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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.

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

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

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Preventing the Spread of Clostridioides Difficile in Oncology Units

Hospital-acquired infections can negatively affect outcomes in patients with cancer, so it is imperative that oncology nurses are vigilant about preventing them. After seeing a spike in Clostridioides difficile (C diff) infections a few years ago, nurse investigators at City of Hope National Medical Center in Duarte, California, conducted a root cause analysis and then created an intervention plan to stop the spread.

The results were presented by Karen Wohlgezogen, BSN, RN, CPHON, assistant clinical nurse manager at City of Hope, during the 2020 Oncology Nursing Society Bridge virtual conference, held September 8 to 17, 2020.1

“C diff is a spore-forming [bacterium] that is very resilient and difficult to kill,” Wohlgezogen said. “It causes life-threatening diarrhea and colitis.”

In their initial analysis, the investigators realized that C diff infections were occurring in adjacent rooms during the same time frame, which suggested a role of staff in spreading the infection, Wohlgezogen explained, also noting that some staff members were unable to correctly answer questions about how to adequately clean shared equipment. They also noticed family members of patients in isolation rooms not washing their hands when they left the room.

“Any time you’re cleaning anything having to do with C diff, you definitely have to use bleach so it’ll kill the spores. Alcohol gel and alcohol wipes don’t do it,” Wohlgezogen said. “But we had complaints from staff, patients, and families about using bleach. They didn’t like the strong smell, [and] it seemed to stain the clothes of the staff using it.”

Addressing the issue began with patient and staff education. In addition, nurses were put in charge of providing patients and families with any items they wanted or needed, such as coffee or snacks, and they were tasked with making sure that objects were cleaned appropriately before and after use.

Next, they realized the importance of patients bathing or showering daily to decrease the bacterial count on the body. Then, the team determined that bedside commodes likely were not being cleaned as thoroughly as they should be, particularly the heavy-duty bucket component that catches the waste. Therefore, City of Hope began to invest in single-use patient items.

“Once we [changed] the bedside commode buckets [to] single use, we definitely saw a decrease [in C diff],” Wohlgezogen said.

The team also ensured that there were enough vital sign monitors that one could be kept in the room of each oncology patient in isolation for the duration of their stay without needing to be shared with other patients. Similarly, they encouraged limiting movement of computer workstations on wheels among isolation patients’ rooms when possible.

“Our recommendation is to maintain a high focus on [C diff] infection prevention and [to continue] the education with the nursing [and medical] staff, patients’ families, and all the people who touch the patients,” Wohlgezogen said.

1. Wohlgezogen K. Decreasing C. difficile infection rates: the bundle approach. Presented at: 2020 Oncology Nursing Society Bridge virtual conference; September 8-17, 2020; Virtual. Accessed September 22, 2020.

Opioid Overview: Know What to Use and When

Patients with cancer can experience immense pain, and it is crucial that oncology nurses know how to effectively—and safely&mdash;manage that pain.

“Pain management is both an art and a science. You really have to see how the patient is doing. How are they tolerating the opioids?” said Jeannine Brant, PhD, APRN, AOCN, FAAN, an oncology clinical nurse specialist and the director and lead scientist of Collaborative Science and Innovation at Billings Clinic in Montana. Brant recently led a presentation on opioid use at the 2020 Oncology Nursing Society Bridge virtual conference, held September 8 to 17, 2020.

Brant said that morphine is “the gold standard for comparison for all opioids” because it is inexpensive and can be given orally or rectally, in immediate- or controlled-release form, and can even be injected into the space or fluid around the spinal cord.

Morphine has 2 metabolites (byproducts of the body breaking down the drug): morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Nurses should be aware that for patients with compromised kidney function, M3G and M6G accumulate in the body and can cause adverse events (AEs) such as neurotoxicity, nightmares, hallucinations, or oversedation.

This opioid is not completely off the table for patients with renal insufficiency, but clinicians should adjust the dose appropriately.

Oxycodone, which is primarily administered orally and is sometimes combined with acetaminophen, is another common and versatile opioid option for patients with cancer.

Frequently, patients who experience AEs from morphine will switch to oxycodone. However, clinicians should be cautious when combining oxycodone and acetaminophen.

“We have to be careful of [combining the drugs] because we should limit acetaminophen to even less than 4 [grams] a day. Oftentimes, the limits are lower,” Brant said. “So, many times, giving pure oxycodone [with] acetaminophen on the side is one of the best ways to control pain, even though [oxycodone] has an active metabolite.”

While oxycodone is efficacious and has a tolerable AE profile, nurses and other providers should also remember that it may pose a greater risk for substance use disorder compared with other opioid pain relievers.

Finally, fentanyl is a drug that has various pharmacokinetic properties, depending on how it is administered.

For example, a transdermal patch can take up to 12 hours to start working because the drug must penetrate and saturate the patient’s subcutaneous adipose tissue before entering the systemic circulation. “Then, it finally starts working 12 hours later and lasts about 72 hours,” Brant said. “For some patients, however, you have to apply it every 48 hours because they really drain that patch more quickly.” Nurses must remember that transdermal fentanyl’s analgesic effect will likely be delayed in patients who are obese because the drug must saturate a greater amount of adipose tissue.

Clinicians can also give fentanyl via the transmucosal route. That method has a quick onset of action of approximately 5 to 10 minutes, according to Brant, who explained that fentanyl is absorbed through a mucous membrane—in the patient’s mouth, for example. Intravenous fentanyl also takes effect quickly. ;

Articles

CE lesson worth 1 contact hour that is intended to advanced practice nurses, registered nurses, and other healthcare professionals who care for patients with cancer.

Clinical Insights: December 2020

Adverse Event Management for BRAF/MEK Inhibitors in Melanoma

With BRAF mutations occurring in approximately 50% of patients with cutaneous melanoma,1 the advent of BRAF/MEK inhibitors for this disease type has drastically improved outcomes in recent years, according to Grace Cherry, MSN, RN, NP, a nurse practitioner at the melanoma program at UCLA.

Cherry discussed recent exciting advancements in the melanoma field at the 4th Annual School of Nursing Oncology virtual meeting, held July 31 to August 1, 2020.2

“BRAF [V600] is a driver mutation,” Cherry said. ““It’s like that switch for that signal to have the cells grow is constantly on. It’s like a light has been switched on … When it’s switched on, there’s no stopping that signal. It’s continuing to allow those tumors to grow rapidly. So, when we give a BRAF/MEK inhibitor, it’s like turning off that switch.”

There are 3 FDA-approved BRAF/MEK inhibitor combinations (below). Although there is some overlap between their adverse events (AEs), such as fatigue and nausea, there are specific AEs frequently seen with each regimen that nurses need to be aware of when treating patients, according to Cherry.

• Dabrafenib (Tafinlar)/trametinib (Mekinist): fever

• Vemurafenib (Zelboraf)/cobimetinib (Cotellic): photosensitivity and rash

• Encorafenib (Braftovi)/binimetinib (Mektovi): nausea

“Nurses are our front line as far as giving these treatments and also in teaching our patients about side effects and detecting them,” Cherry said.

The first step in managing AEs from BRAF/MEK inhibition is confirming that the patient has a BRAF V600E or V600K mutation (which represent up to 90% and 10% of BRAF mutations in melanoma, respectively). “If [patients] get these drugs and they’re BRAF wild type [negative for a BRAF mutation], it can have a paradoxical effect and make the tumor grow.”

Patients should then undergo a dermatological examination and echocardiography because there is a small chance that they may have cardiotoxicity. If the patient is experiencing blurred vision, which is rare, they should be referred to an ophthalmologist to check for ocular toxicity.

All patients experiencing AEs from their BRAF/MEK inhibition treatment should undergo laboratory testing. Clinicians can monitor their blood for elevated liver enzymes, reduced white blood cell count, and markers of rare AEs, such as elevated creatine phosphokinase, which may indicate a rare AE, rhabdomyolysis. Cherry also noted that dose interruptions were very common in the clinical trials that led to approval of these drugs.

“If [patients are] having a really severe side effect, it’s warranted to do a dose reduction so they can continue taking it on a continuous basis. Sometimes they may have to discontinue if [toxicities] are really severe,” Cherry said.

Despite the landmark advances of BRAF/MEK inhibitors—as well as other agents, such as immunotherapy&mdash;in melanoma, there is still more work to be done.

“Our patients have come a long way compared [with] before BRAF/MEK inhibitors and immunotherapy came along, but we have a long way to go,” Cherry said. “Not everybody responds to [these agents], and we need to improve on them.”

1. Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod Pathol. 2018;31(1):24-38. doi:10.1038/modpathol.2017.104

2. Cherry, G. Melanoma: treatment updates in advanced melanoma. Presented at: 4th Annual School of Nursing Oncology; July 31-August 1, 2020; Virtual.

Managing Systemic Toxicities and Limiting Therapy Nonadherence in Breast Cancer

One of the most important tasks oncology nurses face is ensuring that patients are taking their medications consistently and correctly and that adverse events (AEs) are properly managed—especially in patients with breast cancer, according to Patricia Jakel, MN, RN, AOCN.

“[Nonadherence] is a nursing issue,” Jakel emphasized. “Learn that patients who think they’re taking their [medications] correctly [can still be mistaken]. … Try to help patients make sure that all medications, especially oral medications, are taken correctly. It really does have an impact on overall life expectancy.”

In her presentation on systemic toxicity management in breast cancer at the 4th Annual School of Nursing Oncology virtual meeting, held July 31 to August 1, 2020, Jakel, an advanced practice nurse with the University of California, Los Angeles (UCLA) Medical Center, Santa Monica, an associate professor of nursing at the UCLA School of Nursing, and a patient with breast cancer herself, discussed the best supportive care strategies that should accompany breast cancer therapy.

Medication adherence rates for patients with cancer range from 15% to 87%, with a mean of 50%. Poor adherence has been found to be associated with patient age older than 65 years, prescriptions written by nononcologists, polypharmacy, and high co-payments. Poor adherence to treatment regimens—whether due to AEs or confusion about how to take medications&mdash;can lead to worse patient outcomes, such as disease progression, development of resistance to certain medications, and even death.

A number of therapeutic agents are currently available for patients with estrogen receptor (ER)—positive breast cancer, including selective ER response modulators such as tamoxifen (Soltamox), toremifene (Fareston), and raloxifene (Evista); luteinizing hormone–releasing agents for ovarian suppression such as goserelin (Zoladex), leuprolide (Lupron), and triptorelin (Triptodur); aromatase inhibitors (AIs) such as anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara); and ER downregulators such as fulvestrant (Faslodex). AEs that accompany these endocrine therapies can lead to therapy nonadherence, according to Jakel. Aside from joint pain known AEs include hot flashes, menopausal symptoms, libido loss, blood clots, and osteoporosis and may contribute to a decrease in long-term adherence to oral endocrine therapies. This issue of nonadherence may affect between 30% and 80% of patients, especially those who have been receiving these therapies for at least 5 years.

“[One patient] stopped [her AI treatment] because of bone pain,” Jakel explained. “We tend to not think about that … but probably about 40% of patients have pretty severe bone pain that makes it hard to get up off the couch.”

Patients who receive CDK4/6 inhibitors also tend to experience AEs such as diarrhea, though this can be managed with other agents such as loperamide (Imodium) and octreotide (Sandostatin), which are likely to be effective. The benefits of agents such as amifostine (Ethyol) and neomycin (Neo-Rx) must be balanced against their possible harm. Jakel stated that encouraging patients with diarrhea to follow the BRAT diet— bananas, rice, applesauce, and toast&mdash;is another expert opinion worth exploring.

Fatigue is also a prevalent AE among patients undergoing breast cancer therapy. Though numerous medications exist to help manage fatigue, Jakel emphasized that exercise can help patients to feel better, coupled with proper sleep hygiene, such as decreasing screen time with electronic devices and reducing alcohol consumption.

Nausea is another gastrointestinal AE associated with CDK4/6 inhibitors that can be managed through recommended lifestyle changes. “What time of day should [patients] take [their CDK4/6 inhibitor]?” Jakel asked. “How should they take it? Should they take it with food? Should they take it before bed? Should they take it in the morning and [risk] being nauseated during the day? Have that conversation [with patients] because if it’s only once a day—though many drugs are twice a day&mdash;you can play around with the time of day [patients] take it to help with nausea.”

A large proportion (75%) of patients with breast cancer experience cognitive impairment, or “chemo brain,” which can lead to confusion and memory loss. Thus far, cognitive training has been shown to be an effective way to manage cognitive impairment. Other activities that help to focus the mind, such as yoga, meditation, and psychoeducational interventions may also help; however, their effectiveness has not yet been established.

Another AE that is not discussed enough, according to Jakel, is ongoing problems with sexual function—an issue that half of all cancer survivors report. Especially following antiestrogen breast cancer therapies, a large number of female patients report having low or absent sexual desire. Menopausal symptoms and dyspareunia (painful intercourse) due to vaginal dryness may be 2 contributing factors, as well as issues with body image after reconstructive surgery.

Clinical Insights: October 2020

Evaluating the benefits of the subQ vs IV formulation of the trastuzumab-pertuzumab combination for the management of HER2+ breast cancer and examining the potential use of at-home administration.

HER2-targeted Therapy: Routes of Administration

Nurse practitioners provide insight on issues surrounding the administration of dual HER2-targeted therapy in the neoadjuvant/adjuvant setting and counseling patients on common AEs associated with trastuzumab-pertuzumab for the treatment of HER2+ breast cancer.

Practical Management of Early Stage HER2+ Breast Cancer

Carfilzomib Triplet Regimen Is Not Superior To Standard of Care in Myeloma

The combination of next-generation proteasome inhibitor carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Decadron) (KRd) did not demonstrate superior progression-free survival (PFS) in newly diagnosed multiple myeloma (NDMM) compared with the current standard-of-care triplet of bortezomib (Velcade), lenalidomide, and dexamethasone (VRd), according to results of the ENDURANCE (E1A11) trial (NCT01863550) presented in a presscast ahead of the 2020 American Society of Clinical Oncology Virtual Scientific Program.1

In the VRd cohort, median PFS was 34.4 months compared with 34.6 months in the KRd arm. Moreover, there were no PFS differences based on age, t(4;14) status, or disease stage.

The randomized phase 3 trial also assessed whether indefinite maintenance with lenalidomide improved overall survival (OS) compared with 2-year maintenance. Data are not yet mature for this end point.For the maintenance phase, patients received lenalidomide at 15 mg on days 1 to 21 every 4 weeks.

Given previous phase 3 trial results showing superior efficacy of carfilzomib compared with bortezomib in the relapsed setting, investigators sought to determine whether carfilzomib could replace bortezomib in the current standard-of-care triplet induction regimen for patients with standard- and intermediate-risk NDMM.

Patients who were enrolled in the trial lacked high-risk features such as chromosome 17p deletion, translocation t(14;16) or t(14;20), plasma cell leukemia, a high-risk profile based on the GEP70 test of 70 genes associated with multiple myeloma aggressiveness. The median age of all patients was 65 years.

The 542 patients in the VRd arm received 12 cycles (3 weeks each) of bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 (days 1 and 8 for cycles 9-12); lenalidomide at 25 mg on days 1 to 14; and dexamethasone at 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12.

The 545 patients in the KRd arm received 9 cycles (4 weeks each) of carfilzomib at 36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide at 25 mg daily on days 1 to 21; and dexamethasone at 40 mg weekly.

The second of 3 planned interim analyses revealed that substituting carfilzomib for bortezomib did not affect PFS (HR, 1.04; 95% CI, 0.83-1.31; P = .74). Three-year OS rates were also similar in both arms, at 84% in the VRd arm (95% CI, 80%-88%) and 86% in the KRd arm (95% CI, 82%-89%).

In the VRd cohort, 57% of patients did not complete the induction treatment. The most common reasons for leaving the trial were pursuit of an alternative therapy (18%), adverse events (AEs; 17%), patient choice (7%), and disease progression (6%).

In the KRd arm, 39% of patients withdrew from treatment early due to pursuit of an alternative therapy (14%), AEs (10%), patient choice (4%), and disease progression (4%).

Overall, treatment-related AEs (TRAEs) of grade 3 or higher occurred in 59% of VRd and 66% of KRd patients. Nonhematologic TRAEs accounted for the majority, with rates of 41% and 48%, respectively. Although peripheral neuropathy was more common with VRd (53% compared with 24% in KRd; P < .001), the KRd arm experienced a significantly higher rate of cardiopulmonary and renal TRAEs (16% compared with 5% in the VRd arm; P < .001).

Based on these study results, investigators determined that VRd remains the superior triplet induction regimen in this patient population, making it a suitable backbone for 4-drug combinations as well.

Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial. J Clin Oncol. 2020;38(suppl 18): LBA3. doi:10.1200/JCO.2020.38.18_suppl.LBA3

Diagnostic Performance of PSMA-Targeted PET Tracer Excels in the Treatment of Recurrent Prostate Cancer

Imaging with 18F-DCF pyrrolysine (PyL) positron emission tomography (PET)/CT outperformed standard imaging modalities—such as bone scan, CT, MRI, and fluorodeoxyglucose PET&mdash;in patients with biochemically recurrent prostate cancer in the phase 3 CONDOR trial (NCT03739684).

“The CONDOR study met its primary end point. Indeed, it well exceeded it. And it demonstrated excellent diagnostic performance of PyL PET in men with biochemically relapsed prostate cancer, even at very low PSA [prostate-specific antigen] values,” said Michael J. Morris, MD, when presenting findings during the 2020 American Society of Clinical Oncology Virtual Scientific Program. “It clearly showed superiority to the standard imaging these men received as part of their local work-ups.”

Prostate-specific membrane antigen (PSMA)—targeting PET has been suggested to be a superior method for imaging in prostate cancer compared with standard imaging modalities, although it is not yet approved for use in the United States. DCFPyL labeled with fluorine 18 (18F-DCFPyL) is an investigational PSMA-targeted PET tracer. PyL is a lysine-linked, urea-based small molecule that targets the extracellular domain of PSMA. For imaging, 9 (±20%) mCi of tracer is administered intravenously as a bolus injection, and then PET imaging is completed 1 to 2 hours later.

CONDOR explored the use of 18F-DCFPyL in patients with rising PSA concentrations. Eligible patients had biochemical recurrence, defined as a PSA of at least 0.2 ng/mL following radical prostatectomy or at least 2 ng/mL above the nadir following radiation therapy or cryotherapy. Eligibility also required negative or equivocal findings on standard-of-care imaging. Patients who were undergoing systemic therapy or who had received androgen deprivation therapy within 3 months were excluded from participating in the trial.1

The primary end point was the correct localization rate (CLR), which is equivalent to positive predictive value with an added requirement of anatomical lesion location matching. The latter was accomplished with an anatomic atlas created before the study. CLR was defined as the percentage of patients with a 1:1 correspondence between 18F-DCFPyL PET/CT and the composite truth standard.

A secondary end point, the percentage of patients who had a change in their treatment plan as a result of the 18F-DCFPyL PET scan, was assessed with pre- and postimaging questionnaires completed by the clinician. Disease detection rate was an exploratory end point.

“Because this patient population has neither available tissue nor informative standard imaging, the end points of this study warrant special scrutiny,” said Morris, clinical director of the Genitourinary Medical Oncology Service and Prostate Cancer Section Head in the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center in New York, New York. A composite truth standard was used to distinguish true-positive from false-positive test results. For the sake of the trial, the composite truth standard was defined as either evaluable local histopathology findings from surgery or biopsy, informative conventional imaging, or a confirmed PSA response (≥50% decline from baseline) in patients treated with radiotherapy only following 18F-DCFPyL PET/CT imaging. These options, listed in order of importance, were based on feasibility.

For a positive test result, the study assumed that the lower bound of the 95% confidence interval of the CLR would exceed 20% for at least 2 of 3 blinded, independent central readers. This rather modest goal was chosen based on previous studies of patient populations with low PSA values. Additionally, 60% of patients were expected to have positive 18F-DCFPyL PET/CT findings, and 30% of positive PSMA PET scan results were expected to be confirmed per the composite truth standard.

All patients who had a positive result on standard imaging were required to undergo a confirmatory study to define the composite truth standard. To further minimize the risk of bias, 2 adjudicators examined the composite truth standard and a statistician compared the outcomes to arrive at a final true-/false-positive verdict.

A total of 208 men were dosed with 18F-DCFPyL in the study. These patients had a median age of 68 years (range, 43-91) and had been diagnosed a median of 71 months (range, 3-356) prior. Nearly half (49.5%) of all patients had undergone radical prostatectomy only, 35.6% had undergone radical prostatectomy and radiation therapy, 14.9% had received only radiotherapy, and 27.9% had received at least 1 systemic therapy for their prostate cancer. Almost three-fourths of the men (73.6%) had a total Gleason score below 8.

The median PSA was 0.8 ng/mL (range, 0.17-98.45), and 31.2% of patients had a PSA of at least 2.0 ng/mL.

“The PSA values were representative of this group of men. As expected, the median PSA of this population was quite low at 0.8,” Morris commented. “And generally, these are the values at which most decisions regarding salvage therapy and therapeutic plans are made.”

Across the 3 readers, the rate of positive 18F-DCFPyL scans ranged from 59.1% to 65.9%; in 11.5% to 15.9% of cases, the detection rate was unevaluable due to the composite truth standard not being submitted or suggesting a false-negative finding.

Clinical Insights: August 2020

The FDA has approved pembrolizumab (Keytruda) for patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Efficacy was investigated in KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial. The trial excluded patients who had previously received therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody and those with autoimmune disease or a medical condition that required immunosuppression. Patients received pembrolizumab 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks during the first year and every 9 weeks during the second year.

The major efficacy outcome measures were objective response rate (ORR) and response duration as assessed by blinded independent central review according to RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The ORR was 34% (95% CI: 24, 44) and median response duration was not reached (range: 2.7, 13.1+ months).

This article was originally published on 

The FDA has approved pembrolizumab (Keytruda) or patients with recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation.

FDA Approves Pembrolizumab for Cutaneous Squamous Cell Carcinoma

Tocilizumab Successfully Treats COVID-19 in Patients With Myeloma

Special attention to reducing the risk of cardiovascular disease should be a priority for long-term care of patients with breast cancer, according to Jean-Bernard Durand MD, FACC, FACP, FHFSA, FAHA.1

The oncology supportive care agent tocilizumab (Actemra) successfully treated COVID-19 in a patient with multiple myeloma, according to a case study from Wuhan, China, published in Blood Cancers.1,2

The investigators specifically concluded that their research suggests that tocilizumab might effectively treat cytokine storm caused by COVID-19, and that this benefit could potentially be extrapolated to patients with other blood cancers. Cytokine storm is a type of severe immune overreaction that can cause life-threatening respiratory complications.

"Our patients with hematologic malignancies are immunosuppressed, which may put them at higher risk for novel coronavirus infection. What are the characteristics of COVID-19 in patients with blood cancers? What is the optimal treatment approach? Everything is unknown, and that was the motivation for this study," the study’s lead author Changcheng Zheng, MD, of the University of Science and Technology of China, said in a press release.

In the patient with multiple myeloma, tocilizumab successfully resolved COVID-19 symptoms after standard treatments failed, and he was able to be released from the hospital. Zheng emphasized that the patient did not have the standard COVID-19 symptoms of cough and fever, suggesting that patients with hematologic malignancies may not typically have these clinical symptoms of the coronavirus.

Going forward, Zheng is hopeful that the success of tocilizumab in this patient can be a model across hematologic malignancies, but cautions that much more research is still needed.

"Tocilizumab was effective in the treatment of COVID-19 in this patient with multiple myeloma, but further prospective and randomized clinical trials are needed to verify the findings," said Zheng.

The case study involved a 60-year-old male with multiple myeloma diagnosed in 2015. He was receiving maintenance therapy for myeloma at the time of his hospitalization on February 1, 2020, for chest tightness and shortness of breath. He tested positive at the time for COVID-19 that was considered severe, despite not having the standard symptoms of cough or fever.

Antiviral and corticosteroid therapies were initially used but did not completely resolve his symptoms. A chest CT scan done on his second day of hospitalization revealed that there were ground glass opacities in his lungs, a characteristic of pneumonia. Additionally he had high levels of the proinflammatory cytokine IL-6.

The patient received 8 mg/kg of tocilizumab (IV, administered 1 time) on day 9 in the hospital, which was day 24 of his having COVID-19. The patient’s IL-6 levels went down after the single intravenous dose of tocilizumab, continuing to decrease over the next 10 days (121.59 to 20.81 pg/mL). The levels then started to increase rapidly, peaking at 317.38 pg/mL, but eventually settled to 117.10 pg/mL.

“The transient rebounding of the IL-6 level to the peak does not mean COVID-19 relapse: instead, this might be attributed to the recovery of the normal T cells,” Zheng et al explained in the article.

His chest tightness resolved 3 days after initiating tocilizumab and on his 19th day in the hospital, a CT scan showed an obvious decrease in the range of ground-glass opacities. On March 13, 2020, the hospital considered the patient to be cured and he was discharged. He also showed no symptoms of multiple myeloma and had normal laboratory results.

The FDA recently approved the initiation of a double-blind, randomized phase III clinical trial of tocilizumab for use in combination with standard of care for the treatment of hospitalized adult patients with severe COVID-19 pneumonia, according to Genentech (Roche), the manufacturer of the interleukin-6 receptor antagonist.3

Genentech is collaborating with the Biomedical Advanced Research and Development Authority (BARDA), a part of the US Health and Human Services Office of the Assistant Secretary for Preparedness and Response (ASPR), to evaluate tocilizumab combined with standard of care versus placebo plus standard of care.

Enrollment is expected to start soon, with a target accrual of 330 patients across the United States and other countries. Investigators will follow patients for 60 days after randomization and early proof of efficacy will be assessed at an interim analysis. Key study endpoints will be clinical status, mortality, mechanical ventilation, and intensive care unit variables.

As the CAR T-cell therapy revolution has spread across the treatment paradigm for patients with hematologic malignancies, tocilizumab has become critical to ensuring that patients are able to receive this type of therapy. Specifically, tocilizumab is approved by the FDA for the treatment of cytokine release syndrome (CRS) that is severe or life-threatening. CRS is the most severe toxicity associated with CAR T-cell therapy. Tocilizumab is used in adults and children aged 2 years and older who have CRS caused by CAR T-cell therapy.

Tocilizumab has been a critical component to ensuring the success of several pivotal clinical trial of CAR T-cell therapy. For example, the FDA is currently reviewing a biologics license application for the anti-CD19 CAR T-cell therapy lisocabtagene maraleucel for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after at least 2 prior therapies, based on data from the multicenter phase I TRANSCEND NHL 001 study.4 In this pivotal trial, the incidence of any grade CRS was 42%, which occurred at a median onset of 5 days. Nineteen percent of patients received tocilizumab to manage CRS. Nearly all cases of CRS were entirely reversible.

Another oncology drug, ruxolitinib (Jakafi), is being explored in the planned phase III RUXCOVID trial as a treatment for cytokine storm in patients with COVID-19. The RUXCOVID trial will specifically evaluate the JAK1/2 inhibitor in combination with standard of care treatment versus standard of care alone in patients with severe COVID-19 pneumonia caused by SARS-CoV-2 infection.

Novartis and Incyte, the covdevelopers of ruxolitinib, decided to launch the trial based on preclinical and preliminary clinical findings indicating ruxolitinib could lower the number of patients with these complications who need intensive care and mechanical ventilation. In a press release, the companies reported that they plan to initiate a compassionate use program for patients with COVID-19 to have access to ruxolitinib.5

1. Case Study: Treating COVID-19 in a Patient with Multiple Myeloma. Published online April 3, 2020. https://prn.to/2JzIakv. Accessed April 3, 2020.

2. Zhang X, Song K, Tong F, et al. First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Adv. 2020;4(7):1307-1310. https://doi.org/10.1182/bloodadvances.2020001907

3. Genentech Announces FDA Approval of Clinical Trial for Actemra to Treat Hospitalized Patients With Severe COVID-19 Pneumonia. Posted March 23, 2020. https://www.gene.com/media/press-releases/14843/2020-03-23/genentech-announces-fda-approval-of-clin. Accessed March 23, 2020.

4. U.S. Food and Drug Administration (FDA) Accepts for Priority Review Bristol-Myers Squibb’s Biologics License Application (BLA) for Lisocabtagene Maraleucel (liso-cel) for Adult Patients with Relapsed or Refractory Large B-Cell Lymphoma. Published February 13, 2020. https://bit.ly/39uYC0l. Accessed February 13, 2020.

5. Novartis announces plan to initiate clinical study of Jakavi® in severe COVID-19 patients and establish international compassionate use program. Published April 3, 2020. https://bit.ly/3aHA2dF. Accessed April 3, 2020.  

Shifting Lung Cancer Treatment Strategies in Response to COVID-19

Through the use of telemedicine and modified treatment plans, experts in the cancer community are working hard to prevent patient exposure to COVID-19. These efforts are particularly important for patients with lung cancer, as this population is at increased risk of developing more severe complications from the virus, according to Joshua M. Bauml, MD.

“It seems that patients with lung cancer are at higher risk for more severe complications, likely due to multiple issues. For one, there is cancer in the lung that can limit the amount of normal lung tissue,” said Bauml. “Some patients have also undergone surgery or radiation that further limits the amount of healthy lung tissue. In addition, many patients with lung cancer have underlying lung disease, such as emphysema, asthma, or chronic bronchitis, that puts them at higher risk [for complications].”1,2

Bauml, an assistant professor of medicine at the Hospital of the University of Pennsylvania, discussed challenges in providing care to patients with lung cancer in light of the COVID-19 pandemic and ongoing efforts to reduce exposure to the virus.

What do we know so far about COVID-19 and how it is affecting patients with lung cancer specifically?

 We have very limited data available now; it is a very fluid situation. Based on data that have come out of both China and Italy, it does seem that patients with cancer in general, and lung cancer specifically, are at higher risk for complications from COVID-19 infection. That being said, it is important to remember that all these data remain very preliminary; there is so much more we don’t know versus what we do know at this point.1,3,4

Clinical Insights: June 2020

The FDA has approved selinexor (Xpovio) as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, who have received ≥2 prior therapies.

The approval was based on the phase 2b SADAL trial, in which the agent demonstrated a 28.3% overall response rate (ORR), including an 11.8% complete response (CR) rate and a median duration of response (DOR) of over 9 months.

Selinexor is an oral selective inhibitor of exportin 1 (XPO1), which is the major nuclear export protein for tumor suppressor proteins and eIF4E-bound oncoprotein RNAs. XPO1 inhibition via selinexor promotes nuclear localization of eIF4E and activation of tumor suppressor proteins relevant to non-Hodgkin lymphoma including p53, p21, and IκBα, along with reductions in c-Myc and Bcl-2 oncogenes.

In the open-label, randomized phase 2b SADAL study, investigators are comparing a 60-mg versus 100-mg dose of twice-weekly selinexor monotherapy administered in 28-day cycles in this patient population.&#8239;Eligible patients received 2 to 5 prior treatment regimens, and those who achieved a CR or a partial response (PR) to prior therapy required an 8-week washout before enrolling into SADAL.

A total of 129 patients were enrolled as of November 15, 2018. Their median age was 67 years (range, 35-87) and the median time from their DLBCL diagnosis was 2.1 years (range, <1-16.2). Patients received a median of 2 prior lines of treatment (range, 1-6), and 31% had prior transplant. Sixty patients had the germinal center B-cell (GCB)&#8239;histology subtype, 63 had non-GCB, and 5 were unclassified.

Patients were evenly split between good prognosis (45%) and poor prognosis (46%) by the Revised-International Prognostic Index (2% were very good and 7% were unknown). One hundred fifteen patients have been evaluated for response.

Initial data were previously presented at the 2018 ASH Annual Meeting, which showed an ORR of 29.6%, along with a CR rate of 9.6%.3 The response rates were 34.0% in patients with the GCB subtype and 21.1% in those with the non-GCB subtype. Median overall survival (OS) was 9.1 months in the modified intent-to-treat (mITT) group, improving to 29.7 months in patients who achieved a CR or PR.

The mITT group included patients who discontinued selinexor due to toxicity or disease progression, or who had died. The mITT population formed the primary analysis population and was used for exploratory analyses of efficacy.

In addition to the 11 patients who achieved CR, 23 (20.0%) achieved PR and 8 (7.0%) had stable disease. Among the 34 responders, the median DOR was 9.2 months (95% CI, 4.9-23.0). The median DOR was 23.0 months (95% CI, 4.9-23.0) among those who achieved CR and 7.8 months in those with PR (95% CI, 2.8-NE).

Seven of the 11 patients who achieved a CR are still on treatment. Forty-six patients with a post-baseline response reading had reductions in tumor burden.

Among patients with the GCB subtype, 5 (9.4%) had a CR, 13 (24.5%) had PR, and 5 (9.4%) had stable disease. Among those with the non-GCB subtype, the corresponding rates were 10.5%, 10.5%, and 5.3%, respectively.

The updated SADAL findings were presented at the 2019 International Conference on Malignant Lymphoma. The analysis included 127 evaluable patients who had received a median of 2 (range, 1-6) prior treatment regimens. Results showed that the 28.3% ORR comprised 36 responses, including 13 CRs and 23 PRs; the data submitted in the NDA included an additional 2 CRs. The disease control rate was 37%, which included 11 patients with stable disease.

Deep and durable responses occurred in patients, regardless of DLBCL subtype. Among the 59 patients with GCB&#8239;histology, the ORR was 33.9%, and in the 63 patients with the non-GCB subtype, the ORR was 20.6%. In the remaining 5 patients, in whom the disease subtype was unclassified, there was 1 CR and 2 PRs. Responses were often rapid, and the median DOR was 9.2 months. Across the overall population, the median OS was 9 months. Among responders, the median OS had not yet been reached.

Regarding safety, cytopenias and gastrointestinal and constitutional symptoms, were the most frequently reported treatment-related adverse events (AEs). For the most part, the AEs were reversible and alleviated with standard supportive care and dose modifications. Common nonhematologic AEs were mostly grade 1/2 and included nausea (52.8%), fatigue (37.8%), and anorexia (34.6%). Grade 3/4 AEs included thrombocytopenia (39.4%), neutropenia (20.5%), and anemia (13.4%).

The most common nonhematologic treatment-related AEs were gastrointestinal and constitutional, and included nausea (50%), fatigue (35.9%), anorexia (32.0%), vomiting (22.7%), diarrhea (21.9%), and weight loss (21.1%). The vast majority of these were grade 1/2. Hematologic treatment-related AEs observed were thrombocytopenia (49.2% total; 35.2% grade 3/4), anemia (28.1% total; 11.0% grade 3/4), and neutropenia (25.8% total; 20.3% grade 3/4).

The FDA has approved selinexor as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma, not otherwise specified, who have received ≥2 prior therapies.

FDA Approves Selinexor for Pretreated Relapsed/Refractory DLBCL

The FDA has granted a Fast Track designation to CLR 131 for use as a treatment for patients with lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) who have received at least 2 prior treatment regimens.

The designation is based on findings from the ongoing phase 2 CLOVER-1 study, which is investigating CLR 131 in patients with relapsed/refractory B-cell lymphomas (NCT02952508).

“LPL/WM patients that do not respond optimally or are intolerant of ibrutinib, currently have limited treatment options and poor survival rates. Fast Track designation for LPL/WM further supports our clinical development strategy to quickly and efficiently provide these patients with an effective therapeutic alternative,” James Caruso, president and CEO of Cellectar, said in a press release.

“All 4 LPL/WM patients treated in our CLOVER-1 phase 2 study to date achieved a 100% overall response rate and a 25% complete response rate. This strong response rate may represent an important improvement in the treatment of relapsed/refractory LPL/WM as no approved or late-stage development treatments for relapsed or refractory patients have reported complete responses,” added Caruso.

CLR 131 is a small-molecule radiotherapeutic phospholipid-drug conjugate that directs cytotoxic radiation to cancer cells and cancer stem cells. The drug conjugate consists of the CLR1404 cancer-targeted small molecule compound, which is radiolabeled with the isotope iodine-131.

The FDA previously granted CLR 131 a Fast Track designation for use as a treatment for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Interim results from the DLBCL cohort of CLOVER-1 were announced in 2018, which demonstrated that CLR 131 elicited a 33% overall response rate (ORR) in patients with DLBCL and a 50% clinical benefit rate (CBR) following a single administration of 250 mCi/m2 of CLR 131 intravenously.2 Moreover, tumor reductions were observed in 60% to >90% of patients.

The open-label, multicenter, phase 2 CLOVER-1 trial is enrolling patients with select relapsed/refractory B-cell malignancies. Patients are eligible for enrollment if they have received prior treatment for multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), LPL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and DLBCL. Patients with transformed DLBCL were also allowed to enter the trial.

Patients with multiple myeloma were required to have received ≥2 prior lines of therapy, including ≥1 approved proteasome inhibitor and ≥1 approved immunomodulatory drug with or without maintenance. Patients with CLL/SLL, LPL, or MZL had to have received ≥2 prior regimens, which could include chemotherapy, an anti-CD20 antibody with or without maintenance therapy, and targeted therapy. In the MCL cohort, patients were required to have received ≥1 prior treatment regimen. For those with DLBCL, patients were required to have relapsed on, be refractory to, or intolerant of combination chemotherapy that includes rituximab (Rituxan) and an anthracycline.

Across the B-cell cancer cohorts, patients received either a single dose or multiple doses of CLR 131. The primary endpoint of the trial is CBR and secondary endpoints include ORR, time to progression, and overall survival. The investigators expect to enroll 80 patients in the trial.

CLR 131 also previously received a Fast Track designation for the treatment of patients with relapsed/refractory multiple myeloma.

1. Cellectar Receives FDA Fast Track Designation for CLR 131 in Lymphoplasmacytic Lymphoma/Waldenstrom’s Macroglobulinemia. Published Online May 26, 2020. https://www.cellectar.com/news-media/press-releases/detail/238/cellectar-receives-fda-fast-track-designation-forclr-131. Accessed May 26, 2020.

2. Cellectar Reports Positive Phase 2 Interim Data for CLR 131 in Relapsed/Refractory DLBCL Patients [press release]. Florham Park, NJ: Cellectar Biosciences; July 18, 2018. https://bit.ly/2Nt0LyW. Accessed July 9, 2019.

This article was originally published on OncLive as, "

FDA Grants CLR 131 Fast Track Status for LPL/WM

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