relapse Free Survival (RFS) and Secondary end points included Overall Survival (OS), Distant metastasis-free survival, Freedom from relapse, and Safety.

At a median follow up of 2.8 years, the estimated 3-year RFS rate was 58% in the combination therapy group and 39% in the placebo group (HR=0.47; P<0.001), and this represented a 53% lower risk of relapse. At the time of this analysis, median RFS rate had not yet been reached in the combination therapy group and was 16.6 months in the placebo group. The improved RFS benefit with the combination therapy was consistent across patient subgroups, regardless of lymph node involvement or primary tumor ulceration. The risk of distant metastases or death was reduced by 49% with the combination therapy versus placebo (HR=0.51; P<0.001). The safety profile of TAFINLAR® plus MEKINIST® was consistent with that observed with the combination, in patients with metastatic melanoma, and the common side effects were pyrexia, fatigue, nausea, vomiting, diarrhea, headache, rash, arthralgia, and myalgia.

It was concluded that adjuvant combination therapy with TAFINLAR® plus MEKINIST® in patients with stage III melanoma with BRAF V600E or V600K mutations, resulted in a significantly lower risk of recurrence, compared to placebo, with no new adverse events. With more than half the patients with stage III melanoma having a recurrence after surgery, this first effective oral targeted combination therapy, will be an important adjuvant treatment option. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. Long GV, Hauschild A, Santinami M, et al. N Engl J Med 2017; 377:1813-1823

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

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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

KYPROLIS® along with REVLIMID® and Dexamethasone Improves Overall Survival in Relapsed or Refractory Multiple Myeloma

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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

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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

FDA Approves TAVALISSE® for Chronic ITP

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SUMMARY: The FDA on April 17, 2018, approved TAVALISSE® (Fostamatinib tablets) for the treatment of thrombocytopenia in adult patients with chronic Immune Thrombocytopenic Purpura (ITP), who have had an insufficient response to a previous treatment. ITP can manifest as an acute self limited disease often seen in children (Acute ITP) or in a chronic form (Chronic ITP) seen in adults with the thrombocytopenia lasting for 6 months or longer.

TAVALISSE is an oral Tyrosine Kinase Inhibitor that targets SYK kinase (Spleen Tyrosine Kinase). SYK associates with Fcγ receptors (FcγR) on the cell surface of various inflammatory cells, including macrophages, which are in turn responsible for platelet clearance in ITP. Inhibition of SYK by the active metabolite of TAVALISSE® reduces the destruction of platelets by macrophages, that are activated in the immune system. TAVALISSE® is the first and only SYK inhibitor indicated for adults with Chronic ITP and the present study validated the therapeutic effect of SYK inhibition in an autoimmune disease.

The approval of TAVALISSE® was supported by data from two randomized placebo-controlled phase III trials and an open label extension study, as well as an initial proof-of-concept study. FIT-1 and FIT-2 are two identical, multicenter, randomized, double-blind, placebo-controlled, phase III trials that included 150 patients with persistent or Chronic ITP, who had an insufficient response to previous treatment, which included Corticosteroids, Immunoglobulins, Splenectomy, and/or a Thrombopoietin Receptor Agonist (TPO-RA). Patients were randomized 2:1 to receive either TAVALISSE® 100 mg orally twice daily or placebo for 24 weeks. Dose could be escalated to 150 mg orally twice daily after one month. The median age was 54 years and enrolled patients had three documented platelet counts of 30,000/µL or less. Patients had ITP for a median of 8.5 years prior to enrollment and the median baseline platelet count was 16,000/μL. The most common prior treatments for ITP were Steroids (94%), TPO-RAs (47%), Splenectomy (35%), and Rituximab (32%). The Primary endpoint was Stable platelet response of 50,000/ µL or more on at least 4 of the 6 biweekly visits between Weeks 14 and 24 of the study, without rescue treatment.

The Overall Response Rate with TAVALISSE® in the two trials, FIT-1 and FIT-2 was 29% versus 2% in the placebo group (P<0.001). Among the responders on TAVALISSE®, Stable Response (Primary end point) was noted in 18% versus 1% in the placebo group (P=0.007) and Intermediate Response (defined as at least 2 consecutive biweekly platelet counts of 50,000/μL or more, without rescue treatment) was noted in 11% versus 0% in the placebo group (P<0.001).

Among patients treated with TAVALISSE®, the median platelet counts at 24 weeks of follow up was 95,000/μL for those who had a Stable Response, 49,000/μL for those who had Intermediate Response, and 20,500/μL in non-responders. For those in the placebo group, however, median platelet counts only reached 17,500/μL. More than half of patients treated with TAVALISSE® (54%) had increment in platelet count (20,000/μL or more), compared with 29% of patients receiving placebo (P=0.005). The median time to response (platelet count of 50,000/μL or more) in those treated with TAVALISSE®, was two weeks. Rescue medications (including Platelet transfusions and intravenous Immunoglobulin) were required in 26% of responding patients in the TAVALISSE® group and for 45% of patients in the placebo group. Response rates were not influenced by Age, Sex, baseline platelet count, Splenectomy or prior treatment with a TPO-RA. Among patients who had received and later failed to respond to a TPO-RA before enrollment, 17% had a Stable Response to TAVALISSE®. Serious bleeding was not noted in the 29% of patients who achieved a response, whereas it occurred in 5.6% of non-responders and 10.2% of those receiving placebo.

Patients from FIT-1 and FIT-2 trials were also included in an open label expansion cohort (FIT-3). In this study, 23% of those who received placebo in FIT-1 or FIT-2 had a Stable platelet response to TAVALISSE®. The most common toxicities were rash, fatigue, nausea, diarrhea, abdominal pain, hypertension, liver function abnormalities and neutropenia.

It was concluded that TAVALISSE® is the first and only Spleen Tyrosine Kinase (SYK) inhibitor, and by its unique mechanism of action, is an important alternative for patients with difficult to treat chronic ITP. Bussel J, Mayer J, Cervinek L, et al. Treatment of primary adult chronic immune thrombocytopenia (CITP) with fostamatinib, an oral SYK inhibitor: results of two randomized, placebo-controlled phase 3 studies. Abstract #S435. Presented at the 22nd Congress of the European Hematology Association, June 24, 2017; Madrid, Spain.

FDA Approves TAGRISSO® for First-Line Treatment of Metastatic NSCLC

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SUMMARY: The FDA on April 19, 2018, approved TAGRISSO® (Osimertinib) 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.

Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. 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 10-15% of Caucasian patients and 35-50% 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 EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% 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 9-14 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. Put another way, T790M is not relevant in about 40% of patients whose disease progression may be related to other mechanisms.

TAGRISSO® is a third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, who had progressed on prior systemic therapy, including an EGFR-TKI. Previously published studies had suggested that TAGRISSO® may also be effective as initial therapy for EGFR mutation-positive advanced NSCLC.

The recent new indication for TAGRISSO® was based on FLAURA, which is a randomized, double blind, phase III clinical trial, conducted to compare the efficacy and safety of first line TAGRISSO® to TARCEVA® or IRESSA® (which are considered standard first line therapies), in NSCLC patients with activating mutations EGFR exon 19 deletions or L858R substitution mutation on exon 21. This study randomized 556 advanced NSCLC treatment naïve patients, with EGFR exon 19 or 21 mutations in a 1:1 ratio, to TAGRISSO® 80 mg orally once daily (N=279) or Standard of Care EGFR-TKI, IRESSA® 250 mg or TARCEVA® 150 mg, orally once daily (N=277). Patients were stratified by mutation status (exon 19 vs 21 mutations) and race (Asian vs non-Asian). Patients with CNS metastases who were neurologically stable, were allowed in this study. The Primary endpoint was Progression Free Survival (PFS).

The median PFS was 18.9 months with TAGRISSO® compared to 10.2 months for the standard therapy (HR=0.46; P<0.001), suggesting a 54% reduction in the risk of disease progression, compared with Standard of Care. TAGRISSO® extended the median Time To Progression by about 9 months. This PFS benefit was consistent across all subgroups of patients, including those with and without CNS metastases at study entry. The Objective Response Rate (ORR) with TAGRISSO® was 80% compared with 76% for TARCEVA® and IRESSA®. The median Duration of Response with TAGRISSO® was 17.2 months versus 8.5 months in the comparator arm. The median Overall Survival was not reached. Grade 3 and 4 toxicities were lower for TAGRISSO® (34%) compared with 45% for TARCEVA® and IRESSA®. Toxicities led to treatment discontinuation for 13% and 18% of patients in the TAGRISSO® and comparator groups, respectively.

It was concluded that TAGRISSO® demonstrated superior efficacy, with a near doubling in median Progression Free Survival, and better tolerability, compared to the Standard of Care, when given as first-line therapy, for patients with advanced EGFR mutation positive NSCLC. Studies are underway, assessing treatments, following resistance to TAGRISSO®.

Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. Soria J-C, Ohe Y, Vansteenkiste J, et al. for the FLAURA Investigators. N Engl J Med 2018; 378:113-125

FDA Approves OPDIVO® plus YERVOY® Combination Immunotherapy for intermediate or Poor-risk Advanced Renal Cell Carcinoma

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SUMMARY: The FDA on April 16, 2018, granted approvals to OPDIVO® (Nivolumab) and YERVOY® (Ipilimumab) in combination, for the treatment of intermediate or poor-risk, previously untreated advanced Renal Cell Carcinoma (RCC). 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 the standard first-line intervention for treatment naïve patients with advanced Renal Cell Carcinoma. In a large, multi-center, randomized, phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.International-Metastatic-RCC-Database-Consortium-(IMDC)

OPDIVO® 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, whereas YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® was approved by the FDA in November 2015, for the treatment of advanced RCC in patients who had received prior anti-angiogenic therapy, based on an Overall Survival benefit. YERVOY® is approved for the treatment of metastatic melanoma. Combining OPDIVO® with YERVOY® (Combination immunotherapy) has shown promising efficacy in multiple tumor types, including advanced RCC, with higher Objective Response Rate than either agent alone, and is presently approved for the treatment of advanced malignant melanoma.

This FDA approval was based on CheckMate 214, a randomized open-label phase III trial in which a combination of OPDIVO® plus YERVOY® (N=550) was compared with SUTENT® (N=546), among treatment naïve, clear-cell, advanced Renal Cell Carcinoma (RCC) patients. The authors randomly assigned 1096 patients in a 1:1 ratio to receive OPDIVO® 3 mg/kg IV plus YERVOY® 1 mg/kg IV every 3 weeks for four doses (induction phase) followed by OPDIVO® monotherapy at 3 mg/kg every 2 weeks (maintenance phase) or SUTENT® 50 mg orally once daily for 4 weeks, of each 6-week cycle. Four hundred and twenty five (425) patients in the combination group and 422 patients in the SUTENT® group had intermediate or poor-risk patients. It is estimated that approximately 75% of patients with advanced RCC have intermediate or poor-risk disease and have worse outcomes than those with favorable-risk disease. The coprimary end points were Overall Survival, Objective Response Rate and Progression Free Survival among patients with intermediate or poor prognostic risk disease.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

At a median follow-up of 25.2 months, the combination of OPDIVO® and YERVOY® had a significant Overall Survival benefit over SUTENT®. The 18-month Overall Survival rate was 75% with combination immunotherapy and 60% with SUTENT®. The median Overall Survival was not reached with combination immunotherapy versus 26.0 months with SUTENT® (HR=0.63; P<0.001). The Objective Response Rate was 42% with combination immunotherapy versus 27% with SUTENT® (P<0.001), and the Complete Response rate was 9% versus 1% respectively. The median Progression Free Survival was 11.6 months and 8.4 months, respectively but this was not statistically significant per the prespecified threshold. The benefit with combination immunotherapy was not noted in patients with favorable-risk disease. The superior outcomes with combination immunotherapy in patients with intermediate and poor-risk RCC may very well be related to a higher tumor mutational load in this group of patients, compared to those with favorable-risk disease.

In exploratory analyses among 776 intermediate and poor-risk patients, who had quantifiable PD-L1 expression in this study, Overall Survival was longer with Immunotherapy combination compared with SUTENT®, across PD-L1 expression levels. In patients with PD-L1 expression of 1% or greater, the 18-month Overall Survival rate was 81% with combination immunotherapy and 53% with SUTENT®, and the median Overall Survival was not reached versus 19.6 months respectively (HR=0.45). Among patients with PD-L1 expression of 1% or greater, the Objective Response Rate was 58% versus 22% for SUTENT® (P<0.001), the median PFS was 22.8 and 5.9 months, respectively (HR=0.46). A similar trend was noted in patients with PD-L1 expression 5% or greater, as compared with patients with less than 5% PD-L1 expression. Treatment discontinuation, related to adverse events occurred in 22% of the patients in the combination immunotherapy group and 12% in the SUTENT® group.

It was concluded that treatment with a combination of OPDIVO® and YERVOY® resulted in a significantly higher Overall Survival and Objective Response Rates, compared with SUTENT®, among intermediate and poor-risk, previously untreated patients, with advanced Renal Cell Carcinoma. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. Motzer RJ, Tannir NM, McDermott DF, et al. N Engl J Med 2018; 378:1277-1290

Shorter Duration of Adjuvant Chemotherapy for Stage III Colon Cancer

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 140,250 new cases of ColoRectal Cancer will be diagnosed in the United States in 2018 and over 50,630 patients are expected to die of the disease. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (stage III) colon cancer, has been the standard of care since the 1990s. Adjuvant treatment with an ELOXATIN® (Oxaliplatin) based chemotherapy regimen has been considered standard intervention since 2004, for patients with stage III colon cancer, following surgical resection, and has been proven to decrease the chance of recurrent disease. Chemotherapy regimens have included (FOLFOX – Leucovorin, 5-FluoroUracil, ELOXATIN®) or CAPOX/XELOX (XELODA®/Capecitabine and ELOXATIN®), given over a period of 6 months. ELOXATIN® can however be associated with neuropathy which can be long lasting or permanent, depending on the duration of therapy. Additional toxicities with longer duration of chemotherapy include diarrhea, fatigue as well as more office visits.

The IDEA Collaboration is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials, which included 12,834 patients from 12 countries. The goal of this study was to determine if 3 months of adjuvant chemotherapy would be as effective as 6 months of therapy and would be non-inferior. Of the enrolled patients with stage III disease, 13% had T1-2 disease, 66% had T3 tumors and 21% had T4 tumors. Seventy one percent (71%) had N1 disease and 28% of the patients had N2 disease. Approximately 60% had low-risk disease (T1-3, N1) and 40% had high-risk (T4 or N2). Overall, about 40% of patients received CAPOX regimen and 60% received FOLFOX regimen. The primary endpoint was Disease Free Survival (DFS).

At a median follow up of 41.8 months, although non-inferiority of 3 months of therapy as compared with 6 months of therapy could not be confirmed in the overall treatment population, clinically relevant findings according to treatment were noted, in prespecified subgroups of patients. Among those patients who received FOLFOX regimen, 6 months of adjuvant therapy was superior to 3 months (HR=1.16; P=0.001 for superiority of 6-month therapy). However, among those patients who received CAPOX, the Disease Free Survival for 3 months versus 6 months was non-inferior (HR=0.95; P=0.006), and this was highly significant.

In an exploratory analysis, it was noted that among the patient group with low-risk cancers (T1-3, N1 cancers), 3 months of therapy was non-inferior to 6 months of therapy (HR= 1.01) with 3-year disease-free survival of 83.1% and 83.3%, respectively. However, among the patients with high-risk cancers (T4, N2, or both), 6 months of adjuvant therapy was superior to 3 months (HR= 1.12; P=0.01 for superiority).

When subgroup analysis was performed according to treatment and risk group, among the patients with low-risk tumors, 3 months of adjuvant therapy with CAPOX was non-inferior to 6 months of therapy. Outcomes after 3 months of adjuvant FOLFOX therapy were worse than those after 6 months, independent of risk group. For patients with high-risk tumors, 6 months of adjuvant therapy with FOLFOX was superior to 3 months, with a 3-year disease-free survival of 64.7% versus 61.5%. It has been hypothesized that the protracted delivery of a Fluoropyrimidine with CAPOX might have been more effective than the twice-monthly 5-FUinfusions with FOLFOX as an adjuvant therapy. Grade 2 or more neurotoxicity was significantly lower for patients who received 3 months of adjuvant therapy versus 6 months (P <0.0001), regardless of the treatment regimen (17% vs 48% for FOLFOX and 15% vs 45% for CAPOX/XELOX, respectively).

It was concluded by the IDEA collaboration that, a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with stage III colon cancer, taking into consideration choice of treatment regimen and duration of therapy. In patients treated with adjuvant CAPOX/XELOX regimen, 3 months of therapy was as effective as 6 months, particularly in the low risk subgroup. In patients treated with FOLFOX, 6 months of adjuvant therapy compared to 3 months, resulted in a higher rate of Disease Free Survival, particularly in the high-risk subgroup. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. Grothey A, Sobrero AF, Shields AF, et al. N Engl J Med 2018; 378:1177-1188

FDA Approves RUBRACA® for Maintenance Treatment of Recurrent Ovarian Cancer

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SUMMARY: The FDA on April 6, 2018, approved RUBRACA® (Rucaparib), a Poly ADP-Ribose Polymerase (PARP) inhibitor, for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a Complete or Partial Response to platinum-based chemotherapy. RUBRACA® was initially approved in December 2016 as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies.

RUBRACA® is an oral, small molecule inhibitor of Poly-Adenosine diphosphate [ADP] Ribose Polymerase (PARP), developed for treatment of ovarian cancer, associated with Homologous Recombination DNA repair deficiency (HRD). Previously published clinical data had suggested that ovarian cancer patients with and without evidence of a germline BRCA mutation, benefit from treatment with a PARP inhibitor, and that maintenance treatment with a PARP inhibitor following a response to platinum-based treatment increases Progression Free Survival (PFS), in patients with ovarian cancer. Even though patients with or without BRCA mutation benefited, the most benefit was derived in those with BRCA mutation.MOA-of-RUBRACA

The approval of RUBRACA® was based on ARIEL3, a randomized, double-blind, placebo-controlled, phase III trial, which evaluated the benefit of RUBRACA® versus placebo, after response to second-line or later platinum-based chemotherapy, in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. In this trial, 561 patients were randomly assigned in a 2:1 ratio to receive RUBRACA® 600 mg orally twice daily (N=372) or placebo (N=189). Treatment was continued until disease progression or unacceptable toxicity. Eligible patients had recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, and had been treated with at least two prior treatments of platinum-based chemotherapy, and were in Complete or Partial Response to the most recent platinum-based chemotherapy. Patients had CA-125 level of less than the upper limit of normal. Using Next-Generation Sequencing assay, tumor tissue was examined to determine whether DNA contained a deleterious somatic or germline BRCA mutation (tBRCA), in addition to determining the percentage of genomic Loss of Heterozygosity (LOH). Positive Homologous Recombination Deficiency (HRD) status was defined as tBRCA-positive and/or LOH high. The Primary end point was Progression Free Survival in three patient cohorts – all patients, HRD subgroup, and tumor BRCA subgroup.

It was noted that there was a statistically significant improvement in median Progression Free Survival (PFS) for all patients assigned to RUBRACA®, compared with placebo (median PFS 10.8 versus 5.4 months, HR=0.36; P<0.0001). In the HRD subgroup, the median PFS was 13.6 months for those assigned to RUBRACA®, versus 5.4 months for the placebo group (HR=0.32; P<0.0001), and in the tumor BRCA subgroup, the median PFS was 16.6 versus 5.4 months (HR=0.23; P <0.0001), respectively. The most common adverse reactions were fatigue, rash, nausea, vomiting, diarrhea, abdominal discomfort, cytopenias and abnormal liver function studies. Discontinuation due to adverse reactions occurred in 15% of patients receiving RUBRACA®.

It was concluded that RUBRACA® significantly improved Progression Free Survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy, and could be considered a new standard of care for women with platinum-sensitive ovarian cancer, following a complete or partial response to second-line or later lines of platinum-based chemotherapy. The FDA also concurrently approved the complementary diagnostic test, FoundationFocusTM CDx BRCA LOH for tumor samples, to determine HRD status.

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Coleman RL, Oza AM, Lorusso D, et al. The Lancet 2017;390:1949-1961

Frontline TECENTRIQ® along with AVASTIN® and Chemotherapy Improves Survival in Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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. Immunotherapy is an accepted second line intervention after platinum-based chemotherapy in patients with advanced NSCLC, and is an approved first line therapy, for patients with high PD-L1 expressing tumors (50% or more). Further, immunotherapy with KEYTRUDA® (Pembrolizumab), in combination with chemotherapy, has been approved for first line treatment of patients with advanced non-squamous NSCLC, irrespective of PD-L1 expression.

TECENTRIQ® (Atezolizumab) is an anti-PDL1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors and thus enabling the activation of T cells. TECENTRIQ® was approved by the FDA in October 2016 for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose disease progressed during or following Platinum-containing chemotherapy. AVASTIN® (Bevacizumab) is a biologic antiangiogenic antibody, directed against Vascular Endothelial Growth Factor (VEGF), and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors has been shown to result in endothelial cell proliferation and new blood vessel formation. Combining TECENTRIQ® and AVASTIN® is supported by the following scientific rationale. AVASTIN® in addition to its established anti-angiogenic effects, may further enhance the ability of TECENTRIQ® to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.Unleashing-T-Cell-Function-with-PD-1-and-PD-L1-Antibodies

IMpower150 is a multicenter, open-label, randomized, phase III study, conducted to evaluate the efficacy and safety of TECENTRIQ® in combination with Carboplatin and Paclitaxel with or without AVASTIN®, in patients with stage IV, treatment naïve, non-squamous NSCLC. This study enrolled 1,202 patients, who were randomized (1:1:1) to receive either TECENTRIQ® along with Carboplatin and Paclitaxel (Group A), TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel (Group B), or AVASTIN® plus Carboplatin and Paclitaxel (Group C – control arm). During the treatment-induction phase, patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and Paclitaxel 200mg/m2 IV on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, patients received maintenance treatment with TECENTRIQ® on the same dose schedule until disease progression. Patients in Group B received AVASTIN® 15 mg/kg IV, along with TECENTRIQ®, Carboplatin and Paclitaxel IV, Day 1 of a 3-week treatment cycle for 4 or 6 cycles followed by maintenance treatment with the TECENTRIQ® and AVASTIN® until disease progression. Patients in the control Group C received AVASTIN® plus Carboplatin and Paclitaxel every 3 weeks for 4 or 6 cycles followed by AVASTIN® maintenance treatment until disease progression. Patients with tumors demonstrating ALK and EGFR mutations were excluded from the primary Intention-To-Treat (ITT) analysis. Patients were also tested for a tumor T-effector gene expression signature (based on phase II trial finding of prolonged Overall Survival in patients with high gene expression signature levels, treated with TECENTRIQ®). The median age was 63 years and the minimum follow up at the time of the analysis was 9.5 months. For the interim analysis, the study was only designed to compare Groups B and C. The co-Primary endpoints were Progression Free Survival (PFS) and Overall Survival in the Intention-to-Treat (ITT) population comparing patients in Group B and C. These end points were also evaluated in subgroup of people who had a specific biomarker (T-effector gene signature expression).

It was noted that at this interim analysis, the combination of TECENTRIQ® and AVASTIN® plus Carboplatin and Paclitaxel, significantly improved PFS and reduced the risk of disease worsening or death by 38% (HR=0.62; P<0.0001), compared to AVASTIN® plus Carboplatin and Paclitaxel alone. This PFS benefit was observed across key subgroups, regardless of PD-L1 expression status, including PD-L1–negative patients (HR 0.77). Further, the median PFS in the population of patients with defined expression of a T-effector gene signature expression in the tumor tissue, was 11.3 months versus 6.8 months (HR 0.51; P<0.0001). Roche on March 26, 2018 announced that the IMpower150 study met its co-primary endpoint of Overall Survival as well. Details will soon become available.

It was concluded that combining chemotherapy with immunotherapy and antiangiogenic agents significantly improved PFS as well as Overall Survival, in patients with treatment naïve, advanced non-squamous NSCLC. This strategy can completely eliminate the need for patient selection based on a particular biomarker, and could benefit larger number of patients with advanced NSCLC. Reck M. Primary PFS and safety analyses of a randomized Phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150). Annals of Oncology, 2017;28(11). Abstract LBA1_PR. https://www.roche.com/media/store/releases/med-cor-2018-03-26.htm