Author: RR

FDA Approves TAGRISSO® (Osimertinib) Blood-Based T790M Companion Diagnostic Test

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SUMMARY: The FDA on September 29, 2016 approved a blood-based companion diagnostic for TAGRISSO® (Osimertinib). The companion diagnostic for TAGRISSO® is the only FDA approved and clinically validated companion diagnostic test that uses either tissue or a blood sample to confirm the presence of a T790M point mutation in patients with metastatic Epidermal Growth Factor Receptor (EGFR) mutation-positive Non Small Cell Lung Cancer (NSCLC), who have had progression of disease on or after EGFR Tyrosine Kinase Inhibitor 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. The American Cancer Society estimates that for 2016 about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Non Small Cell Lung Cancer accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Approximately 10% to 15% of Caucasian patients and 50% of Asian patients with Adenocarcinomas, harbor activating EGFR 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.

TAGRISSO® is 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. The application of precision medicine with targeted therapy requires detection of molecular abnormalities in a tumor specimen, following progression or recurrence. Archived biopsy specimens may not be helpful as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping circulating-free tumor DNA (cfDNA) in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The COBAS® Mutation Test v2, is a real-time PCR test for the qualitative detection of defined mutations of the EGFR gene in NSCLC patients. Defined EGFR mutations are detected using DNA isolated from Formalin-Fixed Paraffin-Embedded Tumor tissue (FFPET) or circulating-free tumor DNA (cfDNA) from plasma, obtained from EDTA anti-coagulated peripheral whole blood (purple top tube). This new blood-based companion diagnostic test offers an important option to identify T790M mutation in patients with metastatic EGFR mutation-positive NSCLC, who have progressed on an EGFR TKI therapy, and for whom a tissue biopsy may not be feasible.

US FDA approves Tagrisso (osimertinib) blood-based T790M companion diagnostic test. AstraZeneca website. https://www.astrazeneca-us.com/content/az-us/media/press-releases/2016/us-fda-approves-tagrisso-osimertinib-blood-based-t790m-companion-diagnostic-test-09292016.html. Updated September 29, 2016.

MammaPrint® Identifies Women with Early Stage Breast Cancer Who Can Avoid Adjuvant Chemotherapy

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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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy. Chemotherapy recommendations for early stage breast cancer are often made based on tumor size, grade, hormone receptor and HER-2 status, immunohistochemical markers such as Ki-67, nodal status, patients age, menopausal and performance status. Adjuvant! Online is one of the tools that incorporates these features and assists in treatment decision making. This tool however does not take into account individual tumor molecular signatures which can better predict clinical outcomes. MammaPrint® is a 70-gene signature assay approved by the FDA and is able to distinguish low risk and high risk tumors based on the risk of distant recurrence at 5 and 10 years. The authors in this study selected patients for adjuvant chemotherapy utilizing 70-gene signature assay in addition to standard clinicopathological criteria and prospectively reported 5-year outcomes in the treatment groups.

MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study is a international, prospective, randomized, phase III study which enrolled 6693 women with early-stage breast cancer and determined their genomic risk using the 70-gene signature assay (MammaPrint®) and their clinical risk using a modified version of Adjuvant! Online. Enrolled patients were divided into four groups based on their clinical and genomic risk: low clinical risk and low genomic risk (N=2745, 41%); high clinical risk and high genomic risk (N=1806, 27%), high clinical risk and low genomic risk (N=1550, 23.2%); low clinical risk and high genomic risk (N=592, 8.8%). Patients in the first 2 concordant groups were treated according to their risk category, ie. low-risk group did not receive adjuvant chemotherapy whereas adjuvant chemotherapy was added to endocrine therapy following surgery, in the high-risk patient group. Patients in the last 2 discordant groups were randomly assigned to receive adjuvant chemotherapy or no chemotherapy. The median age of the patients was 55 yrs, 79% of the patients had node-negative disease and 21% had 1-3 positive nodes. A total of 88% of the tumors expressed ER, PR, or both, and 9.5% were HER-2 positive.

The primary endpoint of this study was to show noninferiority against a predefined benchmark of a 5-year metastasis-free survival rate of 92%, in patients at high clinical risk, for whom a discordant low genomic risk led to the omission of otherwise standard adjuvant chemotherapy. It was noted that in this group of patients at high clinical risk and low genomic risk (N=1550) at 5 years, the rate of survival without distant metastasis was 94.7% among those not receiving chemotherapy, and this met the study criterion for noninferiority, with similar outcomes noted in all sub groups of patients.. The absolute difference in the survival rate between those who did not receive adjuvant chemotherapy and those who received chemotherapy was 1.5%, with the survival rate slightly higher in those who received adjuvant chemotherapy. The 5-year metastasis-free survival rate for women who were low risk by both genomic and clinical criteria and who did not receive adjuvant chemotherapy was 97.6%, compared with 90.6% for those women who were high risk by both criteria and who did receive adjuvant chemotherapy.

It was concluded that in patients with early stage breast cancer, who were considered to be at high clinical risk for recurrence, 70-gene signature assay was able to identify those with low genomic risk, who had marginal benefit with adjuvant chemotherapy. With treatment guidance using 70-gene signature assay, approximately 46% of early stage breast cancer patients with high clinical risk and low genomic risk might not require adjuvant chemotherapy. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. Cardoso F, van’t Veer LJ, Bogaerts J, et al. N Engl J Med 2016; 375:717-729

Location of Primary Tumor Predicts Survival and Choice of Treatment in Metastatic Colorectal 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 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die of the disease. Even though prognosis for patients with Colon Cancer has improved over the past two to three decades, it has remained unclear if improvement in survival was greater for left sided Colon Cancer versus cancer originating in the Right hemicolon.

Venook and colleagues had previously presented data from the primary analysis of a phase III CALGB/SWOG 80405 study which compared AVASTIN®: (Bevacizumab) or ERBITUX® (Cetuximab), given in conjunction with FOLFOX (Leucovorin, 5-Fluorouracil, Oxaliplatin) or FOLFIRI (Leucovorin, 5-FU, Irinotecan), as first line treatment of metastatic colorectal cancer. This study showed that chemotherapy plus ERBITUX® resulted in similar Overall Survival (29.9 months) as chemotherapy plus AVASTIN® (29 months) as well as Progression Free Survival (PFS). The present publication is a retrospective evaluation from the phase III 80405 clinical trial which included data from 1,025 patients with KRAS wild-type disease. The researchers assessed the impact of tumor location on Overall and PFS in this group of patients. The median age was 59 yrs and 293 patients had a right-sided primary tumor (location in the cecum to hepatic flexure) and 732 patients had a left-sided primary tumor (location in the splenic flexure to rectum).

It was noted that patients with tumors originating in the right side of the colon had much shorter median Overall Survival (19.4 months) compared to patients with left-sided tumors (33.3 months), (HR=1.60; P<0.001), with a 14 month survival improvement in the left versus right-sided primary tumors, for patients with metastatic disease. Tumor location in the colon also had a bearing on response to ERBITUX® and AVASTIN®. For the patient group who received ERBITUX®, the median Overall Survival (OS) was 36 months for patients with left-sided tumors but 16.7 months for patients with right-sided tumors. For those who received AVASTIN®, the median OS was 31.4 months for patients with left-sided tumors and 24.2 months for those with right-sided tumors. The median PFS was also influenced by the site of the primary tumor and was 8.9 months for right-sided tumors versus 11.5 months for left-sided tumors in the overall cohort of patients (HR = 1.26; P = 0.002). In a separate analysis, the authors also evaluated data from an additional 213 patients in CALGB/SWOG 80405 study who harbored KRAS mutations. These patients were originally included in this study prior to knowledge that ERBITUX® only benefited KRAS wild-type tumors. In this group of patients, those with left-sided primary tumors again achieved a longer median OS (30.3 months) compared to 23.1 months, among patients with right-sided tumors.

It was concluded that the biology of tumors originating in the right colon may be different from those originating in the left colon with ERBITUX® showing superiority over AVASTIN® when combined with chemotherapy in KRAS wild-type patients with left-sided colon cancer, whereas patients with right-sided colon cancer appear to benefit more from AVASTIN® based chemotherapy regimen. Regardless of KRAS mutational status, AVASTIN® based, first line chemotherapy regimen should be considered, for all patients with metastatic colorectal cancer, with a right-sided primary tumor. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Venook AP, Niedzwiecki D, Innocenti F, et al. J Clin Oncol 34, 2016 (suppl; abstr 3504)

Andexanet Alfa – An Antidote for Acute Major Bleeding Associated with New Oral Anticoagulants

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SUMMARY: There are presently four New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism. They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), 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, there are no specific agents presently 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 October 16, 2015, granted accelerated approval to Idarucizumab (PRAXBIND®), for the treatment of patients treated with Dabigatran (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 other New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism such as XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), are Factor Xa inhibitors and do not have an antidote. As such, some Health Care Providers have discouraged their patients from taking these direct oral anticoagulants until an antidote became available, should their patients need urgent surgical intervention.

Andexanet alfa (AndexXa®) is a recombinant, modified human Factor Xa decoy protein without intrinsic catalytic activity, that binds Factor Xa inhibitors. In a previously published study, AndexXa® reversed the anticoagulant activity of ELIQUIS® and XARELTO® in older healthy participants within minutes after administration, and reduced both the unbound fraction of the plasma level of factor Xa inhibitor and anti-Factor Xa activity, with minimal clinical toxicity (N Engl J Med 2015; 373:2413-242). The AndexXa®, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors (ANNEXA-4) study is an ongoing, multicenter, prospective, open-label, single-group study designed to evaluate the use of AndexXa® in patients with acute major bleeding that was potentially life-threatening.

The authors in this interim report described the outcomes of 67 patients, for whom complete data was available. Patients in this study had acute major bleeding within 18 hours after the administration of one of four Factor Xa inhibitors – ELIQUIS®, XARELTO®, SAVAYSA®, or LOVENOX® (Enoxaparin). Acute major bleeding was defined as potentially life-threatening with signs or symptoms of hemodynamic compromise, decrease in hemoglobin of at least 2 gm/dl, symptomatic bleeding in a critical area or organ. The mean patient age was 77 years, and most patients had a history of cardiovascular disease and thrombotic events and bleeding was predominantly gastrointestinal or intracranial. An independent committee determined hemostatic efficacy on the basis of predetermined criteria. The baseline value for anti-Factor Xa activity was at least 75 ng/ml and 0.5 IU/ml or more for those receiving LOVENOX® and patients had confirmed bleeding severity. 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.

It was noted that following the bolus dose of AndexXa®, the median anti-Factor Xa activity decreased by 89% from baseline, among patients receiving XARELTO® and by 93% among patients receiving ELIQUIS® and these levels remained the same during the 2-hour infusion. Four hours after the end of the infusion, the relative decrease in the anti-Factor Xa activity from baseline, among patients receiving XARELTO® was 39% and 30% among those receiving ELIQUIS®. Twelve hours after the AndexXa® infusion, hemostatic efficacy was adjudicated as excellent or good by the independent committee, in 79% of the patients and was consistent across all subgroups. During the 30-day follow up period, thrombotic events occurred in 18% of the patients.

The authors concluded that AndexXa® rapidly reversed anti-Factor Xa activity without significant toxicity, in 79% of the patients, 12 hours after an infusion of AndexXa®. This study also demonstrated that prolonged reversal of Factor Xa inhibition may not be necessary to achieve a good hemostatic response with AndexXa®. 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

Clinically Localized Prostate Cancer – Treatment or Active Monitoring

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease. The widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on Prostate Specific Antigen (PSA) levels remains controversial and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer. Previously published trials evaluated the effectiveness of treatment, but they did not compare Surgery, Radiotherapy and Active Monitoring.

Prostate Testing for Cancer and Treatment (ProtecT) study is a prospective, randomized trial, which compared Active Monitoring, Radical Prostatectomy, and External Beam Radiotherapy, for the treatment of PSA-detected clinically localized prostate cancer. A total of 1,643 patients were randomly assigned to Radical Prostatectomy (N=553), Radiotherapy (N=545) or Active Monitoring (N=545). Patients in the Active Monitoring group were evaluated every 3 months for the first year, then every 6-12 months thereafter and radical treatment with curative intent was offered, based on changes in PSA levels. This is different from “watchful waiting”, which has no planned curative radical treatment on disease progression. The median age in this study was 62 yrs, the median PSA level was 4.6 ng/ml, 77% had tumors with a Gleason score of 6 and 76% had Stage T1c disease. The primary end point was prostate cancer mortality at a median of 10 years of follow-up, with prostate cancer-related deaths defined as deaths that were definitely or probably due to prostate cancer or its treatment. Secondary end points included all-cause mortality and the rates of metastases, clinical progression, primary treatment failure, and treatment complications.

At a median follow up of 10 years, prostate cancer-specific mortality was low at approximately 1% irrespective of treatment and all-cause mortality was also low at approximately 10%. However, higher rates of disease progression were seen in the Active Monitoring group (22.9 events per 1000 person-years) compared to the Surgery group (8.9 events per 1000 person-years) or the Radiotherapy group (9.0 events per 1000 person-years). This meant that patients assigned to Active Monitoring were significantly more likely to have metastatic disease than those assigned to treatment (P<0.001 for the overall comparison).

The authors in a companion article (N Engl J Med. DOI: 10.1056/NEJMoa1606221) focused on the patient-reported outcomes after Monitoring, Surgery and Radiotherapy over 6 years of follow up. Prostatectomy had the greatest negative effect on urinary continence and sexual function, whereas Radiotherapy plus neoadjuvant androgen-deprivation therapy had more of a negative effect on bowel function, urinary voiding and nocturia, although patients recovered some function over time. Approximately 44% of the patient’s who were assigned to Active Monitoring, did not receive radical curative treatment and were able to avoid these toxicities.

It was concluded that at a median follow up of 10 yrs, prostate cancer-specific mortality was low, irrespective of the treatment given, with similar efficacy outcomes but with a variable impact on quality of life. However, it should be noted that patients assigned to Active Monitoring were significantly more likely to have metastatic disease than those assigned to treatment. This in turn would warrant salvage treatment, which could result in toxicities as well. Further follow up, evaluating long term survival and the accompanying risk/benefits, will allow patients to make informed decisions, with regards to the treatment options, for clinically localized prostate cancer. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. Hamdy FC, Donovan JL, Lane JA, et al. for the ProtecT Study Group. September 14, 2016DOI: 10.1056/NEJMoa1606220

Proton Beam Therapy May Improve Survival Compared to Conventional Radiation in Stage II and III NSCLC Patients

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SUMMARY: Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016 about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Even though Photon-based external beam radiation plus concurrent chemotherapy is the current standard of care for patients with unresectable stage III NSCLC, Proton beam therapy is emerging as an alternative to conventional Photon beam therapy for many cancer types. Radiation Therapy involves the use of X-Rays, Gamma rays and charged particles for cancer treatment. External beam radiation therapy is most often delivered using a linear accelerator in the form of Photon beams (either X-rays or Gamma rays). Photons have no mass and are packets of energy of an electromagnetic wave. Electrons and Protons are charged particles and Electrons are considered light particles whereas Protons are considered heavy particles. Electron beams are used to irradiate skin and superficial tumors, as they are unable to penetrate deep into the tissues. The different types of external beam radiation treatments include 3-Dimensional Conformal Radiation Therapy (3D-CRT) meant to deliver radiation to very precisely shaped target areas, IMRT or Intensity Modulated Radiation Therapy which allows different areas of a tumor or nearby tissues to receive different doses of radiation, Image Guided Radiation Therapy (IGRT) which allows reduction in the planned volume of tissue to be treated as changes in a tumor size are noted during treatment, Stereotactic RadioSurgery (SRS) which can deliver one or more high doses of radiation to a small tumor, Stereotactic Body Radiation Therapy (SBRT) or CYBERKNIFE® which is similar to SRS but also takes the normal motion of the body into account while treating malignancies involving the lung and liver and Proton beam therapy. Proton beams unlike Photons, enter the skin and travel through the tissues and deposit much of their energy at the end of their path (known as the Bragg peak) and deposit less energy along the way. This is unlike Photons which deposit energy all along the path through the tissues and the deposited dose decreases with increasing depth. As a result, with Proton beam therapy, normal tissues are exposed to less radiation compared with Photons. Despite this advantage, tissue heterogeneity such as organ motion, tumor volume changes during treatment can have a significant negative impact on target coverage for Proton beam therapy and can result in damage to the surrounding tissues and potential complications.

It has remained unclear whether Proton beam therapy improves Overall Survival (OS) in patients with NSCLC. To address this question, the authors conducted a retrospective analysis using the National Cancer Data Base (NCDB) and analyzed outcomes and predictors associated with Proton beam therapy for NSCLC. This analysis included 140,383 patients with stage I to stage IV NSCLC, treated with thoracic radiation from 2004-2012, of whom 59% had stage II and III disease. Of these patients, 140,035 were treated with Photon beam therapy and 348 with Proton beam therapy. The median age was 68 yrs, 57% were males, 85% were Caucasian, 27% were treated at academic centers and 78% in metropolitan areas. To reduce treatment selection bias, propensity score matching method was implemented.

It was noted that patients were less likely to receive Proton beam therapy in community or comprehensive community centers compared to academic centers (P< 0.001). Further, patients who received Proton beam therapy were more likely to have a higher education and income. On multivariate analysis, it was noted that the risk for death was greater with use of Photon beam therapy compared to Proton beam therapy (HR=1.46; P<0.001). Among patients with stage II and III disease, 5 year OS was superior with Proton beam therapy compared with Photon beam therapy (22.3% versus 15%; P=0.01). Patients with stage II and III disease who received Photon beam therapy had worse OS both in multivariate (HR=1.19; P=0.06) and univariate (HR=1.23; P=0.02) analyses, compared with Proton beam therapy. Proton beam therapy was associated with better 5 year OS compared to Photon beam therapy (23% vs. 14%; P=0.02), on propensity matched analysis. The median OS was 11 months with Photon therapy compared to 19 months with Proton therapy.

The authors concluded that in this retrospective database analysis, thoracic radiation with Proton beam therapy was associated with better survival rates for patients with stage II and III NSCLC. An ongoing randomized phase III trial (NRG Oncology 1308) involving stage III NSCLC patients is evaluating if chemotherapy and Proton beam therapy is superior to chemotherapy and Photon beam therapy. National Cancer Data Base analysis of proton versus photon radiotherapy in non-small cell lung cancer (NSCLC). Behera M, OConnell KA, Liu Y, et al. J Clin Oncol 34, 2016 (suppl; abstr 8501)

STIVARGA® Improves Overall Survival in Advanced Hepatocellular Carcinoma

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SUMMARY: The American Cancer Society estimates that about 39,230 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the US for 2016 and 27,170 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC). There are however no proven or approved second line treatment options for patients with advanced HCC. STIVARGA® (Regorafenib) is a small molecule, multikinase inhibitor, that blocks a variety of kinases known to promote angiogenesis (VEGF Receptor Tyrosine Kinases), oncogenesis (c-kit, BRAF, BRAF-V600E) and the tumor microenvironment (PDGFR, FGFR). STIVARGA® demonstrated significant activity as second line treatment in a phase II study, in patients with intermediate or advanced HCC, who had disease progression on NEXAVAR®.

RESORCE (REgorafenib after SORafenib in hepatocellular Carcinoma) is a double-blind, placebo-controlled, multicenter, phase III trial in which 573 patients were randomized in a 2:1 ratio to receive either STIVARGA® (N=379) or placebo (N=194). Enrolled HCC patients had Barcelona Clinic Liver Cancer (BCLC) stage B or C, Child-Pugh A liver function and had received NEXAVAR® for 20 days or more at 400 mg/day or more and had documented radiological progression on NEXAVAR®. Patients received either STIVARGA® 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. All patients received Best Supportive Care and treatment was continued until disease progression, death, or unacceptable toxicity. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS), Time to Progression (TTP), Response Rate (RR), and Disease Control Rate (DCR).

After a median of 3.6 months of treatment, the OS was 10.6 months for the STIVARGA® group versus 7.8 months for the placebo group (HR=0.62; P<0.001). The median PFS with STIVARGA® versus placebo was 3.1 months vs 1.5 months (HR=0.46; P<0.001) respectively. These findings meant a 38% reduction in the risk of death and a 54% reduction in the risk of progression or death, compared to placebo. When compared with placebo, median TTP with STIVARGA® was 3.2 vs 1.5 months (HR 0.44; P<0.001), DCR defined as complete and partial responses plus stable disease was 65.2% vs 36.1% (P<0.001) and overall RR (Complete and Partial responses) were 10.6% vs 4.1% (P=0.005), respectively. Grade 3 or higher adverse events occurred more frequently with STIVARGA® when compared with placebo and included hypertension, hand-foot syndrome, fatigue and diarrhea.

The authors concluded that STIVARGA® significantly improved OS in patients with HCC who progressed during treatment with NEXAVAR®, pointing out that we have an effective second-line agent for a very difficult-to-treat cancer. Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international, randomized phase 3 RESORCE trial. Bruix J, Merle P, Granito A, et al. Ann Oncol (2016) 27 (suppl 2): ii140-ii141 doi:10.1093/annonc/mdw237.03

Long Term Survival in Advanced Renal Cell Carcinoma with OPDIVO®

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SUMMARY: The American Cancer Society estimates that about 62,700 new cases of kidney cancer will be diagnosed in the United States in 2016 and over 14,000 patients will die from this disease. The 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® was approved by the FDA in November 2015, for the treatment of advanced Renal Cell Carcinoma in patients who have received prior anti-angiogenic therapy. This approval was based on a randomized, open-label, phase III study (CheckMate 025), in which previously treated patients with advanced clear cell RCC, were randomly assigned to receive either OPDIVO® or AFINITOR® (N Engl J Med 2015; 373:1803-1813). It was noted that the median Overall Survival (OS) 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 seen with a minimum follow up of 14 months.

The authors in this publication reported the long term OS results from phase I and II OPDIVO® studies, leading to CheckMate 025 phase III study. In the phase I open-label study, 34 patients with advanced Renal Cell Carcinoma, with ECOG Performance Status of 2 or less and who had prior systemic treatment with 1-5 regimens, received OPDIVO® at a dose of 1 or 10 mg/kg every 2 weeks (J Clin Oncol 2015;33:2013-2020). At a minimum follow up of 50.5 months, the Objective Response Rate (ORR) was 29% and the median Duration of Response was 12.9 months. The 3 and 5 year OS rates were 41% and 34% respectively. In the phase II study, 167 patients with advanced Renal Cell Carcinoma with KPS of 70% or more and who had prior treatment with 1-3 regimens in the metastatic setting, received OPDIVO® at a dose of 0.3, 2, or 10 mg/kg every 3 weeks (J Clin Oncol 2015;33:1430–37). At a minimum follow up of 38 months, ORR was 21% and the median Duration of Response was 22 months. The 3 year OS rate was 35% and 4 year OS rate was 29%. Long-term survival was observed in MSKCC good, intermediate and poor-risk patients, as well as in patients with excellent or reduced Karnofsky Performance Status.

The authors concluded that with this longest follow up data reported to date with any anti-PD-1/PD-L1 agent in advanced Renal Cell Carcinoma, about 33% of patients treated with OPDIVO® are alive at 5 years in the phase I study and at 3 years in the phase II study. Potential predictors of long term survival with OPDIVO® are being explored, in this previously treated patient population. Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. McDermott DF, Motzer RJ, Atkins MB, et al. J Clin Oncol 34, 2016 (suppl; abstr 4507)

New NCCN Guidelines for the Diagnosis and Treatment of 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, about 30,330 new cases will be diagnosed in 2016 and 12,650 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. With a record number of regulatory approvals for Myeloma treatment over the past 12 years, the median survival for patients with Myeloma is over 10 years. The recent new drugs approved for the treatment of relapsed/refractory Multiple Myeloma include a Histone Decetylase inhibitor (FARYDAK®) and 2 monoclonal antibodies, Daratumumab (DARZALEX®) and Elotuzumab (EMPLICITI®). The two most important determinants of Myeloma patient outcomes include, Performance Status and tumor genomics. Performance Status can be assessed using currently validated instruments and patients can be defined as Fit, Intermediate Fit, or Frail. Patients with chromosomal abnormalities t(4;14), t(14;16), t(14;20) or del 17p are considered to fall in the high risk group.

The updated Multiple Myeloma guidelines were presented at the National Comprehensive Cancer Network (NCCN) 21st Annual Conference on April 1, 2016. These guidelines include the use of the Revised International Staging System for Multiple Myeloma, treatment of asymptomatic patients even if they do not fit the CRAB criteria (Calcium elevation, Renal insufficiency, Anemia, or Bone abnormalities) and incorporation of a triplet instead of doublet for newly diagnosed Fit Myeloma patients, regardless of transplant eligibility.

Revised International Staging System for Multiple Myeloma

The revised ISS (R-ISS) combines the International Staging System (ISS) with chromosomal abnormalities detected by interphase Fluorescent In Situ Hybridization after CD138 plasma cell purification and serum Lactate DeHydrogenase (LDH).

R-ISS I: ISS stage I (serum β2-microglobulin level less than 3.5 mg/L and serum albumin level 3.5 g/dL or more), absence of high risk cytogenetics and normal LDH level (less than the upper limit of normal range)

R-ISS III: ISS stage III (serum β2-microglobulin level more than 5.5 mg/L) and high-risk cytogenetics or high LDH level

R-ISS II: Includes all the other possible combinations

New Definition of Active MM in Asymptomatic Patients Qualifying for Treatment

• Bone marrow plasmacytosis 60% or more

• Abnormal free light chain ratio 100 or more (involved kappa) or less than 0.01 (involved lambda)

• Focal bone marrow lesions detected by functional imaging such as a PET scan or a MRI

New Treatment Options

For newly diagnosed patients, who are transplant candidates or Fit non-transplant candidates, Lenalidomide/Bortezomib/Dexamethasone should be incorporated as the preferred regimen based on a phase III randomized trial showing superiority of this triplet therapy over a doublet. This triplet improved Complete Response (CR) rates (including molecular CR), Progression Free Survival (PFS), and Overall Survival (OS) compared with Lenalidomide/Dexamethasone doublet. (Blood. 2015;126:25). Another all oral triplet included in the guidelines is a combination of Lenalidomide, Ixazomib and Dexamethasone. Ixazomib (NINLARO®) is an oral proteasome inhibitor and has a half-life of 3 to 4 days and requires only once weekly administration. The combination of Carfilzomib/Lenalidomide, and Dexamethasone was included in the new guidelines as a category 2A front-line treatment, based on a phase 1/2 study (Blood. 2012;120:1801-1809). Maintenance therapy is now considered standard of care regardless of transplantation and for newly diagnosed non-transplant candidates, a new standard of care is continuous Lenalidomide/Dexamethasone, which was found to improve PFS significantly, with a favorable safety profile (N Engl J Med. 2014;371:906-917). Three drug maintenance therapy may benefit high risk patients and should be considered.

In conclusion, these latest updates reflect the rapid advances in the diagnosis and treatment of Multiple Myeloma. National Comprehensive Cancer Network (NCCN) 21st Annual Conference. Presented April 1, 2016, Hollywood, FL.

Anthracycline Regimen Superior in High Risk Early Stage Breast Cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. The superiority of Anthracycline based chemotherapy regimens for the treatment of breast cancer was demonstrated in the mid 1980’s. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) overview analysis published in the Lancet in 1998 concluded that there was a 12% proportional reduction in the risk of recurrence and 11% proportional reduction in mortality with Anthracycline containing regimens versus non-Anthracycline containing chemotherapy regimens. There is however a small risk of cardiotoxicity even with cumulative doses of Doxorubicin of less than 550 mg/m2. Jones and colleagues in 2009 published the results of US Oncology Research Trial 9735 which compared TC with AC and concluded that TC is superior to AC chemotherapy regimen and would be a reasonable option for both younger and older patients requiring chemotherapy, who are hormone receptor positive or negative with either node negative disease or have 1-3 positive lymph nodes.

The ABC (Anthracyclines in early Breast Cancer) adjuvant phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49) done in sequence, were developed by USOR and NSABP to determine if a regimen of TC for 6 cycles was non-inferior to combination regimens of Doxorubicin/Cyclophosphamide with Docetaxel or Paclitaxel (TaxAC), in patients with resected, high risk, HER2-negative breast cancer. The final analysis set from these collective trials known as ABC included 4130 patients, of whom 2078 patients were randomized to TC and 2052 patients to TaxAC. The treatment groups were well balanced. Sixty nine percent (69%) were hormone receptor positive, 41% were node negative and 51% had high grade tumors. The Primary Endpoint was invasive Disease Free Survival (iDFS) and the median follow up was 3.2 years.

At the time of pre-planned analysis with 399 invasive Disease Free Survival events, the 4 year DFS was significantly higher with TaxAC (90.7%) compared to 88.2% with TC (P=0.04). TaxAC provided little or no added benefit in hormone receptor positive and node negative patients. There was some benefit for patients with hormone receptor positive disease with 1-3 positive lymph nodes and those with hormone receptor negative disease with negative nodes. The most benefit was seen with TaxAC in patients with hormone receptor positive disease with 4 or more positive lymph nodes and in those with hormone receptor negative disease with positive nodes. The 4 year Overall Survival was comparable in both treatment groups although longer follow up is needed.

It can be concluded based on these findings that in early stage breast cancer, Anthracycline containing regimens are superior to non-Anthracycline regimens in patients with triple negative breast cancer and for those hormone receptor positive patients with 4 or more positive lymph nodes. There may be some benefit in select group of hormone receptor positive patients with 1-3 positive lymph nodes and in some patients with node negative, hormone receptor negative disease. Non-Anthracycline regimen such as TC is appropriate in node negative, hormone receptor positive patients. Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. Blum JL, Flynn PJ, Yothers G, et al. J Clin Oncol 34, 2016 (suppl; abstr 1000)