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Clinical Insights: December 2018

Thursday, December 20, 2018

Release Date: December 22, 2018
Expiration Date: December 22, 2019


This activity is provided free of charge.

STATEMENT OF NEED

This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may participate in this CE activity.
 
EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:
  • Describe new preventive options and treatments for patients with cancer
  • Identify options for individualizing the treatment for patients with cancer
  • Assess new evidence to facilitate survivorship and supportive care for patients with cancer
ACCREDITATION/CREDIT DESIGNATION STATEMENT

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 1 Contact Hour.
 
DISCLOSURES/RESOLUTION OF COI

It is the policy of Physicians’ Education Resource®, LLC (PER®) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER® has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.

METHOD OF PARTICIPATION
  1. Read the articles in this section in its entirety.
  2. Go to www.gotoper.com/go/ONN18December
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your CE Certificate.
OFF-LABEL DISCLOSURE/DISCLAIMER

This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®.

Liver Cancer

Regorafenib Sustains OS Benefit in RESORCE Trial Update

Anita T. Shaffer

Regorafenib (Stivarga) as second-line therapy prolonged overall survival (OS) for patients with advanced hepatocellular carcinoma (HCC) in a 2-year updated analysis of key findings from the pivotal RESORCE trial, according to results presented at the 2018 International Liver Cancer Association Annual Conference.

In the follow-up data, the multikinase inhibitor improved median OS to 10.7 months (95% CI, 9.1-12.2) compared with 7.9 months (95% CI, 6.4-9.0) with placebo, which translated into a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.51-0.78; P <.0001).1

Those results were very similar to findings from the primary analysis that prompted the FDA to approve regorafenib in April 2017 for patients with HCC previously treated with sorafenib (Nexavar). The updated findings are worth revisiting, considering regorafenib’s place in the timeline of HCC advancements, according to lead study investigator Jordi Bruix, MD, PhD, who presented the data at the conference. “This was the trial that suddenly opened an era of more success after 10 years of failures,” said Bruix, director of the Barcelona Clinic Liver Cancer (BCLC) Group at the Hospital Clinic of Barcelona in Spain.

The RESORCE trial (NCT01774344) randomized patients 2:1 to receive regorafenib at 160 mg daily (3 weeks on/1 week off) versus placebo until progression, death, or unacceptable toxicity. In all, 573 patients participated; 379 received regorafenib, and 194 were given placebo.

The study recruited patients with radiologic progression during sorafenib treatment who had Child-Pugh A status and BCLC stage B or C disease not amenable to resection or locoregional therapy. The median age was 64 years (range, 54-71) in the regorafenib arm and 62 years (range, 55-68) in the placebo group.

The efficacy population was balanced at baseline between regorafenib and placebo, respectively, for macrovascular invasion (29% vs 28%), extrahepatic disease (70% vs 76%), α-fetoprotein ≥400 ng/mL (43% vs 45%), and the presence of cirrhosis (75% vs 74%).

Tolerance to prior sorafenib also was required; this was defined as having taken ≥400 mg daily for at least 20 of the last 28 days of treatment. Additionally, patients had to be randomized within 10 weeks after their last sorafenib dose.

Bruix noted that regorafenib improved outcomes for the primary OS endpoint and the secondary endpoints of progression-free survival, time to progression, disease control rate, and overall response rate. The most common clinically relevant grade 3/4 treatment-related adverse events were hypertension, hand-foot skin reaction, fatigue, and diarrhea.

In the primary analysis, which had a data cutoff of February 29, 2016, the median OS with regorafenib was 10.6 months (95% CI, 9.1-12.1) versus 7.8 months (95% CI, 6.3-8.8) with placebo (HR, 0.62; 95% CI, 0.50-0.78; P <.0001).

As of January 14, 2018, the data cutoff for the updated analysis, the estimated OS rates for regorafenib compared with placebo at 12, 18, and 30 months were 47% versus 28%, 32% versus 15%, and 16% versus 8%, respectively, Bruix and colleagues reported in their abstract. Results for OS favored regorafenib in all preplanned subgroup analyses.

The updated findings support the validity of analyzing outcomes by patterns of progression, Bruix said. In prior research, the development of new vascular invasion or extrahepatic spread emerged as a significant predictor of a worse survival.2

The new data show that patients who developed new extrahepatic lesions during sorafenib therapy had a longer probability of postprogression survival (PPS) with second-line regorafenib than with placebo. The median PPS for patients with new extrahepatic lesions on sorafenib was 10.6 months (95% CI, 8.4-12.3) with regorafenib versus 8.2 months (95% CI, 5.9-10.0) with placebo (HR, 0.66; 95%CI, 0.50-0.89). For those without new extrahepatic lesions during prior sorafenib, the median PPS was 14.1 months (95% CI, 12.3-15.7) on regorafenib versus 10.6 months (95% CI, 9.5-12.8) with placebo (HR, 0.67; 95% CI, 0.52-0.85).

REFERENCES
  1. Bruix J, Merle P, Granito A, et al; RESORCE Investigators. Overall survival (OS) update: 2-year follow-up from the phase 3 RESORCE trial of regorafenib for patients with hepatocellular carcinoma (HCC) progressing on sorafenib. Presented at: 12th ILCA Annual Conference; September 14-16, 2018; London, England. Abstract O-023. ilca2018.org/wp-content/uploads/2018/08/ILCA-2018-Final-Programme-and-Book-of-Abstracts_LR_compressed-2.pdf.
  2. Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial [published erratum appears in Lancet. 2017;389(10064):36. doi: 10.1016/S0140-6736(16)32615-0]. Lancet. 2017;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
 
Lymphoma

Asymptomatic Young Patients With MCL May Avoid Active Treatment

Angelica Welch

Young, fit, asymptomatic patients with mantle cell lymphoma (MCL) may be able to avoid frontline therapy and its associated toxicities, according to Simon Rule, MD, PhD, a professor of hematology at University of Plymouth Peninsula Medical School in the United Kingdom.

During a presentation at the 2018 Society of Hematologic Oncology Annual Meeting, Rule also discussed therapeutic options for patients with newly diagnosed MCL and highlighted the benefits of the watch-and-wait approach.1

WATCH AND WAIT

Asymptomatic patients should be considered for the watch-and-wait approach, with treatment initiated if the disease becomes aggressive. “I have been watching and waiting in MCL for a long time—well over a decade. People thought I was mad when I was doing it to start off with. Now it has become quite well established,” Rule said in an interview with Targeted Oncology®, a sister publication to Oncology Nursing News®. “There is no advantage in treating somebody early at diagnosis if they are well.”

A study in the United Kingdom aims to establish a biobank and database as a national resource for characterizing indolent and aggressive forms of MCL. Upon registration, users have access to a central data collection to record clinical data and diagnostic samples, tissue repositories, and genetic, molecular, and immunological laboratory studies.

In the study, patients either undergo up-front therapy or follow the watch-and-wait approach. Data on the date, type of therapy, and reason for treatment are recorded for those receiving therapy and, eventually, for those undergoing observation, once therapy begins. Date and cause of death will also be recorded for both groups.

STANDARD AND EXPERIMENTAL TREATMENTS

If a patient with MCL has symptoms and requires therapy, the current algorithm recommends that a patient who is fit for an autograft receive a regimen containing rituximab (R; Rituxan) and high-dose cytosine arabinoside; if they achieve a partial or complete response, they will undergo an autograft and then receive maintenance. A patient who is not fit for an autograft is considered for CHOP (cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin], vincristine sulfate [Oncovin], and prednisone); if fit, they will receive R-CHOP or R-bendamustine followed by rituximab maintenance. A patient not fit for CHOP will receive R-bendamustine, R–cyclophosphamide, vincristine, and prednisone (R-CVP), or R-chlorambucil and then move on to maintenance.

Aside from traditional chemotherapy regimens, agents such as bortezomib (Velcade) and lenalidomide (Revlimid) have been studied as first-line therapy for patients with MCL. Some of the most highly anticipated data, though, involve the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica).

The SHINE study (NCT01776840) is a phase III trial of ibrutinib in combination with bendamustine plus rituximab in patients with newly diagnosed MCL. Patients are randomized to 1 of 2 arms. The first arm is placebo orally once daily plus 90 mg/m2 of bendamustine intravenously (IV) on days 1 and 2, cycles 1 to 6, plus rituximab at a dose of 375mg/m2 IV on day 1, cycles 1 to 6. If a complete or partial response is achieved, 375 mg/m2 of rituximab is given on day 1 of every second cycle for a maximum of 12 doses. The second arm is 560 mg of oral ibrutinib once daily plus IV bendamustine at a dose of 90 mg/m2 on days 1 and 2, cycles 1 to 6, plus rituximab at a dose of 375mg/m2 IV on day 1, cycles 1 to 6. If a patient achieves a complete or partial response, 375 mg/m2 of rituximab is administered on day 1 of every second cycle for up to 12 doses.2

The primary objective of this study is progression-free survival. Secondary objectives include overall survival, complete response rate, overall response rate, duration of response, and safety.

ENRICH is an NCI multicenter, randomized, open-label phase II/III trial of rituximab plus ibrutinib versus rituximab plus chemotherapy in elderly patients with MCL. Patients are randomized to either rituximab plus chemotherapy, which is considered the standard of care, or ibrutinib plus rituximab.

In older patients with MCL, CHOP or bendamustine-based therapies can be appropriate, Rule said. In current studies, investigators are seeking to determine the optimal frontline therapy for this population.

“Clinical trials are how we improve outcomes,” Rule concluded. “New agents are rapidly moving into the frontline and are likely to be a part of the standard of care soon.”

REFERENCE
Rule S. MCL. Presented at: 2018 Society of Hematologic Oncology (SOHO) Annual Meeting; Sept. 12-15, 2018. Houston, TX.


Nurse Perspective

 Phyllis McKiernan, MSN, APN, OCN Phyllis McKiernan, MSN, APN, OCN
Blood and Marrow Stem Cell Transplantation Program
John Theurer Cancer Center
Hackensack, NJ


Mantle cell lymphoma (MCL) is a rare, typically aggressive lymphoma, and 70% of patients present with stage IV disease. A comprehensive medical plan for newly diagnosed patients involves considering features of the disease, as well as patient characteristics to determine optimal treatment approaches. In MCL, there is a subset of young, asymptomatic patients on initial presentation, and using a watch-and-wait approach with this population can avoid unnecessary toxicity.

Patients are often fearful of delaying treatment and need reassurance that early treatment does not always provide additional clinical benefit. Using current data, nurses can provide education regarding the utility and benefits of initial observation.

Resources such as the biobank and database for MCL currently being established in the United Kingdom will provide valuable outcome data to help guide treatment pathways and give patients information they need to participate in clinical decisions. In addition, information from these types of databases can provide a stimulus for future clinical trials. For the majority of patients who present with advanced stage IV MCL, numerous ongoing studies are investigating newer agents in various combinations with established agents and regimens. If the results of these studies show improved response rate and survival without added toxicity, the frontline approach to MCL may include newer agents such as ibrutinib. For older patients with advanced disease who have a poor prognosis, several ongoing trials aim to determine optimal frontline treatment with minimal toxicity. Different patient populations have unique needs, and using data from clinical trials allows therapeutic options to be tailored appropriately.
Brain Cancer

Radiation Treatment May Impair Recent Memory in Pediatric Patients With Brain Tumors

Kristie L. Kahl

Children with pediatric posterior fossa tumors such as medulloblastoma who receive radiotherapy may be less likely to recall specific details of events that occurred after treatment compared with events that happened before, according to study results published in the Journal of Neuroscience.1

After treatment, children had less volume in the hippocampus, a part of the brain that plays an important role in memory, said lead study author Melanie Sekeres, PhD, noting the findings’ significance.

Medulloblastoma, the most common malignant brain tumor in children, is typically treated with radiotherapy, which has been found to improve survival rates but significantly affects a developing brain. This treatment option is known to suppress neurogenesis—the growth of new neurons in the nervous system—including the hippocampus. This process is critical for the formation of new memories.

“Key brain regions that we know are typically involved in autobiographical memory formation and retrieval, especially the hippocampus, are located quite far from the primary tumor bed and, thus, far from the site of focal radiation,” Sekeres, director of the Sekeres Memory Laboratory at Baylor University in Waco, Texas, said in an interview with CURE®, a sister publication of Oncology Nursing News®. “But, given that whole-head radiation and systemic chemotherapy are typically used as part of the treatment protocol, it should not be that surprising that we see brain-wide effects of these treatments.”

As a result, radiotherapy and chemotherapy appeared to be impairing these pediatric patients’ long-term ability to form new, posttreatment memories but leaving the older, pretreatment memories unaffected.

Although several aspects of memory have been examined in this population before, the impact of radiotherapy on autobiographical memory—the link to unique personal events, which involves the recollection of emotional and perceptual details that allow a person to mentally reexperience the event—had not been evaluated. So, Sekeres and colleagues retrospectively assessed episodic and nonepisodic details for events that either preceded or followed treatment in 13 children who received radiotherapy for posterior fossa tumors at least 1 year before the study. These patients were then compared with 28 healthy children of the same age.

All participants completed the Children’s Autobiographical Interview, a standardized memory test, and underwent a magnetic resonance imaging (MRI) of the brain. In addition, during individual interviews, they were asked to recall memories of personal events that happened at a specific time and place and a very old memory from before their radiation treatment, as well as one that occurred within the past month.

Children could either choose from a list of events such as a birthday party, family trip, graduation, or getting a pet or pick another event. The interview allowed them to freely recall without prompting before being asked general and specific questions about the event.

Children treated with radiotherapy reported fewer episodic details of posttreatment events compared with children in the control group. However, all the participants reported equivalent episodic details about pretreatment events.

The researchers concluded that losing episodic details was associated with hippocampal volume loss, which is linked with conditions such as Alzheimer’s disease, dementia, brain injury, epileptic amnesia, encephalitis, and aging.

“These findings have significant implications for the patient’s quality of life. The ability to form and to retain detailed personal memories for important events in one’s life is a big part of what gives our lives rich meaning,” said Sekeres, who is also an assistant professor of psychology and neuroscience at the Baylor College of Arts & Sciences. Clinicians should take this into consideration when deciding on treatment options, she said, noting that further research is warranted.

“Given the decreased volume we observed in the hippocampus and other cortical regions of the recollection network, it will be important for follow-up studies to assess differences in neural network activity and in functional connectivity within these regions using MRI in patients and healthy controls in order to gain a better understanding of potential functional disruptions that may be underlying the observed deficits in memory performance,” Sekeres said.

REFERENCES
  1. Sekeres MJ, Riggs L, Decker A, et al. Impaired recent, but preserved remote, autobiographical memory in pediatric brain tumor patients. J Neurosci. Sep 19, 2018;38(38):8251-8261. doi: 10.1523/JNEUROSCI.1056-18.2018.
  2. Martin P, Ruan J, Leonard JP. The potential for chemotherapy-free strategies in mantle cell lymphoma. Blood 2017;130:1881-1888; doi: https://doi.org/10.1182/blood-2017-05-737510?rel=0" .
 
Kidney Cancer

Avelumab/Axitinib Nearly Doubles PFS, ORR in Frontline RCC

Gina Columbus

The combination of avelumab (Bavencio) and axitinib (Inlyta) doubled objective response rates (ORRs) and significantly improved progression-free survival (PFS) compared with sunitinib (Sutent) in patients with treatment-naïve advanced renal cell carcinoma (RCC) regardless of PD-L1 expression, according to findings from the phase III JAVELIN Renal 101 trial presented at the 2018 European Society for Medical Oncology Congress.

“This trial demonstrated longer progression-free survival and higher objective response rates for avelumab plus axitinib, a checkpoint inhibitor plus a VEGF inhibitor regimen, compared with sunitinib as first-line treatment for advanced RCC,” said lead study author Robert J. Motzer, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York. “The results support this being a new standard of care for first-line treatment of [patients with] advanced RCC.”

The trial enrolled 886 patients with advanced or metastatic RCC who were randomized 1:1 to receive 10 mg/kg of avelumab intravenously every 2 weeks plus 5 mg of oral axitinib twice daily in 6-week cycles or 50 mg of oral sunitinib once daily for a 4-weeks-on/2-weeks-off schedule. Patients with all independent data monitoring committee criteria with good- (21%), intermediate- (62%), and poor-risk disease (16%) were included.

The total population included 560 (63.2%) PD-L1–positive patients. In that group, 270 patients received the combination and 290 were treated with sunitinib. In the overall group, 442 patients were treated with the combination and 444 received sunitinib. PFS by blinded independent central review and overall survival (OS) in the PD-L1–positive group were the primary endpoints; secondary endpoints were PFS and OS in the overall population irrespective of PD-L1 status, ORR, and safety.

In the PD-L1–positive population, the median PFS was 13.8 months (95% CI, 11.1-nonestimable [NE]) with avelumab/axitinib compared with 7.2 months (95% CI, 5.7-9.7) with sunitinib, leading to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95% CI, 0.475-0.790; P <.0001). The ORR with the combination was 55.2% (95% CI, 49.0-61.2), which included 4 complete responses (CRs) and 51 partial responses (PRs); the ORR with sunitinib was 25.5% (95% CI, 20.6-30.9). Twenty-seven patients in the combination arm had stable disease (SD), and 11 had progressive disease (PD).

In the overall population, the median PFS with the combination of avelumab and axitinib versus sunitinib was 13.8 months (95% CI, 11.1-NE) and 8.4 months (95% CI, 6.9-11.1), respectively (HR, 0.69; 95% CI, 0.563-0.840; P = .0001). Moreover, the ORR with avelumab/axitinib was 51.4% (95% CI, 46.6-56.1) and 25.7% (95% CI, 21.7-30.0) with sunitinib. In the combination arm, the ORR included 3 CRs and 48 PRs; 30 patients had SD and 12 patients had PD.

In the PD-L1–positive and overall population arms, 73% and 70% of patients on avelumab/ axitinib, respectively experienced an ongoing response, versus 65% and 71% of those on sunitinib. Median duration of response was not yet reached in either treatment arm in either population. OS data are not yet mature, said Motzer, who is one of the 2017 Giants of Cancer Care® (for genitourinary cancers).

“The benefit was [observed] regardless of risk group and regardless of PD-L1 status,” Motzer said. “I don’t believe you need to test [for PD-L1] to choose patients for this therapy. It may be that it helps you get a sense for the hazard ratio a little bit better in the PD-L1–positive group, but I don’t think it’s required to use this medicine.”

The immunotherapy/tyrosine kinase inhibitor (TKI) regimen also elicited a favorable safety profile. Fifty-one percent on the combination arm and 48% on the sunitinib arm experienced grade 3 treatment-related adverse events (TRAEs), the most common being diarrhea. All-grade TRAEs were similar between arms, with diarrhea again being the most common. Four percent of TRAEs led to avelumab/axitinib discontinuation versus 8% with sunitinib; 1 percent on avelumab/axitinib died due to TRAEs.

The rationale in combining these agents is that avelumab stimulates the immune system and axitinib inhibits tumor neoangiogenesis by preventing VEGF activity. Preclinical data have shown that combining this class of agents is effective because their mechanisms of action complement each other, Motzer said. Axitinib is FDA approved as a second-line therapy for patients with advanced RCC.

“We’re now, almost every year, receiving data from different combinations or single agents [in advanced kidney cancer], and it is very interesting that these data presented may increase the number of options for patients,” said Ignacio Durán, MD, PhD, of the Department of Medical Oncology at the Hospital University Virgen del Rocío and Instituto de Biomedicina de Sevilla Biomedical Institute of Seville in Spain, during a press briefing.

J.B.A.G. Haanen, MD, professor by special appointment in the Department of Clinical Oncology of Leiden University Medical Center in the Netherlands, also commented on the findings during the briefing. “Kidney cancer was a very complicated disease to treat. The development of checkpoint molecules really let the idea in that perhaps kidney cancer could be sensitive to checkpoint inhibition,” he said. “This is the first study of a TKI plus an anti–PD-L1 drug showing an improved PFS in this patient population. What we do not know is: patients who fail this treatment—how do we treat them next? Those are the questions we need to answer. But for patients with this disease, this in itself is the real step forward.”

The release of the phase III data follows the release of top-line findings from the phase III KEYNOTE-426 trial, highlighting that combining pembrolizumab (Keytruda) with axitinib significantly improved survival versus sunitinib as a first-line treatment for patients with advanced or metastatic RCC.

“From the information in the press release, it confirms the same approach—of a VEGF TKI plus an immunotherapy—showing benefit in kidney cancer patients,” Motzer said, commenting on the KEYNOTE-426 trial. “It also emphasizes the progress we’ve made in this disease in the last 20 years with these positive phase III trials showing benefit for our patients.”

REFERENCE
Motzer RJ, Penkov K, Hannen JBAG, et al. JAVELIN Renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). Presented at: 2018 European Society for Medical Oncology Congress; October 19-23, 2018; Munich, Germany. Abstract LBA6_PR.
 
Multiple Myeloma

Carfilzomib-Based Regimens Appear Safe in Multiple Myeloma

Jessica Skarzynski

Findings from 2 trials show that carfilzomib (Kyprolis; K)–based regimens appear to be safe and effective for patients with relapsed/refractory multiple myeloma, according to updated data from the ASPIRE and ENDEAVOR trials presented at the 2018 Society of Hematologic Oncology Annual Meeting.

The post hoc subgroup analysis of both studies revealed progression-free survival (PFS) improvements; moreover, consistent responses were reported regardless of prior autologous stem-cell transplant (ASCT), explained Rafat Abonour, MD, during the presentation.

In ASPIRE, results showed a significant 7.9-month improvement in median overall survival (OS) for carfilzomib, lenalidomide (Revlimid), and dexamethasone (KRd) versus lenalidomide plus dexamethasone (Rd). Median OS for the regimens was 48.3 months versus 40.4 months, respectively (HR, 0.79; 95% CI, 0.67-0.95].1 Median PFS improved by 8.7 months for patients treated with KRd versus Rd: 26.3 versus 17.6 months, respectively (HR, 0.69; 95% CI, 0.57-0.83).2

In ENDEAVOR, carfilzomib was given at a dose of 56 mg/m2 along with dexamethasone (Kd56) and compared with bortezomib (Velcade) plus dexamethasone (Vd). Investigators observed a significant 7.6-month improvement in median OS with Kd56 over Vd: 47.6 months versus 40.0 months, respectively (HR, 0.79; 95% CI, 0.65-0.96).3 Median PFS for Kd56 was 18.7 months compared with 9 months for Vd (HR, 0.53; 95% CI, 0.44-0.65).4

“In ASPIRE, patients with prior ASCT treated with KRd had an 11.4-month improvement in median OS, and, for those with first relapse after ASCT, the benefit was further pronounced with an 18.6-month improvement in median OS,” said Abonour, medical director of the Bone Marrow Transplant Program and Stem Cell Laboratory at Indiana University School of Medicine in Indianapolis. “In ENDEAVOR, OS benefits were observed for Kd56 versus Vd across ASCT subgroups; the benefit of Kd56 was more evident in the no prior transplant group.” Safety results showed that discontinuation rates due to adverse events (AEs) were similar for the KRd regimen versus Rd across ASCT subgroups. All other AEs were consistent with what has been seen with carfilzomib, Abonour said.

Of the patients on the ASPIRE trial who received prior ASCT to KRd (n = 215), 99.5% experienced AEs of any grade and 89.8% experienced grade ≥3 AEs, but just 14.9% discontinued treatment due to AEs. All 87 patients who received KRd after first relapse following ASCT experienced AEs of any grade, 92% experienced grade ≥ 3 AEs, and 27.6% discontinued treatment due to AEs. For those who had no prior ASCT (n = 177) and received KRd, 96% experienced AEs of any grade, 83.6% experienced grade ≥3 AEs, and 24.3% discontinued treatment due to AEs. These were comparable to rates of AEs observed with Rd, investigators noted.5

The grade ≥3 AEs of interest in ASPIRE for patients receiving KRd versus Rd with prior ASCT were comparable—anemia (18.6% vs 17.4%), thrombocytopenia (20.9% vs 14.3%), and neutropenia (36.3% vs 30.8%). For those who received KRd versus Rd after first relapse following frontline ASCT, there were, again, comparable rates of anemia (17.2% vs 20.8%), thrombocytopenia (17.2% vs 16.9%), and neutropenia (32.3% vs 24.7%). For patients who had not received prior ASCT, rates of anemia (18.6% vs 17.6%), throm-bocytopenia (11.9% vs 11.5%), and neutropenia (24.9% vs 23.0%) were similar, as well.

Across the subgroups of patients enrolled in ENDEAVOR who received Kd56 or Vd, AEs were similarly comparable. Of the patients who had received prior ASCT and received Kd65 (n = 266), 98.9% experienced AEs of any grade, whereas 81.6% experienced grade ≥3 AEs and 28.6% discontinued treatment due to AEs. For those who received Kd65 after first relapse following ASCT (n = 123), 98.4% experienced AEs of any grade, 78% experienced grade ≥3 AEs, and 26% discontinued treatment due to AEs. Of those who had no prior ASCT and received Kd56 (n = 197), 98.5% experienced AEs of any grade, 81.2% experienced grade ≥3 AEs, and 28.9% discontinued treatment due to AEs.

The grade ≥3 AEs of interest in the ENDEAVOR trial for patients receiving Kd56 versus Vd were also comparable in the group that received prior ASCT—anemia (16.9% vs 8.2%), thrombocytopenia (10.2% vs 11.6%), and neutropenia (3.4% vs 2.6%). Varying rates of AEs were observed for those who received Kd65 versus Vd after first relapse following ASCT: anemia (13% vs 5.8%), thrombocytopenia (4.9% vs 10.8%), and neutropenia (1.6% vs 1.4%). For those with no prior ASCT, AEs were comparable in those who received Kd56 versus Vd—anemia (15.7% vs 12.8%), thrombocytopenia (7.1% vs 6.4%), and neutropenia (1% versus 1.6%).

REFERENCES
  1. Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36(8):728-734. doi: 10.1200/JCO.2017.76.5032.
  2. Stewart AK, Rajkumar V, Dimopoulos MA, et al; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-152. doi: 10.1056/NEJMoa1411321
  3. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(10):1327-1337. doi: 10.1016/S1470-2045(17)30578-8.
  4. Dimopoulos MA, Moreau P, Palumbo A, et al; ENDEAVOR Investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27-38. doi: 10.1016/S1470-2045(15)00464-7.
  5. Goldschmidt H, Mateos M, Siegel D, Abonour R, Heinz Ludwig H, et al. Overall survival of patients according to prior transplant: Study results from the two carfilzomib phase 3 trials ASPIRE and ENDEAVOR. Presented at Society of Hematologic Oncology Sixth Annual Meeting, Houston, Texas, September 12–15, 2018.
 
Nurse Perspective

Charise Gleason MSN, NP-BC, AOCNP Charise Gleason MSN, NP-BC, AOCNP
Advanced Practice Provider, Chief
Department of Hematology and Medical Oncology
Emory Winship Cancer Institute
Atlanta, GA


With the development of so many agents over the past decade, overall survival for multiple myeloma has improved dramatically. Proteasome inhibitors (PIs) have shown to be an effective therapeutic class for myeloma, with second-generation carfilzomib (Kyprolis) being approved in 2012. With so many treatment options, the oncology nurse, who has a strong role in patient education, is an integral part of the care team.

Treatment for multiple myeloma usually include multidrug regimens. Carfilzomib, for example, is typically used in combination with other immunomodulatory agents. It is usually well tolerated and rarely exacerbates peripheral neuropathy as compared with the first-generation PI, bortezomib. Potential adverse events [AEs] such as thrombocytopenia and cardiac toxicity are associated with carfilzomib, but with appropriate monitoring, carfilzomib combinations can be very effective and safe.

How does the oncology nurse keep up with all the treatment options and related toxicities? Clinical pearls to consider with carfilzomib include close monitoring of the patient’s cardiopulmonary status. If a patient has any cardiac risk factors, a baseline cardiac evaluation and echocardiogram should be obtained. The patient should not be overhydrated or underhydrated and should be monitored for weight gain and shortness of breath. Patients on a PI should be on an antiviral prophylactic drug, and dose modifications may be necessary for recurrent infections or hematological toxicities. Routine monitoring and AE management are important for adherence to therapy.

Oncology nurses will continue to play an important role in the ongoing support and education of patients with multiple myeloma.


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