TASIGNA® Maintains Durable Deep Molecular Responses Even after Treatment Discontinuation in Chronic Phase CML

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,220 new CML cases will be diagnosed in the United States in 2016 and about 1,070 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC®, share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected, using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that deep molecular response (MR4.5) is a new molecular predictor of long term survival in CML patients and was achieved in a majority of patients treated with optimized dose of GLEEVEC®. It has been hypothesized based on previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, stopping CML therapy is currently not a clinical recommendation and should only be considered in the context of a clinical trial.

ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trial – Following REsponsE in De nOvo CML-CP Patients) is a single arm, open-label, international, multicenter phase II study, which evaluated Treatment-Free Remission (TFR) of patients with CML-Chronic Phase, after stopping TASIGNA® (Nilotinib), following frontline treatment with this agent. This analysis included 215 patients Philadelphia Chromosome positive (Ph+) CML patients in the Chronic Phase, who received at least 2 years of frontline treatment with TASIGNA® and had achieved a Molecular Response 4.5 (BCR-ABL International Scale 0.0032%). Patients then continued TASIGNA® for an additional year (Consolidation Phase) with close monitoring for sustained deep molecular response using real-time quantitative PCR assessments at 12-week intervals. Patients who had a molecular response no worse than MR4 (0.01% or less) in the last assessment of the Consolidation phase (N=190), were then eligible to stop treatment (TFR phase). The median age of these patients was 55 years. The median time from study entry to first MR4.5 was 18 months. The median duration of treatment on TASIGNA® prior to TFR was 43 months.

After 48 weeks without treatment, 51.6% of the 190 patients in the TFR phase remained in MMR and did not require re-initiation of treatment. Of the 86 patients who restarted treatment with TASIGNA® due to loss of MMR, 99% were able to regain MMR and 88% were able to regain MR4.5. The median time to MMR for these patients was 7.9 weeks and for MR4.5 was 13.1 weeks. About 25% of the patients experienced musculoskeletal pain during the first year of the TFR phase, which is an expected adverse event from TKI withdrawal.

The authors concluded that TFR is clinically meaningful and a high rate of sustained MR4.5 leads to stable disease. TASIGNA® is the first Tyrosine Kinase Inhibitor to demonstrate successful TFR in a large proportion of eligible patients after relatively short duration of treatment of 3.6 years. Over 50% of patients who stopped therapy were able to remain treatment free at 48 weeks. The authors recommended that frequent patient monitoring during Treatment-Free Remission (TFR) period, allows timely determination of loss of MR4.0 and MMR and the need for treatment re-initiation. Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTFreedom study. Hochhaus A, Masszi T, Giles FJ, et al. J Clin Oncol 34, 2016 (suppl; abstr 7001)

Late Breaking Abstract – ASCO 2016 Biosimilar of HERCEPTIN® Equally Effective and Safe

SUMMARY: A Biosimilar product is a biological product that is approved based on its high similarity to an already approved biological product (also known as reference product). Biological products are made from living organisms including humans, animals and microorganisms such as bacteria or yeast and are manufactured through biotechnology, derived from natural sources or produced synthetically. Biological products have larger molecules with a complex structure than conventional drugs (also known as small molecule drugs). Unlike biological products, conventional drugs are made of pure chemical substances and their structures can be identified. A generic drug is a copy of brand name drug and has the same active ingredient and is the same as brand name drug in dosage form, safety and strength, route of administration, quality, performance characteristics and intended use. Therefore, brand name and the generic drugs are bioequivalent. The Affordable Care Act in 2010 created an abbreviated licensure pathway for biological products that are demonstrated to be “Biosimilar” to, or “interchangeable” with an FDA-licensed (FDA approved) biological product (reference product). The Biosimilar must show that it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. A Biosimilar product can only be approved by the FDA if it has the same mechanism of action, route of administration, dosage form and strength as the reference product, and only for the indications and conditions of use that have been approved for the reference product. Biosimilars are not as easy to manufacture as generics (copies of brand name drugs) because of the complexity of the structure of the biologic product and the process used to make a biologic product. The facilities where Biosimilars are manufactured must also meet the FDA’s standards.

Heritage is a double-blind, randomized phase III trial in which the efficacy and safety of Myl-1401O, a Biosimilar, was compared with HERCEPTIN®. The randomization included 500 patients treated at 95 sites worldwide, with centrally confirmed, measurable HER2 positive metastatic breast cancer, who had not received prior chemotherapy or HERCEPTIN® for their metastatic disease. Patients received either Myl-1401O or HERCEPTIN® along with TAXOTERE® (Docetaxel) or TAXOL® (Paclitaxel) administered every 3 weeks for a minimum of 8 cycles (24 weeks), with the antibody therapy continued, until disease progression. Both antibodies were administered with a loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg every 3 weeks. Approximately 44% of the enrolled patients had hormone receptor positive disease and 84% received TAXOTERE®. The final analysis included 458 patients of whom 230 were in the Myl-1401O group and 228 were in the HERCEPTIN® group. The Primary endpoint was Overall Response Rate (ORR) at 24 weeks and Secondary endpoints include Progression Free Survival (PFS), Overall Survival (OS) and Safety.

The ORR after 24 weeks of treatment was 69.6% for the Myl-1401O group and 64% for the HERCEPTIN® group and this was not statistically significant. The median PFS had not yet been reached. Safety data in both treatment groups were comparable and there was no significant change in cardiac function from baseline to Week 24 in either group. The dose-normalized maximum concentration and Area Under the Curve, were similar for both antibodies.

The authors concluded that this study is one of the first trials of Biosimilars in oncology to demonstrate similar results and they added that MYL-1401O is equivalent to HERCEPTIN®, when given in combination with a Taxane, as first line therapy, for patients with HER2 positive metastatic breast cancer. Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin. Rugo HS, Barve A, Waller CF, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA503)

Influence of MSI on Prognostic Effect of BRAF and KRAS Mutations in Patients with Stage III Colon Cancer

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. The role of adjuvant chemotherapy in patients with Stage III ColoRectalCancer (CRC) has been well established, with improvement in Disease Free Survival (DFS) and Overall Survival (OS). However, not all patients equally benefit from this therapy. Patients with MSI (Micro Satellite Instability) tumor phenotype have better survival when cancer is at an earlier stage although this beneficial effect in Stage III colon cancer remains unclear.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and when sporadic, the DNA MisMatchRepair gene is MLH1. Defective MisMatchRepair can also manifest as a germline mutation occurring in 1 of the 4 MisMatchRepair genes which include MLH1, MSH2, MSH6, PMS2. This produces Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC), an autosomal dominant disorder and is the most common form of hereditary colon cancer, accounting for 35% of the MSI colorectal cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. MSI (Micro Satellite Instability) testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). MLH1 gene is often lost in association with PMS2.

Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations because KRAS mutations are predictive of resistance to EGFR targeted therapy and BRAF V600E is recognized as a marker of poor prognosis in this patient group. BRAF mutations occur in approximately 45% of patients with sporadic colorectal cancer with MSI but not seen in patients with Lynch syndrome. The prognostic effect of these mutations in early stage disease has however remained controversial. This is a Post Hoc Analysis of the PETACC-8 study, a randomized phase III trial, in which patients with resected Stage III colon cancer received treatment with adjuvant FOLFOX with or without Cetuximab. The authors in this publication examined the prognostic effect of BRAF and KRAS mutations in this patient population, as it relates to MSI of the tumor.

The PETACC-8 trial enrolled 2559 patients with surgically resected colon cancer, treated with adjuvant FOLFOX chemotherapy regimen. The median age was 60 years. MisMatch Repair, BRAF V600E, and KRAS exon 2 mutational status, were determined on tumor blocks that were collected prospectively from the enrolled patients. MSI phenotype was noted in 9.9% (N=177), KRAS mutations in 33.1% (N=588) and BRAF V600E mutations in 9% (N=148) of the patients. The primary end point was Disease Free Survival (DFS) and Overall Survival (OS), as it relates to these mutations.

In multivariate analysis, MSI and BRAF V600E mutations for DFS were not prognostic, whereas KRAS mutation was associated with significantly shorter DFS (P<0.001) and OS (P=0.008). The subgroup analysis showed that in patients with Micro Satellite Stable (MSS) tumors, DFS and OS was inferior among those with KRAS and BRAF V600E mutation and were independently associated with worse clinical outcomes. In patients with MSI tumors, KRAS status was not prognostic, whereas BRAF V600E mutation was associated with significantly longer DFS (P=0.04), but not OS (P=0.08).

The authors based on this large analysis of patients with Stage III colon cancer receiving FOFOX adjuvant chemotherapy, concluded that BRAF V600E and KRAS mutations were significantly associated with shorter DFS and OS in patients with Micro Satellite Stable (MSS) tumors, but not in patients with MSI tumors. Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab. A Post Hoc Analysis of the PETACC-8 Trial. Taieb J, Zaanan A, Le Malicot, et al. JAMA Oncol. 2016;2:643-653.

SOMATULINE® – Tumor Growth Rate (TGR) a Better Indicator of Therapeutic Activity than RECIST in NeuroEndocrine Tumors

SUMMARY: NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis.

SOMATULINE® (Lanreotide) is a synthetic analogue of Somatostatin, a naturally occurring inhibitory hormone, which blocks the release of other hormones, including Insulin, Glucagon, Growth hormone, Thyroid Stimulating Hormone, etc. The approval of SOMATULINE® by the FDA for the treatment of patients with unresectable, well or moderately differentiated, locally advanced or metastatic GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs), was based on the demonstration of improved Progression Free Survival (PFS) in the CLARINET trial, a multicenter, international, randomized placebo-controlled study. This study enrolled 204 patients of whom 55% (113/204) had NeuroEndocrine Tumors arising outside the pancreas. Patients were randomized to receive either SOMATULINE® 120 mg or placebo, subcutaneously every 28 days. This trial demonstrated a significant prolongation of PFS for the SOMATULINE® group compared to the placebo group (HR 0.47; P<0.001).

The authors now report an exploratory analysis of Tumor Growth Rate (TGR) with SOMATULINE® in patients with NeuroEndocrine Tumors from the CLARINET study. TGR has been proposed as a novel measure of tumor response. Target lesions were assessed by central radiologic review based on RECIST criteria. TGR was defined as the percentage of variation of tumor volume per month. This was calculated from sum-of-longest-diameters (SLD) of original target lesions (excluding new ones) on 2 CT scans during defined periods, which was 12-24 weeks prior to randomization versus baseline (pretreatment) and baseline versus each visit or between consecutive visits. TGR pre- and post-treatment were compared between treatment groups.

It was noted that even though all patients were classified as stable based on RECIST, a significant proportion of patients treated with SOMATULINE® showed changes in the TGR, following 12 weeks of treatment. This benefit was not seen in those on placebo. The TGR benefit with SOMATULINE® was significant compared to placebo and was maintained at subsequent study visits.

The authors concluded that in patients with NeuroEndocrine Tumors, Tumor Growth Rate provides an early and more precise characterization of therapeutic activity than RECIST and requires validation in prospective studies. Exploratory analysis of tumor growth rate (TGR) with lanreotide depot/autogel (LAN) in patients (pts) with neuroendocrine tumors (NETs) from the CLARINET study. Caplin ME, Pavel ME, Ruszniewski P, et al. J Clin Oncol 34, 2016 (suppl; abstr 4096)

Ovarian Suppression in Premenopausal Women with ER Positive Breast Cancer – ASCO Clinical Practice Guideline Update

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. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol, in extragonadal/peripheral tissues. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues.

An Update Panel of the ASCO conducted a systematic review of randomized clinical trials investigating ovarian suppression and published this update. This information is an update of the ASCO adjuvant endocrine therapy guideline, regarding the risks and benefits of ovarian suppression in addition to standard adjuvant therapy, in premenopausal women with Estrogen Receptor positive breast cancer. The ASCO Update Panel addressed the following questions with regard to premenopausal women with stage I-III hormone receptor-positive Breast Cancer:

1) Should premenopausal women with ER positive tumors receive adjuvant ovarian suppression in addition to standard adjuvant therapy, and, if so, in which subsets of patients?

2) If ovarian suppression is recommended, should ovarian suppression be administered in combination with Tamoxifen or an Aromatase Inhibitor?

Recommendation 1

1.1 The panel recommends that higher risk patients should receive ovarian suppression in addition to adjuvant endocrine therapy, whereas lower-risk patients should not. (For women with higher risk cancers who receive chemotherapy but remain premenopausal, ovarian suppression added to Tamoxifen reduces the risk of breast cancer recurrence).

1.2 Women with stage II or III Breast Cancers who would ordinarily be advised to receive adjuvant chemotherapy should receive ovarian suppression in addition to endocrine therapy.

1.3 Women with stage I or II breast cancers at higher risk of recurrence, who might consider chemotherapy, may also be offered ovarian suppression in addition to endocrine therapy.

1.4 Women with stage I breast cancers not warranting chemotherapy should receive endocrine therapy but not ovarian suppression.

1.5 Women with node-negative cancers 1 cm or less (T1a, T1b) should receive endocrine therapy but not ovarian suppression.

Qualifying Statements

• The standard duration of ovarian suppression in the included trials was 5 years. The panel therefore supports ovarian suppression for 5 years as there is no comparative data available on alternative durations.

• To date, there is no adequate evidence for assessing the benefit of adjuvant ovarian suppression in women at sufficient risk to warrant chemotherapy compared with 10 years of Tamoxifen.

• There is no current role for ovarian suppression as adjuvant therapy in ER negative breast cancers.

• There are substantial adverse effects related to ovarian suppression. Clinicians and patients should take this into consideration when choosing ovarian suppression.

• The long-term effects of ovarian suppression on breast cancer risk and survival are not yet established.

Recommendation 2

Ovarian suppression may be administered with either Tamoxifen or an Aromatase Inhibitor.

Qualifying Statements

• Tamoxifen and Aromatase Inhibitor therapy differ in their side effect profiles, which may affect patient preferences.

• Clinicians should be alert to the possibility of incomplete ovarian suppression with Gonadotropin-Releasing Hormone agonist therapy and evaluate patients for whom there is concern about residual ovarian function.

Burstein HJ, Lacchetti C, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol 2016;34:1689-1701

FDA Approves KEYTRUDA® for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

SUMMARY: The FDA on August 5, 2016, granted accelerated approval to KEYTRUDA® (Pembrolizumab) for the treatment of patients with recurrent or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC), with disease progression on or after Platinum containing chemotherapy. The American Cancer Society estimates that 61,760 people will be diagnosed with Head and Neck cancer in 2016 and 13,190 patients will die of the disease. Patients with recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck have a poor prognosis with a median Overall Survival (OS) of about 13 months with first line therapy and about 6 months or less with later lines of therapy. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The accelerated approval of KEYTRUDA® was based on a multicenter, nonrandomized, open-label, multi-cohort phase Ib study (KEYNOTE-012), which included 192 patients with recurrent or metastatic HNSCC. Approximately 33% of the patients were HPV positive and patients have a median of two prior lines of therapy. Almost all enrolled patients (95%) had prior radiation therapy. Median patient age was 60 years. Treatment consisted of KEYTRUDA® 10 mg/kg IV every 2 weeks or 200 mg IV every 3 weeks and continued until disease progression or unacceptable toxicities. Patients without disease progression were treated for up to 24 months. The primary end point was Objective Response Rate (ORR) and Duration of Response. Secondary endpoints included response by HPV status, Progression Free Survival (PFS), and safety. Efficacy was evaluated in 174 of the enrolled patients. The ORR was 16% with a Complete Response Rate of 5%. The median response duration had not been reached at the time of analysis. Among the responding patients, 82% had responses of 6 months or longer. The ORR and Duration of Response were similar irrespective of dosage regimen or HPV status. In a pooled analyses after long term follow up, responses were ongoing in 76% of the patients with a median follow up duration in responders of 12.5 months. Median Overall Survival was 8.5 months and 6 month PFS rate was 24.9%. The most common adverse reactions ((20% or greater) were fatigue, decreased appetite, and dyspnea and these were similar to those occurring in patients with Melanoma or Non Small Cell Lung Cancer, with the exception of an increased incidence of facial edema and new or worsening hypothyroidism.

It was concluded that KEYTRUDA® has significant antitumor activity in recurrent/metastatic Head and Neck Squamous Cell Carcinoma and PD-L1 testing is not needed prior to use of KEYTRUDA® for this indication. As a condition of the accelerated approval, a multicenter, randomized trial is to be conducted for continued approval, establishing the superiority of KEYTRUDA® over standard therapy. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Pooled analyses after long-term follow-up in KEYNOTE-012. Mehra R, Seiwert TY, Mahipal A, et al. J Clin Oncol 34, 2016 (suppl; abstr 6012)

KEYTRUDA® (Pembrolizumab)

The FDA on August 5, 2016 granted accelerated approval to KEYTRUDA® injection for the treatment of patients with recurrent or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. KEYTRUDA® is a product of Merck Sharp & Dohme Corp.

Detection of HPV DNA in the Oral Cavity Increases the Risk of Head and Neck Cancer

SUMMARY: The American Cancer Society estimates that 61,760 people will be diagnosed with Head and Neck cancer in 2016 and 13,190 patients will die of the disease. Over 90% of these malignancies are Squamous Cell Carcinomas (SCCs). Oropharyngeal Squamous Cell Carcinomas (OPSCC) involve the tonsils and base of the tongue and recent studies have shown that over 70% of these tumors are caused by Human Papilloma Virus (HPV) and HPV-16 is the predominant type present in the tumor cells. The CDC estimates that more than 2,370 new cases of Human Papilloma Virus associated Oropharyngeal Squamous Cell Carcinomas (OPSCC) are diagnosed in women and nearly 9,356 are diagnosed in men, each year in the United States and this incidence has been on the rise. The malignant behavior of these tumors is dependent on the expression of viral E6 and E7 oncoproteins that inactivate the tumor suppressor proteins p53 and the retinoblastoma protein (pRb), respectively. HPV-positive OroPharyngeal Squamous Cell Carcinoma is more common among never smokers or light smokers and patients tend to be younger with better performance status.

The authors conducted this prospective study to examine the temporal association between HPV DNA detection of alpha, beta and gamma Human Papilloma Virus (HPV) types in the oral samples and risk of Head and Neck Squamous Cell Carcinoma (HNSCC). A nested case-control study was carried out among 96,650 participants, cancer free at baseline, who provided mouthwash samples in 2 large prospective cohorts: the American Cancer Society Cancer Prevention Study II Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Molecular Detection of DNA from alpha, beta and gamma HPV types in mouthwash samples was performed by next-generation sequencing method. Associations between oral HPV infection and Head and Neck Squamous Cell Carcinoma (HNSCC) were adjusted for smoking status, pack-years and number of alcoholic drinks per week, which are all known and established risk factors for HNSCC.

During an average follow up of 3.9 years in both cohorts, 132 cases of HNSCC were identified which included cancers of the Oropharynx, Oral cavity and Larynx. The authors after analyzing the 132 cases of HNSCC and 396 controls nested within 2 prospective cohorts, found that detection of oral HPV-16 DNA was associated with a 22.4 fold increased risk of incident Oropharyngeal Cancer. Detection of oral beta1-HPV-5 type and gamma11-HPV and gamma12-HPV species was associated with a 3.3 to 5.5 fold higher risk of HNSCC.

The authors concluded that HPV-16 detection in the oral cavity precedes the incidence of Oropharyngeal Squamous Cell Carcinoma and this is the first study to demonstrate a temporal association between HPV DNA detection in mouthwash specimens and risk of HNSCC. Further, other HPVs including beta and gamma species may also play a role in the etiology of HNSCC. Detection of HPV DNA in the oral cavity may have important implications for its use in Oropharygeal cancer screening program. Associations of Oral α-, β-, and γ-Human Papillomavirus Types with Risk of Incident Head and Neck Cancer. Agalliu I, Gapstur S, Chen Z, et al. JAMA Oncol. 2016;2:599-606

XARELTO® Safe and Effective for Cancer Patients with Venous ThromboEmbolism

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality. Patients with unprovoked DVT and PE are two to four times more likely to be diagnosed with cancer within the ensuing 12 months compared to the general population. Approximately 20% of VTE events are related to underlying malignancy and patients with active malignancy have a five to six fold increased risk of VTE. In patients with cancer associated thrombosis, COUMADIN® (Warfarin) and XARELTO® (Rivaroxaban) are often prescribed, despite guidelines recommending Low Molecular Weight Heparin (LMWH) in this patient population. However, patients are less inclined to take LMWH as this is parenteral, expensive, inconvenient and carries the risk of Heparin-Induced Thrombocytopenia. Further, most patients with malignancy require indefinite anticoagulation and the safety and efficacy of LMWH in this setting is unknown. The efficacy and safety of oral, direct Factor Xa inhibitor such as XARELTO® is not well established in patients with VTE and active malignancy.

The authors in this study evaluated the risk and benefits of XARELTO® in this high-risk group of patients. In this case cohort study, the Mayo Thrombophilia Clinic Direct Oral Anticoagulants Registry included patients diagnosed with Deep Vein Thrombosis or Pulmonary Embolism, who were seen and treated with XARELTO® at the Thrombophilia Clinic, Gonda Vascular Center and Mayo Clinic in Rochester, Minn. These units work together and provide streamlined standardized care. Immediate anticoagulation therapy was provided for appropriate patients. Patients with symptomatic PE or extensive symptomatic iliofemoral Deep Vein Thrombosis were hospitalized. All patients with PE also had lower extremity duplex ultrasound to determine the source of embolism. Evaluation included upper extremity venous assessment, if a patient had symptoms suggestive of venous thrombosis or if a Central Venous Catheter was present.

Patients with acute VTE or asymptomatic PE suitable for outpatient anticoagulation therapy were counseled about the pros and cons of each anticoagulant currently approved by the FDA. Additionally, patients with active malignancy and VTE were counseled about the preferred first line of treatment with Low Molecular Weight Heparin, as well as the limited data for XARELTO® in cancer-associated VTE. Patients opting for XARELTO®, were started on treatment within the ensuing hour. Patients were evaluated every 3 months for efficacy and safety and followed prospectively from March 2013 and April 2015. The primary efficacy outcome was symptomatic venous or arterial thromboembolism occurring during the follow up period. The primary safety end point was major bleeding defined as overt bleeding plus a hemoglobin decrease of 2 or more grams/dL after the incident, transfusion of 2 or more units of packed red blood cells, or intracranial, intraspinal, intraocular, retroperitoneal, pericardial, or fatal bleeding.

Two hundred and ninety six (N=296) of the 404 patients in the registry with Venous ThromboEmbolism (VTE), received XARELTO® and had at least 3 months of follow up. Of these 296 patients on XARELTO®, 118 patients (40%) had active malignancy and 178 patients had no cancer. The 3 most common cancer locations were Genitourinary (23.6%), Gastrointestinal (20.3%) and Lung (13.5%). It was noted that there was no significant difference in VTE recurrence between the malignant (3.3%) and the nonmalignant (2.8%) VTE groups (P=0.533). Slightly higher rates for major bleeding (P=0.06) and non major clinically relevant bleeding (P=0.08) were noted in patients with cancer, but this was not statistically significant.

The authors concluded that the efficacy and safety of XARELTO® is similar for VTE patients with and without active malignancy. Efficacy and Safety of Rivaroxaban in Patients with Venous Thromboembolism and Active Malignancy: A Single-Center Registry. Bott-Kitslaar DM, Saadiq RA, McBane RD, et al. Am J Med. 2016; 129: 615-619

Cobas EGFR Mutation Test v2

The FDA on June 1, 2016 approved cobas EGFR Mutation Test v2, using plasma specimens, as a companion diagnostic test for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the Epidermal Growth Factor Receptor (EGFR) gene, to identify patients with metastatic Non Small Cell Lung Cancer (NSCLC) eligible for treatment with TARCEVA® (Erlotinib). Cobas EGFR Mutation Test v2 is a product of Roche Molecular Systems, Inc.