HOPA Publications Committee
Bonnie Labdi, PharmD RPh, Chair
Ashley Glode, PharmD BCOP, Vice Chair
David DeRemer, PharmD BCOP, Board Liaison
Brandi Anders, PharmD BCOP Megan Bodge, PharmD
Megan Brafford, PharmD BCOP
Courtney Cavalieri, PharmD BCOP Morgan Culver, PharmD BCOP
Morgan E. Culver, PharmD BCOP
Erika Gallagher, PharmD BCOP
Lisa Lohr, PharmD BSPharm BCOP BCPS
Jennifer Kwon, PharmD BCOP
Trevor McKibbin, PharmD MS BCOP
Christan Thomas, PharmD BCOP
Board Update: A Year of Introspection and External Connections
Scott Soefje, PharmD MBA BCOP FCCP
As professional organizations grow and mature, it is necessary to stop and self-assess to determine if everything is going well and if the organization is moving in the right direction. This year is one of those times for HOPA. We have started a systematic review of all aspects of HOPA. I would like to explain what we are looking at and then talk about several of the organizations that we have connected with in the past few months.
Earlier this year, we completed negotiations on a new contract with Association Management Center (AMC). We feel this contract has measurable outcomes, meets the needs of HOPA, and provides fair compensation for AMC. We also have completed a review of our health policy advisors and, through a request for proposal, elected to stay with the District Policy Group. We will be negotiating a new contract with them at the end of the year.
The AMC staff completed a review of HOPA policies and procedures and we have updated and modified the policies to match our current initiatives. We also asked each committee to review their policies and submit any updates and changes by the end of the year. Our goal is to begin the next committee year (which starts in June 2016) with a complete and updated set of policies and procedures.
The board completed a self-assessment using a tool provided by BoardSource. We identified gaps, changed some of our board orientation process to fill those gaps, and started an action plan to finish addressing the areas we felt needed the most attention. This is an ongoing evaluation process. As part of this process, we have developed a twice yearly review of the HOPA Executive Director (ED) that addresses board feedback and the progress made toward goals that the ED develops at the beginning of the year. We finalize the evaluation process by providing annual feedback to the ED on the effectiveness of the AMC staff. We feel this total review process creates an environment of continuous improvement in which we learn from mistakes and capitalize on successes.
As many people have realized, the committee structure at HOPA has become unwieldy. With the addition of BCOP recertification, we added fix to six new committees and task forces to meet the needs of the proposal that we submitted. Charges originally given to one committee have moved to another to meet current needs; we have overlapping charges in some cases, and overall the committee structure is losing its effectiveness. Our plan is to develop a task force (yes, another one) to develop a new committee structure to meet our current needs. The task force will start in early 2016 and make a recommendation to the board for implementation in the 2017 committee year. It sounds like a long time, but we want to get this right and not rush the process. Stay tuned for updates on committee structure.
We also will be reviewing our bylaws. There are several items, such as certain committees, that may no longer be necessary for our organization. As we develop new ways to do things, we will update the bylaws to reflect our roles and obligations. This review also will occur in 2016 and requires a membership vote.
The last introspection area to discuss is that HOPA has started the process of revitalizing our website and updating our brand. We plan to introduce our new brand and website shortly after the 2016 annual meeting. We will be modernizing the look and feel of the HOPA brand, and the website will be more user friendly and reflect state-of-the-art Web design features. A small part of this was the move to the HOPA Central messaging platform, which has been successful and offers tremendous opportunities as we grow.
From the comments above, you might think HOPA is cloistered in a room somewhere redeveloping our organization. That is far from reality. This year has been a banner year for us in making external contacts. In some cases, organizations sought us out, and in others, we did the reaching out to make the connection.
We had great meetings with the Association of Community Cancer Centers (ACCC), European Society of Oncology Pharmacists, and the Advanced Practice Society for Hematology and Oncology. As a result, we are looking to develop collaborative educational meetings that each organization can share. ACCC helped market our Pharmacy Practice Management Program and endorsed our Investigational Drug Service standards. The United Oncology Pharmacy Organization, a global organization of oncology pharmacy associations, invited HOPA to join. We deferred this membership for now because of our commitment to BCOP education; however, we will continue conversations with our international colleagues. We started a dialog with the Livestrong Foundation because they have several surveys and patient advocacy initiatives that we think would align with HOPA's goals.
Two new groups, the National Community Oncology Dispensing Association (NCODA) and the Community Oncology Pharmacy Association (COPA), a subgroup of the Community Oncology Alliance (COA) met with HOPA to discuss issues around oral chemotherapy. These groups are working to maintain control of the oral medications in the community setting. HOPA is working with both groups to ensure that patients have access to oral chemotherapy. COPA helped promote our Practice Management Program and NCODA has asked us to join their advisory board.
A unique opportunity to develop joint educational material with the American Society of Pediatric Hematology/Oncology and the Association of Pediatric Hematology/Oncology Nurses has arisen. Grant funding will allow these three organizations to develop educational materials focusing on pediatric hematology/oncology patients. We have asked two of our members, Susannah Koontz and Brooke Bernhardt, to represent HOPA in developing this material.
HOPA was one of two pharmacy organizations at the table for the American Society of Clinical Oncology and Oncology Nursing Society (ONS) update and revision of the handling hazardous drugs guidelines. This was a unique opportunity to give the pharmacy perspective on chemotherapy ordering, mixing, handling, and administration. We are working with ONS on several initiatives and have asked them to endorse our IDS standards.
Through our relationship with the Joint Commission of Pharmacy Practitioners (JCPP), we partnered with the Academy of Managed Care Pharmacy (AMCP) to conduct a survey of a random sample of our membership and of AMCP’s membership regarding the naming convention for biosimilars. The survey is complete and will be published shortly. We are considering joining Pharmacy Workforce Coalition, which will give us the opportunity to participate in their workforce surveys. Through JCPP, we are meeting with the American Association of Colleges of Pharmacy to discuss the current quantity of oncology education in pharmacy schools. Finally, we have meetings in November in Washington, DC, with the American Pharmacy Association and American Society of Health-Systems Pharmacy where we plan to discuss the role and impact of the hematology/oncology pharmacist.
As you can see, we have been very busy expanding our recognition and working to find areas where we can collaborate with other organizations. These discussions have been mutually beneficial and set HOPA up as the voice of the hematology/oncology pharma- cist. We plan to continue these collaborations and seek others that benefit HOPA and its membership.
Staged and Confused: Sequencing of Therapy in Metastatic Castration-Resistant Prostate Cancer
Zachary Post, PharmD
PGY1 Pharmacy Practice Resident
Louis Stokes Cleveland VA Medical Center
Prostate cancer is the most prevalent cancer among North American men and accounts for the second highest number of deaths from any type of cancer.1 In 2015, there is estimated to be a total of 220,800 new prostate cancer cases diagnosed, resulting in nearly 30,000 deaths in the United States. Prostate cancer is associated with significant morbidity and mortality, which increases as the disease progresses. After prostate cancer becomes metastatic, the estimated 5-year overall survival (OS) is approximately 31%, down from 100% with early-stage disease.2
The cornerstone of treatment is androgen deprivation therapy (ADT).2 Androgens, including testosterone, are taken up by cells within the prostate and bind to the androgen receptor (AR) to promote function and growth. Activation of the AR can promote the growth of both normal and cancerous prostate cells, allowing androgens to play a role in the development and progression of prostate cancer.3,4 For this reason, many treatment regimens for prostate cancer target the AR signaling pathway.
ADT can be surgical or medical; the most common medical approach is treatment with a gonadotropin- releasing hormone (GnRH) modulator, such as leuprolide, goserelin, or degarelix.2,5 These agents suppress luteinizing hormone production and, thereby, the synthesis of testicular androgens through stimulation or inhibition of GnRH.
Although the majority of prostate cancer initially responds to ADT, cancer cells can become resistant to treatment and survive and grow under low levels of circulating testosterone.2,4,5 This is defined as castration-resistant disease. Castration-resistant disease is still driven by AR signaling; therefore, ADT should be continued indefinitely and other chemohormonal therapies should be initiated. The focus of this review will be on treatment options and data behind sequencing strategies for metastatic castration-resistant prostate cancer (mCRPC).
Treatment Options for Metastatic Castration-Resistant Prostate Cancer
Docetaxel (DOC), a microtubule stabilizer, became the standard treatment for mCRPC with the TAX327 trial, which was the first trial to demonstrate an OS benefit with chemotherapy in mCRPC.6 After its initial approval in 2004, there were several years without any new agents approved for mCRPC. Recently, several agents with novel mechanisms have gained approval for use in mCRPC treatment (Table 1).
Cabazitaxel (CAB) is an intravenous agent with a similar mechanism of action as DOC, how- ever it has antitumor activity in mCRPC refractory to DOC therapy.7 In 2010, TROPIC be- came the first trial to demonstrate an OS benefit in the post-DOC setting, comparing CAB Table 1. Novel Chemohormonal Therapy Options Currently Available for mCRPC combined with prednisone to mitoxantrone combined with prednisone. CAB, in combination with prednisone, received U.S. Food and Drug Administration (FDA) approval for use following DOC and, to date, CAB carries only that indication. Abiraterone (ABI) and enzalutamide (ENZ) are both oral agents that inhibit androgen synthesis via different mechanisms. ABI binds and inhibits CYP17A1, a critical component in both the testicular and extragonadal androgen synthesis pathways, while ENZ binds to the AR and serves as a potent androgen antagonist, preventing ligand-bound AR translocation into the nucleus.8–11 ABI was the first of these two agents to gain FDA approval for mCRPC following DOC therapy with COUGAR
301, in which it was compared to placebo with prednisone.8 ENZ was studied in a similar manner and first gained approval following DOC treatment with the results of the AFFIRM trial in 2012.10 Later in 2012, COUGAR 302 became the first trial to trigger regulatory approval of an additional first-line agent, ABI, in mCRPC.9 As of late 2014, with the release of results from the PREVAIL trial, ENZ also carries the indication for first-line treatment of mCRPC.11 Sipuleucel- T and radium-223 were approved for mCRPC in 2010 and 2013, respectively.12,13 These agents have very unique mechanisms, and their use is limited to a small subset of patients.
With the increase in approved agents during the past 5 years, there is much uncertainty about the optimal treatment sequence. Prostate cancer is a progressive disease during which many patients will endure multiple lines of therapy, requiring practitioners to make informed clinical decisions when selecting treatment regimens. Further investigation of suspected resistance mechanisms also is warranted because they have yet to be fully characterized. For these reasons, it is important to search for the appropriate sequences in which to use these therapies when treating patients with mCRPC.
The National Comprehensive Cancer Network (NCCN), American Urological Association (AUA), and American Society of Clinical Oncology (ASCO) have recently updated their guidelines.2,5,14 Although these resources recommend the use of the aforementioned therapies, they do not provide guidance in terms of sequencing agents other than suggesting that clinicians consider the previous treatments, presence or absence of visceral metastases, symptoms, patient preference, and potential side effects when selecting therapies.5,14 The ASCO guidelines highlight the importance of continuous ADT, while outlining the available first- line chemohormonal therapies.2 Unfortunately, the guideline fails to provide guidance about which agent to initiate after the patient progresses past any first-line, or even second-line treatment. Practitioners are left with scarce data from retrospective studies to guide treatment decisions.
All published studies regarding therapy sequencing in mCRPC are retrospective, single-arm studies (Table 2).15–22 Patients included in these studies had progressive mCRPC with similar baseline characteristics, including: median ages of 65–72 years, Gleason scores 6–9, and Eastern Cooperative Oncology Group performance status scores of 0–2.
Third-Line ENZ (DOC ABI ENZ)
There are three published retrospective studies reviewing the use of third-line ENZ in patients with progressive mCRPC after previous treatment with DOC and ABI.17–19 Although less robust than in the second-line setting, these studies have revealed a response to third- line ENZ.17–19 Prostate-specific antigen (PSA) responses, defined by the Prostate Cancer Clinical Trials Working Group as a >50% decline from baseline PSA, were less than those seen with second-line ENZ therapy in the AFFIRM trial.10 In AFFIRM, 54% of patients experienced a PSA response with ENZ, whereas 17%–45.7% of patients had the same response to third-line ENZ.10,17–19
The lower PSA response rates were thought to be due to cross- resistance between ABI and ENZ.17–19 Response to previous therapy was not found to be predictive of response to ENZ. For example, of the 16 (45.7%) patients in the study by Schrader and colleagues with a PSA response to ENZ, 43.8% previously had a PSA response to ABI and 13.8% did not.17
Third-Line ABI (DOC ENZ ABI)
One study by Noonan and colleagues investigated the third-line use of ABI for progressive mCRPC after previous treatment with DOC and ENZ.20 In contrast to the ENZ studies, the primary endpoint was a PSA response of >30% from baseline, with only three (11%) patients meeting that endpoint. In addition, only 4% of patients had a >50% PSA decline with third-line ABI, which was less than the 29.5% of patients who had the same response from second-line ABI in COU- GAR 301.8 The poor responses seen in the study by Noonan and col- leagues20 and the minimal, but apparent, responses seen with the previous studies may suggest that second-line ABI followed by third-line ENZ may be the more favorable treatment sequence. These data must be confirmed with larger, randomized sequencing studies.
Third-Fourth-Line CAB (DOC ABI [ENZ] CAB)
There are two published studies reviewing the third-line use of CAB after DOC and ABI therapy.21,22 Sella and colleagues investigated third-line CAB after previous treatment with DOC and ABI.21 The duration of CAB therapy was comparable to the TROPIC study, which evaluated second-line CAB therapy.7 PSA responses of >50% were similar between both studies, with 31.5% of patients in Sella and colleagues and 39.2% of patients in TROPIC achieving this response. Despite similar PSA responses, the median OS in Sella and colleagues' study (8.2 months, 95% CI: 3.34–13.05) was shorter than in the TROPIC trial (15.1 months, 95% CI, 14.1–16.3).
Nakouzi and colleages cumulatively investigated third- and fourth- line CAB after previous treatment with DOC, ABI, and ENZ.22 Al- though dosage and duration were not specified, this study included six (7.6%) patients who received ENZ before fourth-line CAB. Similar to the aforementioned study, the duration of CAB therapy in Nakouzi et al. was comparable to that in TROPIC.7 PSA responses of >50% were seen in 35% of patients, and median OS was shorter in Nakouzi and colleagues' study (10.9 months, 95% CI: 8–14) than in TROPIC (15.1 months, 95% CI: 14.1–16.3). However, median progression-free survival of 4.4 months (95% CI: 3.5–5.2) in Nakouzi and colleagues' was longer than the 2.8 months (95% CI: 2.4–3.0) seen in the TROPIC study.
Although the results of Sella and colleagues and Nakouzi and colleagues do not adequately address CAB in the third- and fourth-line setting due to the limited number of patients, these data suggest that CAB retains activity after prior treatment exposure. The optimal place in therapy for CAB requires further investigation.
Several sequences and combinations have not yet been addressed in the literature. Studies continue to investigate therapies in mCRPC, including the active phase 3 trial (NCT01949337) of ENZ monotherapy against the combination of ENZ, ABI, and prednisone in recurrent mCRPC.23 Along with new combinations and sequencing strategies being investigated, there also are a few new agents in the pipeline for treatment of mCRPC. Oral agents cabozantinib and tasquinimod and subcutaneous vaccine PROSTVAC-V/ F are being studied in phase 3 clinical trials for use in mCRPC.24 Cabozantinib is a tyrosine kinase inhibitor that targets met proto-oncogene and vascular endothelial growth factor receptor 2 and is FDA-approved for use in medullary thyroid carcinoma.25 It is being studied for third-line use in mCRPC after failure of DOC and either ABI or ENZ.24,25 Tasquinimod binds and inhibits S100A9, a calcium-binding protein implicated in prostate cancer, while PROSTVAC-V/ F contains transgenes for PSA as the target tumor antigen.24 Both agents are being studied for first-line use in mCRPC against placebo. The potential approval of new agents for this indication will certainly add more confusion for providers when initiating treatment and sequencing subsequent therapies.
Prostate cancer is a progressive and potentially deadly disease. Chemo-hormonal therapies result in improved survival for patients with mCRPC, but there is limited evidence for guiding treatment decisions after patients progress beyond first- or even second-line therapy. At this time, there is insufficient evidence to designate the optimal sequence or combination of therapies in mCRPC. Current data regarding sequencing are from retrospective, single-arm studies and offer limited guidance in the third- and later-line settings.17–22 There is likely some cross-resistance between agents, which may be lessened when using ABI before ENZ.20 CAB appears to retain some activity in the third-line setting after treatment with DOC and ABI.21,22 When making treatment decisions, providers must take clinical trial evidence along with patient factors and agent-specific characteristics into consideration. In addition, the identification of appropriate predictors for response to these agents is still needed for clinical trials. Prospective, head-to-head trial comparisons addressing cross-resistance and therapy sequencing are needed to make definitive, evidence-based recommendations for patients with mCRPC.
- Howlander N, Noone AM, Kapcho M, et al. SEER Cancer Statistics Review, 1975–2012. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2011/. Based on November 2014 SEER data submission, posted to the SEER website. Accessed April 15, 2015.
- Basch E, Loblaw A, Oliver TK, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol. 2014;32:3436-3448.
- Genetics of prostate cancer–for health professionals (PDQ®). Bethesda, MD: National Cancer Institute. http://www.cancer.gov/types/prostate/ hp/prostate-genetics-pdq. Updated February 10, 2015. Accessed February 15, 2015.
- Prostate cancer treatment–for health professionals (PDQ®). Bethesda, MD: National Cancer Institute. http://www.cancer.gov/types/prostate/ hp/prostate-treatment-pdq. Updated October 28, 2014. Accessed February 15, 2015.
- Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA guideline. J Urol. 2013;190:429-438.
- Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512.
- de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154.
- Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983-992.
- Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med.2013;368:138-148.
- Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
- Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433.
- Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
- Parker C, Nilsson S, Heinrich ND, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-233.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer [version 1.2015]. http://www.nccn.org/professionals/physician_gls/pdf/ prostate.pdf. Published October 24, 2014. Accessed December 9, 2014.
- Scher HI, Halabi S, Tannock I, et al. Design and endpoints of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol. 2008;26:1148-1159.
- Venook AP, Tabernero J. Progression-free survival: helpful biomarker or clinically meaningless end point? J Clin Oncol. 2015;33:4-6.
- Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol. 2014;65:30-36.
- Thomsen FB, Røder MA, Rathenborg P, Brasso K, Borre M, Iversen P. Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate. Scand J Urol. 2014;48:268-275.
- Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer. 2014;120:968-975.
- Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL,Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol. 2013;24:1802-1807.
- Sella A, Sella T, Peer A, et al. Activity of cabazitaxel after docetaxel and abiraterone acetate therapy in patients with castration-resistant prostate cancer. Clin Genitourin Cancer. 2014;12:428-432.
- Nakouzi NA, Moulec SL, Albigès L, et al. Cabazitaxel remains active in patients progressing after docetaxel followed by novel androgen receptor pathway targeted therapies [published online ahead of print May 2, 2014]. Eur Urol. 2015;68:228-235.
- Madan R, Dahut WL. Abiraterone’s efficacy confirmed; time to aim higher. Lancet Oncol. 2015;16:119-121.
- El-Amm J, Aragon-Ching JB. The changing landscape in the treatment of metastatic castration-resistant prostate cancer. Ther Adv Med Oncol. 2013;5:25-40.
25. Pinto A. Cabozantinib: a novel agent with dual mechanism of action for castration-resistant prostate carcinoma. Cancer Chemother Pharmacol. 2014;73:219-222.
Reliability of PD-L1 as a Predictive Biomarker in NSCLC
Courtney C. Cavalieri, PharmD BCOP
Clinical Hematology/Oncology Pharmacist
Huntsman Cancer Institute at the University of Utah Salt Lake City, UT
Even through numerous developments in treatment, lung cancer re- mains the leading cause of cancer death in the United States.1 Many avenues have been attempted to prolong overall survival of this dis- ease. The most recent has been immunotherapy, specifically immune-checkpoint inhibitors targeted at the programmed death 1 (PD-1) receptor. Nivolumab and pembrolizumab are the two immunotherapies currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of progressive non-small cell lung cancer (NSCLC). Although these agents may be similar in target, their respective journeys to approval revealed we have much to learn about the impact of these therapies.
Nivolumab was approved first for squamous NSCLC in March 2015 based on the CheckMate-017 phase 3 trial. This compared nivolumab to docetaxel in patients with advanced squamous NSCLC who had progressed on or after receiving a platinum-based chemotherapy regimen. Nivolumab provided an improved median overall survival (9.2 versus 6.0 months), response rate (20% versus 9%), and progression- free survival (3.5 versus 2.8 months) over docetaxel. Nivolumab also produced fewer grade 3 or 4 adverse events at 7%, compared with the 55% in the docetaxel group.2 In October 2015, the FDA extended the approval to non-squamous NSCLC based on the results of the CheckMate-057 phase 3 trial. CheckMate-057 compared nivolumab to docetaxel in patients with non-squamous NSCLC after progression during or after platinum-based chemotherapy. Again, nivolumab proved superior to docetaxel, with improved overall survival (12.2 versus 9.4 months) and response rates (19% versus 12%). The data for median progression-free survival did not actually favor nivolumab (2.3 versus 4.2 months). However, at 1 year, a higher percentage of patients treated with nivolumab were alive than those treated with docetaxel (19% versus 8%), representing a delay in response to therapy known to occur with immunotherapy. Nivolumab still proved to be better tolerated, with only 10% reporting grade 3 or 4 adverse events compared to the 54% in the docetaxel group.3
Pembrolizumab was approved for NSCLC in October 2015 based on the data from the phase I KEYNOTE-001 trial. The objectives of KEYNOTE-001 were to evaluate the side effects, safety, and anti- tumor activity of pembrolizumab in NSCLC patients, as well as de- fine and validate a tumor PD-L1 expression level associated with an increased likelihood of benefit from pembrolizumab. Pembrolizum- ab was given at a dose of 2 mg/ kg every 3 weeks, 10 mg/ kg every 3 weeks, or 10 mg/ kg every 2 weeks. PD-L1 positivity was determined by an immunohistochemical (IHC) assay and defined as at least 1% of cells showing membranous staining (proportion score). The investigators determined ≥50% proportion score as the cutoff for validation of PD-L1 as a predictive biomarker. The most common adverse events reported were fatigue, pruritus, and decreased appetite. The overall response rate was 19.4% across untreated and previously treated patients. Median overall survival was 12 months and progression-free survival was 3.7 months. No differences in response rates or toxicities were seen between the varying doses and schedules; therefore, the investigators recommend the 2 mg/ kg every 3 week schedule. Patients with ≥50% proportion score per the validation assay had longer progression-free survival than patients with 1% to 49% or <1% proportion scores (6.3 versus 4.1 versus 4.0 months, respectively) and longer over- all survival (not reached versus 10.6 versus 10.4 months, respectively). The FDA approval for pembrolizumab in NSCLC dictates patients must test positive for PD-L1 with the companion diagnostic assay.4
KEYNOTE-001 suggests that PD-L1 expression (at ≥50% proportion score) may represent a predictive biomarker for the treatment of NSCLC with pembrolizumab.4 However, the CheckMate trials provide conflicting reports on whether PD-L1 expression is a valid biomarker. CheckMate-017 defined samples as PD-L1 positive at pre- defined levels of 1%, 5%, and 10% and found no difference in predictive benefit of nivolumab activity.2 CheckMate-057 used the same IHC assay as CheckMate-017 and the same predefined positivity levels. At the interim analysis, an association between PD-L1 expression and clinical outcome was described. Expression above the predefined levels all correlated with better survival outcomes than docetaxel; however, in patients whose tumors had negative expression, the survival outcomes were similar to docetaxel. The authors concluded that because the safety profile of nivolumab out-performed docetaxel, nivolumab should still be considered an option regardless of PD-L1 expression.3
The question these three trials raise is whether PD-L1 is a reliable biomarker for predictive response to immunotherapy, particularly in NSCLC.
In the CheckMate trials assessing nivolumab in NSCLC, PD-L1 expression was relatively consistent at 83% in CheckMate-017 and 78% in CheckMate-057. 2,3 In KEYNOTE-001, 23.2% of patients had a pro- portion score of at least 50% and 37.6% had 1%-49%.4 Other trials exploring immunotherapies in NSCLC describe positivity for PD-L1 expression ranging from 21% to 95%. PD-L1 expression varies with disease state, with reports for melanoma patients ranging from 38% to 100% and reports for renal cell carcinoma ranging from 14% to 54%, depending on which site of disease was tested (primary versus metas- tasis).5 The wide range of positivity could be explained by each dis- ease state’s heterogeneity; however, trials have not been consistent in which IHC assay has been used to determine PD-L1 positive expression.
As of this time, there is no standard IHC assay used to calculate expression of PD-L1, nor is there a standard definition of “positive” expression. There are about two dozen anti-human PD-L1 antibodies currently being used in IHC assays, including 28-8, 5H1, MIH1, and 20C3. In addition, manufacturers of PD-1 and PD-L1 inhibitors con- currently develop their own proprietary companion test when seeking FDA approval. All these different assays complicate the ability to possibly standardize PD-L1 positive quantification. Cutoff points for positive PD-L1 expression range from >1% to >50%, which would explain the incidence of patients who are considered PD-L1 “positive” yet do not respond to immunotherapy as expected, and conversely, the patients considered PD-L1 “negative” who do respond to therapy.6 Al- though PD-L1 expression may not be the best biomarker to include or exclude patients to receive immunotherapy, levels of expression could possibly be used to guide which regimens of immunotherapy may benefit the patient the most. It is clear that patients who have higher rates of PD-L1 expression do respond better to single-agent immuno- therapy, and patients who have lower or negative rates of PD-L1 expression may be better suited to receive combination immunotherapy. Differing levels of expression could also be used to stratify patients in clinical trials exploring new combinations of immunotherapy.7
Although PD-L1 presents as a tempting predictive biomarker for immunotherapy in NSCLC, there are a few barriers before relying on PD-L1 as a definitive biomarker to choose which patients should or should not receive immunotherapy. Standardization must occur across assays as to which anti-PD-L1 antibody is used for expression description. The cut-offs for what constitute positivity must also be ad- dressed, and may be dependent on tumor type, biopsy site, and assay used to determine positivity. As immunotherapy becomes an option for more patients with oncologic diseases, these issues will hopefully be addressed through future clinical trials.
- National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. V1.2016.
- Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–135.
- Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–1639.
- Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med. 2015;372:2018–2028.
- Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–856.
- Teixido C, Karachaliou N, Gonzalez-Cao M, et al. Assays for predicting and monitoring responses to lung cancer immunotherapy. Cancer Biol Med. 2015;12:87–95.
- Mahoney KM, Atkins MB. Prognostic and predictive markers for the new immunotherapies. Oncology. (Williston Park). 2014;28 (Suppl) 3:39–48.
Ensuring Healthcare Worker Safety When Handling Hazardous Drugs: The Joint Position Statement from the Oncology Nursing Society, the American Society of Clinical Oncology, and the Hematology/Oncology Pharmacy Association
On March 10, 2015, HOPA, ONS, and ASCO announced the release of a joint position statement, “Ensuring Healthcare Worker Safety When Handling Hazardous Drugs.” The intent of this document is to ensure that there are policies and procedures in place to safeguard healthcare workers as well as their patients and minimize exposure risk when handling hazardous drugs.
Hazardous drugs (HDs) are chemicals that demonstrate one or more of the following characteristics: carcinogenicity, genotoxicity, teratogenicity, reproductive toxicity, or organ toxicity.1 Healthcare workers (HCWs) are potentially exposed to HDs in the workplace during drug preparation, administration, and disposal and when handling patients’ excreta following treatment with these drugs. More than 100 studies since 1994 have documented evidence of contamination of the work environment with HDs, which increases the potential for exposure of nurses, pharmacists, and other HCWs when these agents are handled without appropriate precautions. More than 50 studies have demonstrated the presence of HDs in the urine of HCWs, indicating actual exposure. Occupational exposure to HDs has been associated with acute symptoms such as nasal sores and hair loss, adverse reproductive outcomes such as infertility and miscarriages, genetic changes such as DNA damage, and an increased occurrence of cancer.2
The Occupational Safety and Health Administration3 acknowledged the occupational risks of HDs and issued recommendations for their safe handling nearly 30 years ago. Updated guidelines from NIOSH and professional societies subsequently have been published.4-6 All guidelines address the need for HD-related policies and procedures, education and training, and safe handling precautions in organizations where HDs are present. Safe handling precautions include the use of safety equipment, safe work practices, and personal protective equipment (PPE). When used consistently, recommended precautions can reduce occupational HD exposure1.
Occupational HD exposure can be minimized by a comprehensive HD safe-handling program based on a hierarchy of controls.7 When a hazard cannot be eliminated, engineering controls are recommended to control exposure. Biological safety cabinets and compounding aseptic containment isolators are primary engineering controls, and closed-system transfer devices are supplemental engineering controls, both of which reduce HD exposure. Administrative controls are the next level of protection and include safe handling policies and procedures, hazard communication, education, and medical surveillance of those who are potentially exposed. Finally, PPE that has been tested for use with HDs provides barrier protection for workers. PPE includes gowns, gloves, eye and face shields, and respirator protection, depending on the HD handling activities.
Nurses and pharmacists usually work as employees rather than independent practitioners in hospitals, clinics, and offices; therefore, employers and employees share the responsibility for HD safe handling. It is the position of the Oncology Nursing Society, the American Society of Clinical Oncology, and the Hematology/Oncology Pharmacy Association that
- Organizations in which HDs are present will establish evidence-based policies and procedures for safe handling that comply with regulatory requirements.
- Organizations in which HDs are prepared and administered will provide and maintain primary engineering controls and evaluate the utility of supplemental engineering controls, such as closed-system transfer devices, to reduce worker exposure.
- Organizations in which HDs are present will ensure that appropriate PPE is available to all staff to minimize exposure.
- Organizations in which HDs are present will provide education and training specific to each worker’s role for staff who are potentially exposed. Education and training will include the risks of exposure, including the reproductive and developmental effects, the recommended precautions for specific handling activities, safe handling of contaminated patient excreta, proper disposal of contaminated waste, and how to handle acute exposure.
- Organizations in which HDs are present will protect the right of staff who are trying to conceive, pregnant, or breast feeding to engage in alternative duty that does not require HD handling.
- Organizations in which HDs are present will ensure that patients who receive these drugs and their caregivers receive education about safe handling to minimize unintended exposure.
- Organizations will ensure that HD waste is disposed of according to regulatory guidelines and in a manner that protects staff and the environment.
- Our professional societies will continue to explore evidence- based strategies for mitigation of risk associated with handling HDs and share recommendations with our respective members.
- National Institute for Occupational Safety and Health. (2004). Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings (DHHS [NIOSH] Publication No. 2004-165). Retrieved from http://www.cdc.gov/ niosh/docs/2004-165/.
- Centers for Disease Control and Prevention. (2014). Occupational exposure to antineoplastic agents, publications, guidelines, review articles and surveys. Retrieved from http://www.cdc.gov/niosh/topics/antineoplastic/pubs.html.
- Occupational Safety and Health Administration. (1986).Guidelines for cytotoxic (antineoplastic) drugs. Retrieved from https://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=DIRECTIVES&p_id=1702
- American Society of Health-System Pharmacists. (2006). ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm 2006;63:1172–1193.
- NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012 (DHHS [NIOSH] Publication No. 2012-
150). Retrieved from http://www.cdc.gov/niosh/docs/2012-150/pdfs/2012-150.pdf
- Polovich M, Olsen M, LeFebvre KB. (Eds.). (2014). Chemotherapy and biotherapy guidelines and recommendationsfor practice (4th ed.). Pittsburgh, PA: Oncology Nursing Society.
- Connor, TH, McDiarmid, MA. (2006). Preventing occupational exposures to antineoplastic drugs in health care settings. CA Cancer J Clin, 56, 354–365. doi: 10.3322/canjclin.56.6.354
Highlights from the 2015 HOPA Preconference Session Radiation for the Oncology Pharmacist
Megan V. Brafford, PharmD BCOP
Clinical Oncology Pharmacy Specialist
Baptist Health Lexington
One of the featured preconference sessions at HOPA’s 11th annual conference was Radiation for the Oncology Pharmacist, which provided a wonderful overview of how to select the appropriate candidate for radiation therapy after a cancer diagnosis, specifically in the breast and prostate cancer populations. Education was also provided on the different preventive and treatment regimens a pharmacist can recommend to help a patient manage specific radiation-induced toxicities.
The goal of radiation treatment is to destroy cancer cells while pre- serving the integrity of normal tissues within and immediately adjacent to the radiation treatment field. The two major categories of radiation therapy are external beam radiation, which delivers radiation by a ma- chine outside of the body, and brachytherapy, which delivers radiation by radioactive material placed in the body near or within the tumor itself. Advances in radiation therapy now allow for better visualization of the patient’s anatomy to more clearly focus the radiation, improved manipulation of necessary doses, less of an exit dose with proton therapy, and more precise alignment of the patient for daily treatments. The presentation by radiation oncologist Dr. Karen E. Hoffman included multiple images to help the audience to truly envision what a patient would experience throughout his or her time in radiation therapy—from the first day of stimulation, through daily visits, to follow-up care after radiation is complete.
In breast cancer patients, radiation therapy can be utilized after breast- conserving surgery and is administered over the whole breast. Radiation therapy is also used in select women who have clinically significant risks of recurrence after a mastectomy. Radiation therapy can improve both local cancer control and breast cancer survival. Radiation therapy is a treatment option for the majority of men with localized prostate cancer. Dr. Hoffman said dose-escalated radiation therapy improves prostate cancer control compared with standard-dose radiation. The addition of androgen deprivation therapy to external beam radiation therapy improves prostate cancer survival for men whose cancer has unfavorable prognostic factors.
The development of radiation-induced toxicity depends on multiple factors, including the area of the body treated, dose given per day, total dose given, patient’s performance status, and concomitant therapy. Acute toxicity can occur hours to weeks after radiation exposure and lasts up to 3 months after receiving therapy. Primary acute toxicities include radiation dermatitis, otitis externa, serous otitis media, osteoradionecrosis, xerostomia, thick saliva, dysgeusia, mucositis, nausea/ vomiting, diarrhea, proctitis, acute cystitis, and pneumonitis. Chronic toxicities usually present 6 or more months after a course of radiation. Potential chronic toxicities include oropharynx issues, cardiac toxicity, pulmonary fibrosis, radiation necrosis, cognition issues, infertility, and development of a secondary malignancy. Each of these toxicities can negatively affect a patient’s quality of life and potentially duration of life. Pharmacologic strategies are available to manage many acute radiation toxicities and some chronic radiation toxicities. It is essential for pharmacists to be involved in educating patients who are receiving radiation therapy about the potential side effects and risks of treatment as well as assisting providers in management strategies to prevent and treat these radiation-induced toxicities.
Two Residents' Perspectives on the HOPA 11th Annual Conference
Jennifer Grabowski, PharmD Inpatient Clinical Pharmacist
University of Colorado Hospital Aurora, CO
Forger PGY2 Oncology Resident at University of Colorado Hospital
Joseph Kaiser, PharmD Oncology Pharmacy Specialist
St. Mary's Regional Cancer Center
Grand Junction, CO
Forger PGY2 Oncology Resident at University of Colorado Hospital
The 11th Annual HOPA Conference was held in Austin, TX, this past March and provided learning opportunities for all attendees—from students to residents to seasoned clinical pharmacists. Two second-year oncology pharmacy residents from the University of Colorado describe their experiences.
Jennifer Grabowski, PharmD
Because this year was my first time attending the HOPA clinical conference, I wasn’t sure what to expect. I knew it would provide great networking opportunities and educational experiences, but aside from that, I was going in with an open mind. I was pleasantly surprised to find a relaxed, yet professional, atmosphere at the conference. The presentations were educational and enjoyable, and the career fair was less intimidating than I had imagined. It was also great to connect with old classmates and hear about their accomplishments during their residency year. The city of Austin was as unique as it claims to be and just as exciting to explore. I consider this HOPA conference to be my first of many.
I do have some advice for future residents or students who will be going to the HOPA annual conference for the first time:
- Download the handouts ahead of time. And, if you’re technologically challenged like me, print them off to be able to take notes during the conference. Much of the information is not available on the slides, and keeping notes can help you remember the key concepts.
- Take advantage of the career fair. Not only is it a great tool for launching or expanding your career, it also helps you explore a variety of clinical opportunities you may not have otherwise been interested in or even considered. Even if the positions listed don’t seem to interest you on paper, speaking with the representatives will help you gain a better understanding of the opportunities available and may change your opinion of working in various environments.
- Check out the research posters. Support your coresidents nation- wide by appreciating their work. Chances are they are investigating clinical issues you may come across in your future practice.
- Be prepared to hand out your CV. The networking opportunities are everywhere and not only limited to the career fair. You will likely meet somebody who knows somebody who knows some- body who will be beneficial to your future and help to expand your network of colleagues.
- Enjoy the city. Austin was a beautiful city to explore, rich in music, food, and Texas culture. Although we may be there for “business,” take some time and enjoy the atmosphere of whatever city the conference happens to be in that year.
- Don’t forget to turn in your clickers at the end of the conference!
- If you forget, they know who you are and they will find you.
- Most importantly, learn lots and have fun!
Joseph Kaiser, PharmD
The HOPA conference was an extremely valuable and rewarding experience. As a PGY2 oncology pharmacy resident, my initial intent for attending this conference was to present my research project. How- ever, this event turned out to be so much more. The educational sessions provided me with cutting-edge information that can’t be found from some of the other nationally recognized oncology organizations, such as National Comprehensive Cancer Network or American Society of Clinical Oncologists. These discussions were focused on the practical pharmaceutical aspects of cancer care. I gained a great wealth of insight and clinical knowledge that will benefit me and my patients as I move forward in my career. My only regret was that I could not attend all of the sessions.
Besides the vast amount of educational opportunities available, this conference opened my eyes to the fact that oncology pharmacy is a relatively small and tight-knit community. The networking opportunities were endless, and I was able to make contacts that I will be able to count on for shared knowledge and expertise, ultimately bettering the services I offer to the healthcare team I will be working with and improving the treatment of our patients.
I would recommend attending the HOPA annual conference to not only PGY2 oncology pharmacy residents, but to PGY1 residents and students alike. Anyone who has an interest in oncology pharmacy stands to gain from attending this conference. HOPA offers very reasonable registration rates for residents and students, as well as the opportunity to apply for a travel grant, helping to make attendance affordable to those who have limited resources. Considering this and the networking and educational opportunities, the HOPA annual conference is a tremendous value and well worth the cost. I am very much looking forward to the HOPA 12th Annual Conference. See you there!
The Resident’s Cubicle: Advice to Those Embarking on a New Oncology Career
Brandi Anders, PharmD
Hematology/Oncology Clinical Pharmacist
Wake Forest Baptist Health
This time of the year marks new beginnings for individuals in many different aspects of oncology pharmacy. You may have made it through the first few months of your oncology pharmacy residency and you are wondering, “What have I gotten myself into?” Or, maybe you have finished a PGY2 oncology residency and have just started a new position as an oncology clinical pharmacist and you question if you are re- ally ready for this challenge. Whatever situation you may find yourself in, the new and unknown can be a scary place. I have found that the best way to face these challenges is with the help and advice of those who have been there—those who came, saw, and conquered. For this edition of The Resident’s Cubicle, I have compiled advice from several of my colleagues and mentors who have helped me along my path to becoming an oncology clinical pharmacist. I hope that their wisdom will offer support to you as well.
"It is an exciting time as the field of oncology is growing immensely! Begin your PGY2 with an open mind to all oncology specialties. Please also understand that 1 year of training will not make you an oncology expert. The goal of this program is to provide you with the essential tools necessary to pursue any oncology specialty area, with the under- standing that oncology specialization requires years of experience."
Erin Bailey, PharmD BCOP
GYN/GU Oncology Clinical Pharmacist Huntsman Cancer Institute, University of Utah Salt Lake City, UT
PGY2 Oncology Residency: Huntsman Cancer Institute—University of Utah
"My advice to new oncology clinical pharmacists just starting their careers would be to continue to seek mentorship from seasoned oncology clinical pharmacists and to not be afraid to ask your colleagues questions as you set up your practice. One of the great things about practicing in oncology pharmacy is the great community of pharma- cists who are always willing to share innovative ideas and advice. There are some great e-mail discussion and Google groups out there. I would recommend joining HOPA Central if you haven’t already!"
Megan Bodge, PharmD
Inpatient Oncology (Solid Tumor) Clinical Pharmacist
West Virginia University Healthcare
PGY2 Oncology Residency: Vanderbilt University Medical Center
"Learn something from every patient encounter. It could be asking the patient to describe a drug toxicity or looking up the evidence to sup- port a chemo regimen that was given in the past. Every patient offers a unique case study to learn about cancer and chemotherapy. There’s so much to learn that you don’t want to miss an opportunity for patient-centered learning."
John Bossaer, PharmD BCPS BCOP
Associate Professor, Department of Pharmacy Practice
East Tennessee State University Bill Gatton College of Pharmacy
Johnson City, TN
PGY2 Oncology Residency: Medical University of South Carolina
"I would tell a new PGY2 oncology resident to enter the year with an open mind. Oncology is such a diverse and vastly different realm of practice than any other area of clinical pharmacy. The things that were really important during your PGY1 year might be ancillary in the field of oncology. Keep an open mind about what you like and what you don’t like, and search for the area of oncology that really interests you. There are countless subfields of oncology that you may like and others that you don’t, but entering the year with an open mind will help you find what is right for you."
David Eplin, PharmD BCOP
Outpatient BMT Clinical Specialist Nashville VA Medical Center Nashville, TN
PGY2 Oncology Residency: University of Pittsburgh Medical Center
"It will definitely be overwhelming with all the new information that you will have to learn with all the novel agents and mechanisms that are currently being studied in the world of oncology. And the expectations from your preceptors and medical staff will far surpass what you have experienced so far as a PGY1 and as a student. But it will all be worth it in the end. There will be rotations that you may love and experiences that you may dislike, but learn from everyone and everything because you will never have a time like this to dedicate all of your energy into your training. Keep in contact with all of your peers and network with others in your field because you never know when you might need to collaborate and reach out to them!"
Maho Hibino, PharmD BCOP
Clinical Oncology Pharmacist Wake Forest Baptist Health Winston-Salem, NC
PGY2 Oncology Residency: University of Washington Medicine
Recalls and Safety Alerts from the FDA
Jennifer Kwon, PharmD BCOP
Hematology/Oncology Clinical Pharmacy Specialist
VA Medical Center
West Palm Beach, FL
Carboplatin, Cytarabine, Gemcitabine, and Methotrexate
Mylan has issued a voluntary recall of select lots of injectable products including gemcitabine, carboplatin, methotrexate, and cytarabine. This is because of the presence of visible particles observed during a rou- tine quality testing. There have been no adverse events reported related to this recall. http://www.fda.gov/Safety/ Recalls/ucm450140.htm
Fluorouracil Injection (Adrucil)
Teva Parenteral Medicines issued a voluntary recall of eight lots of fluorouracil injection (5 g/100 mL) due to the potential presence of silicone rubber pieces from a filter diaphragm and fluorouracil crystals. There have been no adverse events reported. http://www.fda.gov/ Safety/ Recalls/ucm445584.htm.
Prescription Center Pharmacy Recall in North Carolina
The North Carolina Board of Pharmacy has ordered a recall for all nonsterile and sterile products compounded, repackaged, and distributed by Prescription Center Pharmacy in Fayetteville, NC, during the time period between September 10, 2014 and March 10, 2015. Prescription Center Pharmacy distributed products in all 50 states and Canada during the time period of the recall. The recall was mandated because the pharmacy was unable to ensure sterility, stability, and potency for their products. Furthermore, the North Carolina Board of Pharmacy has ordered the Prescription Center Pharmacy to close. There have been no adverse events reported from the recalled products. http://www.fda.gov/ Safety/ Recalls/ucm441046.htm
An embryo-fetal toxicity section has been added to the warnings and precautions for bevacizumab. Animal studies resulted in congenital malformations with the administration of bevacizumab to pregnant rabbits. These animal models also have linked angiogenesis and vascular endothelial growth factor (VEGF) and VEGF Receptor 2 to essential aspects of female reproduction, embryo-fetal development, and postnatal development. Pregnant women should be aware of the potential risk to a fetus and be counseled on using effective contraception during treatment and for 6 months after completion of therapy with bevacizumab. The package labeling on use in specific populations has been updated to include the animal data in pregnancy and a section on females and males of reproductive potential. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm287610.htm
Patients with certain homozygous or compound heterozygous mutations in the dihydropyrimidine dehydrogenase deficiency (DPD) gene that result in absence of DPD activity are at increased risk for capecitabine toxicity; acute early-onset, severe, life-threatening, or fatal (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity also may be at increased risk for toxicity. These findings were based on postmarketing reports. Capecitabine should be held or discontinued based on clinical assessment of the patient and observed toxicities. There is no capecitabine dose shown to be safe for patients with absence of DPD activity and there is Interferon alfa-2b (Intron A)
The warnings and precautions section for interferon alfa-2b has been updated to include the risk of gastrointestinal disorders, neuropsychiatric disorders, and hepatic monitoring parameters. There is an in- creased risk of hepatic decompensation in patients with cirrhosis. Patients who develop liver function abnormalities during treatment should be monitored closely. Liver function tests (serum bilirubin, ala- nine transaminase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase) should be monitored at 2, 8, and 12 weeks after starting interferon alfa-2b, then every 6 months afterwards. Interferon alfa-2b should be discontinued for severe (grade 3) hepatic damage or hepatic decompensation (Child-Pugh score > 6; class B and C). In patients who experience worsening psychiatric symptoms or those who develop suicidal ideation or aggressive behavior towards others, interferon alfa-2b should be discontinued and patients should be monitored closely with psychiatric interventions as appropriate. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm311115.htm
The updated warnings and precautions address the lack of benefit of panitumumab in patients with metastatic colorectal cancer with RAS- mutations; specifically somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of KRAS or NRAS. Results from a retrospective subset analyses across several randomized clinical trials showed no clinical benefit in patients with tumors having the RAS mutations, and exposed those patients to anti- EGFR-related adverse reactions. In study 3 of the package insert, the subgroup analysis demonstrated the overall survival was shorter in patients with metastatic colorectal cancers with RAS mutations who re- ceived panitumumab and FOLFOX versus FOLFOX alone. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ucm319207. Htm
The updated warnings and precautions section for pazopanib includes the increased risk for hepatotoxicity in patients >65 years. Liver function tests should be monitored regularly while on pazopanib therapy. There have been reports of retinal detachment and this has been added in the postmarketing section under adverse reactions. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm303649.htm
The package labeling for pertuzumab has been updated with additional information on embryo-fetal toxicity. If a patient becomes pregnant while receiving pertuzumab or within 7 months following the last dose of this drug in combination with trastuzumab, the patient should be informed of the potential hazard to the fetus. Female patients of reproductive potential should be counseled on avoiding becoming pregnant while receiving pertuzumab therapy or within 7 months after completion of pertuzumab therapy in combination with trastuzumab. Women who may be exposed to pertuzumab during pregnancy or become pregnant within 7 months after the last dose of pertuzumab should enroll in the Mother Pregnancy Registry by contacting insufficient data to recommend a specific dose in patients with partial DPD activity. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm422806.htm
The warnings and precautions section of the prescribing information for carfilzomib has been updated to include thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome (TTP/ HUS) and posterior reversible encephalopathy syndrome (PRES). Therapy should be interrupted if TTP/ HUS is suspected and the syndromes should be managed appropriately. The safety of starting carfilzomib therapy after a TTP/ HUS diagnosis is unknown. Though rare, there have been reports of PRES with carfilzomib use. Symptoms of PRES include seizure, headaches, lethargy, confusion, blindness, altered consciousness, hypertension, and other visual or neurological disturbances. Therapy should be discontinued if PRES is suspected. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm441458.htm
The updated warnings and precautions section now includes information about increased tumor progression and increased mortality in patients with RAS-mutant metastatic colorectal cancer. Cetuximab is not indicated for the treatment of patients with colorectal cancer having mutations in the exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either K-RAS or N-RAS. Sub- set analyses of RAS-mutant and wild-type populations across several randomized clinical trials showed cetuximab given to patients with RAS mutations had no clinical benefit with treatment-related toxicity. Reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, and life-threatening and fatal bullous mucocutaneous disease have been made with cetuximab use. These dermatologic toxicities are now included in the warnings and precautions section of the product labeling. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm289979.htm
The new labeling for ferumoxytol includes a boxed warning regarding the risk of serious and potentially fatal hypersensitivity reactions. Ferumoxytol should only be administered when personnel and therapies are immediately available to treat anaphylaxis and other hypersensitivity reactions. Patient should be observed for signs and symptoms of hypersensitivity for at least 30 minutes following the infusion. Blood pressure and pulse should also be monitored during and after the in- fusion. Hypersensitivity reactions have occurred in patients that previously tolerated ferumoxytol. A contraindication also has been added for patients with a history of allergic reaction to any intravenous iron product. The warnings and precautions section for ferumoxytol has been updated to caution use in elderly patients (>65 years of age) or patients with multiple comorbidities, as these patients may have more severe outcomes if they experience a serious hypersensitivity reaction. http://www.fda.gov/ Safety/MedWatch/ SafetyInformation/ ucm235636.htm 800.690.6720. If a patient becomes pregnant while receiving treatment with pertuzumab or within 7 months following the last dose of this drug, immediately report the exposure to the Genentech Adverse Event Line at 888.835.2555. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm450065.htm
The risk of venous and arterial thromboembolism has been added to the black box warnings and the warnings and precautions section of the package labeling for pomalidomide. There is an increased risk of both arterial and venous thromboembolic events in patients with multiple myeloma receiving pomalidomide with dexamethasone. Due to the increased risk of thrombotic events, modifiable risk factors should be minimized and antithrombotic prophylaxis should be administered. Several updates have been made to the warnings and precautions section of the package insert for pomalidomide, including the risk for hematologic toxicity, hepatotoxocity, hypersensitivity reactions, dizziness and confusion, neuropathy, and tumor lysis syndrome. The most frequently reported grade 3/4 adverse reaction was neutropenia, followed by anemia and thrombocytopenia in patients receiving pomalidomide in combination with dexamethasone. Cases of hepatic failure have been reported in patients receiving pomalidomide. Liver function tests should be monitored at least monthly and pomalidomide therapy should be stopped if elevation in liver enzymes is present. Angioedema and severe dermatologic reactions have occurred with pomalidomide use. The medication should be permanently dis- continued for any severe dermatologic reactions. Patients receiving both pomalidomide and dexamethasone may experience dizziness and a confused state. Patients should be instructed to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause overlapping symptoms. Neuropathy and tumor lysis may also occur in patients treated with pomalidomide. Appropriate monitoring and precautions should be taken for patients at risk for tumor lysis syndrome. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm446484.htm
Updates have been made to the warnings and precautions section to include the risk of thrombotic microangiopathy (TMA). Incidences of thrombotic thrombocytopenic purpura and hemolytic uremia have been reported in clinical trials and in postmarketing surveillance of patients receiving sunitinib. For patients who develop TMA, sunitinib therapy should be discontinued. Additional elements of the warnings and precautions section have been updated. “Left ventricular dysfunction” has been changed to “cardiovascular events,” and “myocardial disorders” has been replaced with “myocardial ischemia, myocardial infarctions.” Sunitinib should be used with caution in patients who are at risk or who have a history of these events. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm224050.htm
The package labeling for trastuzumab has been updated to include in- formation on potential embryo-fetal toxicity. Female patients of reproductive potential should be counseled on avoiding becoming pregnant while receiving trastuzumab therapy. If contraceptive methods are utilized, patients should be advised to use effective contraception during treatment and for at least 7 months after the last dose of trastu- zumab. If a patient becomes pregnant while receiving trastuzumab or within 7 months following the last dose of the medication, inform the patient of the potential hazard to the fetus. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm392225.htm
The boxed warning for vismodegib has been edited to address the embryo-fetal toxicity of the drug. Teratogenic effects of vismodegib include severe midline defects, missing digits, and other irreversible malformations, as well as embryo-fetal death. The pregnancy status of females of reproductive potential should be verified within 7 days prior to starting vismodegib therapy. Education for using effective contraception during and after vismodegib therapy should be provided for female patients. Male patients should be counseled on the risk of vismodegib exposure through semen and to use condoms with a pregnant partner or female partner of reproductive potential.
The updated warnings and precautions section for vismodegib also addresses measures for blood donation and semen donation. Patients should not donate blood or blood products while taking vismodegib and for 7 months after the completion of therapy. Male patients should not donate semen during and for 3 months after the last dose of vismodegib.
The use in specific populations section of the package labeling now discusses pregnancy risk, lactation, and hepatic impairment. In animal reproduction studies, oral administration of vismodegib at doses lower than the recommended doses for humans led to embryotoxicity, fetotoxicity, and teratogenicity in rats. There are no available data on the use of vismodegib in pregnant females. Pregnant woman should be counseled on the potential risk to a fetus. No data are available ad- dressing the presence of vismodegib in human milk, the effects of the drug on breastfed infants, or the effects of the drug on milk production. Due to the potential for serious adverse reactions in breastfed infants from vismodegib, nursing women should be instructed not to breastfeed while on vismodegib therapy. In patients with hepatic impairment, there are no dose adjustments required for vismodegib.
An additional section, females and males of reproductive potential, has been added to the package labeling for the drug. Both female and male patients need to be counseled on vismodegib causing fetal harm and to use effective contraception measures or condoms during sexual intercourse. Vismodegib can potentially cause infertility as amenorrhea can occur in females, and the reversibility of amenorrhea is unknown at this time. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm450147.htm