Interdisciplinary collaboration across the oncology care team is key to improving patient outcomes, according to Darcy Burbage, DNP, RN, AOCN, CBCN.

Burbage, who is also the director-at-large of the Oncology Nursing Society, was selected as one of the featured voices of the 2022 ASCO Annual Meeting and many oncology nurses followed her tweets to track the trending presentations from this year’s meeting. As the only nurse to be selected for this year’s meeting, she helped channel content specific to the oncology nursing community, highlighting practice-changing content surrounding patient-reported outcomes, survivorship, and other aspects of supportive oncology care.

®, Burbage discussed her virtual experience with the 2022 Annual Conference and important nurse takeaways from the meeting.



Which presentations /data to come out of ASCO do you feel will have the largest effect on oncology nursing practice?

 There were so many great presentations, and many will have a huge impact on patient care. For example, the results of the Destiny-04 trial [NCT03734029] are going to be practice changing for a subpopulation of individuals living with metastatic breast cancer. Watching this presentation online and hearing the cheers from those in the audience, gave me chills.

I was also glad to see the voice of the patient being included in presentations on how to expand clinical trial eligibility so that they are more reflective of the populations that we treat, such as expanding the age criteria as well as allowing individuals that may have other health conditions to be included in clinical trials. Without this expansion, we really don’t know how new treatments will benefit as many individuals as possible.

Additionally, I don’t think that we can [underestimate] the impact of the ongoing COVID-19 pandemic on oncology care and on oncology clinicians [and this was clear at this year’s meeting]. 

From the start of the pandemic, patients with cancer were designated as a particularly vulnerable subgroup of the population. The oncology community adapted quickly, pivoting to telehealth to maintain patient continuity, embracing extended-interval dosing strategies, abbreviating radiotherapy schedules, and switching from intravenous to oral chemotherapy regimens. However, we are only beginning to understand the multifaceted impact of the COVID-19 pandemic on cancer incidence, treatment outcomes, and side effects. The conference highlighted the number of oncology clinicians that reduced their hours or left practice and mentioned the large number of nurses that have left the workforce as well. Unless meaningful, system-based changes occur, the shortage will only worsen.

There were some great presentations on cultural humility. What values or applications do you think providers should be taking away from these educational sessions? How does cultural humility play a role in providing quality care?

Cultural humility is essential to provide holistic quality care to all individuals affected by cancer as it values learning from and with our patients. Cultural humility encourages an appreciation and understanding of our unique journeys as its goal is to build a mutually beneficial relationship rather than a provider/patient dynamic. To summarize, cultural humility is a clinical skill requiring curiosity and respect; applying the skill of cultural humility is necessary for culturally competent care, and both are key to providing high quality care.

There has been a lot of conversation surrounding the rising cost of cancer care and financial toxicity following various ASCO presentations. Is financial toxicity a growing problem? What can providers and nurses do to help their patients navigate this toxicity and try to prevent it from becoming worse?

Yes, financial toxicity is a growing concern for our patients. The cost of care itself along with rising deductibles and out of pocket expenses impacts a patient’s quality of life. With newer medications, such as immunotherapy agents, the monthly costs can be thousands of dollars.

All oncology clinicians, nurses, physicians, as well as our administrative staff can help address this by normalizing the financial conversation. For example, some of my patients have questions about the cost of this medication. Because of this, our social worker meets with everyone to review what resources are available. On a federal level, it’s important that oncology nurses continue to advocate for lower insurance premiums and oral parity legislation.

This year’s symptoms and survivorship track showcased data on a variety of topics. Which presentations from this track did you find interesting? How has the focus on symptoms and survivorship grown over the years? Where are their current gaps and where do you think research should continue to focus?

I was glad to see the number of abstracts presented in this category as oncology nurses spend a great deal of time helping individuals manage the long term and late effects of cancer treatment. In particular, I was pleased to see fear of recurrence being addressed.

Individuals living with cancer face a myriad of psychosocial distress throughout the cancer continuum; however, fear of recurrence is one of the most common unmet needs expressed by all of our patients, including those with early-stage cancers and those living with metastatic cancer. Fear of recurrence is associated with increased anxiety which may affect quality of life, and not just that of the individual, but their entire support system. As discussed, we need to assess individuals throughout the cancer continuum, including at the end of active treatment and at all follow-up visits to validate their feelings and provide them with the necessary support.

As the number of individuals living with cancer continues to increase, for example, childhood cancer survivors living well into adulthood, along with the number of individuals diagnosed with cancer that are greater than 65 [years old], there is a need to address comorbidities and how they impact cancer treatment and ongoing effects. For example, how does treatment impact [adverse] effects in individuals with both diabetes and cancer?

In addition, the number of abstract presentations focusing on digital health and patient reported outcomes is another area that continues to increase and where additional collaborative research is needed with our behavioral health colleagues.

Articles

Darcy Burbage, DNP, RN, AOCN, CBCN, discusses the top takeaways from the 2022 ASCO Annual Meeting for oncology nurses.

Burbage Provides Nursing Perspective on 2022 ASCO Meeting

Buprenorphine may be an effective pain management strategy for various populations of patients with cancer, according to palliative care experts Mary Lynn McPherson, PharmD, BCPS, FAAHPM; and Amy A. Case, MD, FAAHPM.

 The agent’s unique pharmacology, and clinical utility and safety data, make it a preferable choice over traditionally used opioids.

McPherson, who is a professor at the University of Maryland, Baltimore, and executive director of the Advanced Post-Graduate Education in Palliative Care, Graduate Studies in Palliative Care, and Online Graduate Studies in Palliative Care programs, and Case, who is the chair of Supportive and Palliative Care at Roswell Park Comprehensive Cancer Center, recently participated in an invited speaker session titled “Why Consider Buprenorphine for Cancer-Related Pain?” at the 2022 Supportive Care in Cancer Annual Meeting.

The oral bioavailability associated with buprenorphine is low. Therefore, it is not swallowed as a pill. It is taken sublingually or through a patch that should be rotated to a different site and then returned to the original site every 21 days according to the package insert.

“It is a really good option [for] those with who cannot swallow,” Case said.

“Generally, we use it on the upper body and areas where there is not a large amount of subcutaneous fats,” she explained.

Moreover, buprenorphine functions differently compared with traditional μ-opioid receptor agonists, explained McPherson. The agent binds to μ, δ, κ, and opioid receptor-like 1 (ORL1). It has a very high binding affinity to the μ receptor, as well as with the δ and κ receptors, but a lower binding affinity for ORL1. However, it is a partial μ agonist and not a full μ-opioid agonist.

As a partial agonist, buprenorphine has less μ-receptor signaling, which may result in fewer opioid-related adverse events. However, this does not mean buprenorphine is not an effective analgesic. It has a higher binding affinity compared with most full μ-opioid agonists, suggesting that it is a very effective pain management option.

Several studies with large numbers of patients with cancer have documented that pain management with buprenorphine is effective, Case said. For example, in one study, 85% of patients reported their pain control to be “good” or “very good” and 48% of patients reported improvement in sleep quality.

“A lot of our patients in palliative care or supportive care in oncology have issues with sleep,” Case explained. “[Buprenorphine,] has been shown to be equivalent to other traditional used opioids [in managing this symptom].”

It has also demonstrated a benefit for neuropathic pain and successfully blocks secondary hyperalgesia from central sensitization. Its analgesic benefit is thought to be comparable to morphine, hydromorphone, oxycodone, fentanyl, and methadone.

Furthermore, its high potency and slow dissociation rate allows for effective treatment at lower doses, Lin added.

Buprenorphine has less beta-arrestin activity than traditional opioids once it binds

, Case explained. Beta-arrestin is linked with negative responses such as endocytosis, physical dependency, respiratory depression, and constipation.

In addition, buprenorphine is associated with less cognitive dysfunction than with other opioids, making it a viable choice for elderly patients. “There is less impairment [compared] with equal doses of morphine,” Case said. “Several studies have shown improved sleep, pain, quality of life in the elderly [who receive buprenorphine].”

Notably, the pharmacokinetics are not altered with age, so there are no required dose reductions for elderly patient populations, and it is the only opioid that is not associated with risk of fracture, although Case noted that there is insufficient literature on this risk.

Across all populations, buprenorphine represents a potentially safer alternative for patients at risk for dependency disorders, since it does not induce euphoria, and is therefore associated with reduce abuse liability. It is safe in patients with renal and liver impairment, although for patients with severe liver impairment, a 50% dose reduction is advised because the drug is metabolized by the liver. It is also associated with a reduced risk of respiratory depression.

Finally, because the drug is a κ antagonist, patients may have less anxiety, lytic effects, depression, or suicidal tendencies compared with traditional opioids.

 This may also limit the addictive potential.

“[There are] some papers out there showing that up buprenorphine is actually used as a treatment for depression,” Case said.

Case acknowledged that some providers may find it difficult to get insurance companies to cover buprenorphine. However, in her experience, most companies will if presented with data on the drugs’ efficacy.

In 2019, the US Department of Health and Human Services published their Pain Management Best Practices Document. The document lists the following recommendations:

Recommendation 4a: Make buprenorphine treatment for chronic pain available for specific groups of patients and include buprenorphine in third-party payer and hospital formularies.

Recommendation 4b: Encourage CMS and private payers to provide coverage and reimbursement for buprenorphine treatment, both for opioid use disorder and for chronic pain. Encourage primary use of buprenorphine rather than use only after failure of standard μ agonist opioids such as hydrocodone or fentanyl, if clinically indicated.

Recommendation 4c: Encourage clinical trials using buprenorphine for chronic pain to better understand indication, usage and dosage.

“When the insurance companies give me a hard time about, I send [the recommendations] to them and clog up their fax machines and then they cover it,” Case concluded.

McPherson ML, Case AA. Why consider buprenorphine for cancer-related pain? Presented at: 2022 Supportive Care in Cancer Annual Meeting; June 23-25, 2022; Toronto, Ontario. 

Gudin J, Fudin J. A narrative pharmacological review of buprenorphine: a unique opioid for the treatment of chronic pain. 

. 2020;9(1):41-54. doi:10.1007/s40122-019-00143-6

Pain management best practices best practices inter-agency task force report, updated gaps, inconsistencies, and recommendations. US Department of Health and Human Services. Accessed June 24, 2022. 

Mary Lynn McPherson, PharmD, BCPS, FAAHPM, and Amy A. Case, MD, FAAHPM, argue that buprenorphine should play a larger role in cancer-related pain management because of its unique pharmacology and consequent safety profile.  



Experts Make the Case for Buprenorphine Use in Cancer-Related Pain Management

Cancer survivors who experience both frontal and occipital late alopecia following cytotoxic or endocrine therapy may derive clinical benefit with oral minoxidil, according to data from a study at Memorial Sloan Kettering Cancer Center (MSK), which were presented during the 2022 ASCO Annual Meeting.

Overall, hair and follicle densities increased by approximately 20% across all tested populations, and 74% of patients showed clinical improvement. Moreover, no patients required treatment discontinuation because of adverse events (AEs).

Alopecia is a common AE with approximately 65% of patients who undergo chemotherapy experiencing some degree of alopecia.1 Furthermore, 58% of patients with cancer report that hair loss is the most traumatic component of receiving chemotherapy, and 1 in 7 patients would consider declining chemotherapy because of fear of hair loss. 

Late alopecia was defined by investigators as the incomplete hair regrowth 6 months following the completion of endocrine therapy or from the initiation of endocrine therapy. This longer-lasting AE reportedly affects between 25% to 30% of survivors.

Scalp cooling is the only known prevention technique, and treatment options include scalp directed topical steroids, compounded topical minoxidil finasteride, intralesional steroids, or systematic oral low dose minoxidil. Oral minoxidil at a dose of 10 to 100 mg daily is currently FDA approved as an antihypertensive agent, but it has been used in low doses off label to treat alopecia at a dosage of 0.25 to 5 mg daily.

Investigators at MSK assessed women with late alopecia who received oral minoxidil at a dose of 1.25 mg daily between January 2018 and May 2021.The efficacy of minoxidil was assessed via standardized photography, and responses were quantified via trichosocpy (HairMetrix).

Results from 42 trichoscopy assessments conducted before and after a median of 91 days (interquartile range, 136) on oral minoxidil showed that the median percentage change in hair density (hairs/cm2) was 20.4% (

= .008) in patients with frontal alopecia and 21.4% (

 = .004) in patients with occipital alopecia, respectively. Similarly, the changes in follicular density (follicles/cm2) were 22.5% (

 = .005), respectively. Hair shaft diameter between the 2 groups was –2.0% (

The literature shows that the most common AEs associated with this treatment include hypertrichosis, lightheadedness, and fluid retention. Prospective, controlled studies are still needed to validate these findings, study authors concluded.

Overall, results from this study demonstrate the importance of symptom management in survivorship care, according to experts.

“Treating late toxicities [is] the bread and butter of survivorship,” Lidia Schapira, MD, FASCO, Professor of Oncology at Stanford University with a specialization in survivorship, said in a discussion of the poster. “Patients are often left to manage these by themselves. The idea of helping patients understand, self-manage, and become better at handling toxicities, [starting] from the first day in the hospital, is a very important concept.”

The key moving forward will be expanding these efforts to populations that have less supportive resources currently available, Schapira added.

“Supportive services such as onco-dermatology and supportive dermatology are available at major cancer centers, and I absolutely am delighted to see our colleagues at Memorial Sloan Kettering continue to find solutions for some of these festering problems,” she said. “The question is how do we scale [these efforts] and how do we bring some of these advances in survivorship care to communities that are less well resourced?”

Kuo AM, Reingold RE, Ketosugbo KF, et al. Oral minoxidil for the treatment of late alopecia in cancer survivors. 

2022;40(suppl 16):12022. doi:10.1200/JCO.2022.40.16_suppl.12022

Results of a single-center study presented at the 2022 ASCO Annual Meeting showed that oral minoxidil may be effective in treating late alopecia. Moving forward, these efforts in survivorship care will need to be expanded to less resourced areas, experts said.  

Oral Minoxidil Demonstrates Efficacy in Treating Later Stage Alopecia in Cancer Survivors

Starting the conversation is a simple, yet important, step to draw attention to DEI—diversity, equity, and inclusion—in oncology nurse leadership, according to Aliènne Salleroli, MS, BSN, RN, OCN.

Salleroli, an assistant patient services manager at Yale-New Haven Health Smilow Cancer Hospital, and cochair of the Yale New Haven Hospital Diversity, Equity, and Inclusion Nursing Task Force, recently spoke on the topic of how racial diversity within oncology leadership is linked with positive outcomes at the 47th Annual Oncology Nursing Society Congress.

®, Salleroli explains that although opening dialogue can be uncomfortable, it yields important results.

“Leadership needs to understand that this is going to be an uncomfortable conversation and part of leadership is becoming comfortable with the uncomfortable,” she said. “But having these conversations [is] actually what bridge[s] that gap. Discussing things like micro-aggressions, implicit biases, language being used… that’s what brings [individuals] together.”

Open dialogue is key to establishing unity across an organization, Salleroli said, adding that these conversations can also inspire local change. For example, once leadership starts the conversation, heads of other teams can bring that information down to their home departments and perpetuate a domino effect.

“We need to walk before we can run,” she concluded.

Videos

Aliènne Salleroli, MS, BSN, RN, OCN, underscores the importance of open dialogue surrounding diversity, equity, and inclusion in oncology leadership. 

Aliènne Salleroli on Starting the DEI Conversation in Oncology Nursing

Music-listening interventions (MLIs) are a form of complementary and integrative treatment that medical professionals may be unaware of. However, my colleagues at the Michigan State University College of Nursing and I are tackling research that suggests music—a fixture in many people’s daily lives—may possess a nausea-reducing capability.

MLIs have already shown considerable effectiveness in managing other symptoms. For example, the National Comprehensive Cancer Network has labeled music as an acceptable treatment modality to treat anticipatory nausea and vomiting related to chemotherapy, so long as the music is prescribed in conjunction with typical pharmaceuticals.

Furthermore, the American Pain Society and the American Society of Regional Anesthesia and Pain Medicine have both endorsed music for its mitigating effects in the setting of postoperative pain.

 In addition, the c linical practice guidelines provided by the Society for Integrative Oncology also endorse music for patients with breast cancer in the setting of anxiety, mood disturbances, and pain.

In all cases, these endorsements came as a result of careful review of the evidence base for MLIs. If pain, anxiety, and mood all can be positively impacted through the incorporation of an MLI—why not chemotherapy-induced nausea?

This research began with a systematic review of the available literature, scouring databases for all prior studies that examined an MLI as treatment for chemotherapy-induced nausea.

This search identified 10 relevant studies across the past 30 years. However, they had a variety of designs, making comparisons between them difficult. Some studies paired music with other interventions, which made it difficult to discriminate what percentage each intervention was contributing to nausea reduction. Variations in timing (when the MLI was delivered and when the effect on nausea was measured) also raised questions.

Moreover, in the world of pharmaceuticals, a drug’s half-life determines how quickly its effects fade. However, variations in how MLIs were timed to intervene on nausea illuminated the fact that MLI’s half-lives are not well understood. It remains unclear whether half-lives even exist for MLIs. Overall, the overarching body of existing literature highlighted a need for more nuanced research.

The greatest uncertainty that remains with MLIs has to do with mechanism of action. Although MLIs have previously demonstrated the potential to relieve nausea, investigators do not yet understand how the brain physiology permits this.

One possible answer to this question comes from surprising research unrelated to chemotherapy-induced nausea. In 2000, Evers and Suhr

 published a study in which healthy participants listened to music that participants rated as “pleasant” and music that participants identified as “unpleasant.” In this study, the concentration of serotonin in blood platelets was measured at baseline (before any music), after the unpleasant music, then after the pleasant music. The release of serotonin from platelets was significantly less after the pleasant music intervention than what was measured after the unpleasant music. These findings connected to chemotherapy-induced nausea by way of its serotonin effects. After chemotherapy, this neurotransmitter becomes a major contributor to the sensation of nausea. This also explains the pharmacologic rationale for prescribing drugs that antagonize serotonin’s ability to bind to receptors at the postsynapse of neurons in the central nervous system.

This interesting physiologic possibility initiated a pilot study that yielded encouraging results. Twelve patients were asked to engage in a 30-minute MLI whenever they felt the need to take their antiemetic medication as needed, beginning on the day of chemotherapy administration and continuing through day 5. Participants used ordinal scales to rate their nausea severity and their distress level before the MLI and again immediately upon completion. Platelet serotonin levels were not drawn due to cost. In total, 66 MLIs were engaged at various points within the 5-day nausea window. The analysis showed a significant reduction in both nausea severity and patient distress, which is an encouraging finding in a pilot study and worth replicating in a larger randomized control trial.

This larger trial will have several refinements. First, a control group using a nonmusic intervention will reveal what percentage of the antinausea effect was attributable to the MLI and what percentage was attributable to medication alone. Creating study groups by time (5-minute MLI and 10-minute MLI) will allow subgroup analysis by dose, which is something not often done in MLI research. Finally, strict attention to competing auditory stimuli (other sounds in the room) through noise-cancelling headphones will help participants more fully engage with the MLI. 

Strategically using music listening to produce improved physiologic states is not new, but its scientific activity is gaining momentum. Work in chemotherapy-related nausea may inspire other investigators to think about MLIs in the setting of other nausea forms, such as pregnancy-induced nausea or postoperative/postanesthesia nausea. As the research builds, the day may come when the oncology nurse delivers acetaminophen alongside 20 mg of Mozart.

NCCN. Clinical Practice Guidelines in Oncology. Antiemesis, version 2.2022. Accessed April 23, 2022.

 https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf

Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. 

. 2016;17(2):131-157. Published correction appears in 

Lyman GH, Greenlee H, Bohlke K, et al. Integrative therapies during and after breast cancer treatment: ASCO endorsement of the SIO clinical practice guideline. 

. 2018;36(25):2647-2655. doi:10.1200/JCO.2018.79.2721

Evers S, Suhr B. Changes of the neurotransmitter serotonin but not of hormones during short time music perception. 

. 2000;250(3):144-147. doi:10.1007/s004060070031

Kottschade L, Novotny P, Lyss A, Mazurczak M, Loprinzi C, Barton D. Chemotherapy-induced nausea and vomiting: incidence and characteristics of persistent symptoms and future directions NCCTG N08C3 (Alliance). 

. 2016;24(6):2661-2667. doi:10.1007/s00520-016-3080-y

A Michigan State University investigator is preparing to expand on an encouraging pilot study that used a music-listening intervention to influence chemotherapy-induced nausea.

Prescribing 20 mg of Mozart for Chemotherapy-Induced Nausea

Patients receiving PD-1/PD-L1 immune checkpoint inhibition therapy who experience adrenal insufficiency are more likely to develop secondary insufficiency than primary insufficiency, according to a retrospective chart review presented at the 2022 ASCO Annual Meeting. Investigators noted that most patients will require long-term replacement steroids to manage low cortisol and adrenocorticotropic hormone (ACTH) levels.

Overall, 6 patients (15%)experienced primary adrenal insufficiency and 34 patients (85%) experienced secondary insufficiency following immunotherapy. Twenty-one patients experienced new primary hypothyroidism. In addition, 10 patients (25%) experienced arthritis, 8 patients (20%) experienced colitis, 4 patients (10%) developed rash, 4 patients (10%) experienced nephritis and 3 patients (8%) experienced pneumonitis.

Although infrequent, endocrine immune-related adverse events (irAES) secondary to anti–PD-1/PD-L1, such as hypophysis, insulin-dependent diabetes mellites, and adrenal insufficiency, are often associated with long term morbidity, the study authors wrote in a poster of the findings. Moreover, adrenal insufficiency is not well characterized in available literature, and the long-term outcomes for patients who develop this irAE are not well known.

Therefore, investigators conducted a retrospective chart analysis of 40 patients treated with nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), or cemiplimab (Libtayo), and who experienced consequent adrenal insufficiency as diagnosed by a board-certified endocrinologist. Patients who received CTLA-4-inhibitors were excluded.

Laboratory values for serum cortisol, and ACTH were collected at time of adrenal insufficiency diagnosis and at last follow-up. Primary adrenal insufficiency was defined as low AM serum cortisol with high AM serum ACTH levels and secondary adrenal insufficiency was defined as low AM serum cortisol with inappropriately low AM serum ACTH levels.

The median age of the study participants (n = 40) was 65 years (range, 38-84). Twenty-six patients were male (65%) and 14 (35%) were female. Genitourinary malignancies accounted for 38% of patient malignancies. Other malignancies included gastrointestinal (20%), skin (18%), lung (5%), breast (5%), head and neck (5%), hematologic (5%), gynecologic (2%), and adrenal (2%). Nine patients (22%) had clinical stage I-III disease and 31 (78%) had stage IV disease.

Nineteen patients (48%) of patients were receiving a PD-1 inhibitor, 11 patients (28%) were taking a PD-1 inhibitor plus chemotherapy, 8 patients (20%) were receiving a PD-1 inhibitor plus a tyrosine kinase inhibitor, 1 patient (2%) was receiving a PD-L1 inhibitor plus chemotherapy, and 1 patient was receiving a PD-L1 inhibitor plus an unspecified additional therapy. Four patients (10%) had history of prior hypothyroidism, and 1 patient (2%) had diabetes mellitus type 2.

Ultimately, 19 patients out of 40 (48%) discontinued immunotherapy following adrenal insufficiency onset. Among these patients, 9 (47%) discontinued because of unmanageable adrenal insufficiency symptoms, 4 had completed their treatment regimen (21%), 3 experienced another toxicity (16%), and 3 (16%) had disease progression. 

Further, among patients with stage IV disease, 5 (16%) achieved a complete response, 20 achieved a partial response (6%), and 6 (19%). None of these patients experienced disease progression.

In the initial steroid treatment for patients experiencing with adrenal insufficiency, 33 patients (82%) received low-dose treatment and 7 patients (18%) received high-dose treatment. At last follow-up, 2 patients (5%) had stopped steroid use, 37 (93%) were receiving low-dose steroids treatment, and 1 patient (2%) was receiving high dose treatment. The 2 patients who stopped use did so after 7 and 10.4 months, respectively. Median follow-up time for the patients who remained on steroid treatment was 9.8 months (range, 0.7-59).

High-dose steroids were defined as daily steroid intake greater than 30 mg of hydrocortisone, 7.5 mg of prednisone, for 2 months. By 5 months, only 1 patient remained on high-dose treatment.

The most common symptom of adrenal insufficiency was fatigue, which affected 88% of patients. Other common symptoms included nausea and vomiting (33%), hyponatremia (30%), dizziness (18%), arthralgia (15%), headache (15%), hypotension (13%), and visual symptom problems (5%).

Nguyen B, Shah NJ, Knezevic A, et al. Long-term outcomes of adrenal insufficiency (AI) due to anti-PD-(L)-1 immune checkpoint inhibitors among cancer patients. 

. 2022;40(suppl 16):12084. doi:10.1200/JCO.2022.40.16_suppl.12084

A study analyzing the long-term adrenal insufficiency outcomes of patients receiving immune checkpoint inhibition therapy found that secondary insufficiency was more common than primary in this patient population. 

Patients Receiving PD-1/PD-L1 Inhibitor Therapy More Frequently Experience Secondary Adrenal Insufficiency 

Evidence supporting a fixed-dose regimen of nivolumab (Opdivo) plus relatlimab-rmbw (Opdualag) as a treatment for patients with treatment-naïve, unresectable or metastatic melanoma were recently presented at the 2022 ASCO Annual Meeting.1 The findings, which show that this regimen elicited a continued progression-free survival (PFS) benefit superior to that of nivolumab alone, were part of updated results from the phase 2/3 RELATIVITY-047 trial (NCT03470922).

Updated PFS data by blinded independent central review (BICR) showed, at a median follow-up of 19.3 months, sustained improvement in PFS with the combination. The median PFS was 10.22 months with nivolumab plus relatlimab (95% CI, 6.51-14.75) vs 4.63 months with nivolumab alone (95% CI, 3.48-6.44; HR, 0.78; 95% CI, 0.64-0.94). The PFS rates were also higher among patients who received the combination than in those who received nivolumab alone. At 12 months, the PFS rate for nivolumab plus relatlimab was 48.0% (95% CI, 42.5%-53.4%) vs 36.9% (95% CI, 31.7%-42.1%) for nivolumab alone. At 24 months, the PFS rate for those who received the combination was 38.5% (95% CI, 32.7%-44.2%) vs 29.0% (95% CI, 23.8%-34.4%) in those who received the monotherapy.

“Nivolumab plus relatlimab continued to demonstrate a sustained and consistent PFS benefit vs nivolumab [alone] with longer follow-up,” said Georgina V. Long, MD, PhD, FRACP, co-medical director, chair of Melanoma Medical Oncology and Translational Research, Melanoma Institute of Australia and Royal North Shore Hospital, The University of Sydney.

Immune checkpoint inhibitors have expanded the treatment options available for patients with advanced melanoma. However, new combinations are necessary to improve the relative benefits and risks associated with these treatments.

PD-1 and LAG-3 are markers of exhausted T cells. Relatlimab, a human LAG-3 blocking antibody, in combination with PD-1 inhibitors, restores the effector function of exhausted T cells, activating them to induce tumor cell death.

The RELATIVITY-047 trial is a global, randomized, gated, double-blind study evaluating first-line therapy with fixed-dose nivolumab plus relatlimab in patients with advanced melanoma.

In addition to having previously untreated, unresectable or metastatic melanoma, patients needed to have an ECOG performance status of 0 or 1 to be eligible for enrollment.

Key stratification factors included PD-L1 expression, 

mutational status, AJCC v8 M stage, and baseline LAG-3 immunohistochemistry.

A total of 714 patients were randomized 1:1 to receive either fixed-dose intravenous (IV) nivolumab at a dose of 480 mg plus 160 mg of relatlimab every 4 weeks (Q4W; n = 355), or IV nivolumab at a flat dose of 480 mg Q4W (n = 359).

The 2 arms had similar baseline characteristics. A total of 36.1% of patients (n = 258) had elevated baseline lactate dehydrogenase levels, including 36.6% (n = 130) of the combination arm and 35.7% (n = 128) of the nivolumab arm.

The trial’s primary end point was PFS by BICR. Key secondary end points included overall survival (OS) and overall response rate (ORR) by BICR. The end points were tested hierarchically, beginning with PFS, then OS, then ORR.

Primary results performed at a median follow-up of 13.2 months showed superior PFS in the combination arm compared with the nivolumab arm (HR, 0.75; 

 = .006), with a manageable safety profile. Data presented at ASCO 2022 included the updated PFS by BICR, as well as OS and ORR by BICR with an additional 6.1 months of follow-up.

In terms of OS, at the median follow-up of 19.3 months, the combination arm displayed a clinically meaningful, though not statistically significant, improvement compared with the nivolumab arm. The median OS had not yet been reached (NR) in the combination arm (95% CI, 34.20-NR) vs 34.10 months in the nivolumab arm (95% CI, 25.23-NR; HR, 0.80; 95% CI, 0.64-1.01; 

Notably, the 12-, 24-, and 36-month OS rates were higher in the combination arm than in the nivolumab arm. At 12 months, the OS rate was 77.0% in the combination arm (95% CI, 72.2%-81.1%) vs 71.6% in the nivolumab arm (95% CI, 66.6%-76.0%). At 24 months, the OS rate was 63.7% in the combination arm (95% CI, 58.1%-68.7%) vs 58.3% in the nivolumab arm (95% CI, 52.7%-63.4%). At 36 months, the OS rate was 55.8% in the combination arm (95% CI, 49.8%-61.4%) vs 48.8% in the nivolumab arm (95% CI, 42.7%-54.7%).

Subsequent therapies were similar between the 2 arms, with 11.8% of the combination arm and 15.9% of the nivolumab arm receiving PD-L1/CTLA-4 inhibitors and 12.4% of the combination arm and 14.8% of the nivolumab arm receiving BRAF/MEK inhibitors.

The PFS and OS benefits for nivolumab plus relatlimab were seen across all stratification factors.

The confirmed ORR by BICR was 43.1% (n = 153) in the combination arm (95% CI, 37.9%-48.4%) vs 32.6% (n = 117) in the nivolumab arm (95% CI, 27.8%-37.7%). There was a 10.3% difference between the ORRs in the 2 arms (95% CI, 3.4-17.3), with an odds ratio of 1.6 (95% CI, 1.2-2.2). Notably, the combination arm had a higher rate of complete response (CR), with 16.3% of the combination arm achieving CR (n = 58) compared with 14.2% (n = 51) of the nivolumab arm. Additionally, the progressive disease (PD) rate was lower in the combination arm than in the nivolumab arm, with 29.6% (n = 105) of the combination arm experiencing PD compared with 41.5% (n = 149) of the nivolumab arm.

A total of 26.8% of the combination arm achieved partial response (n = 95) vs 18.4% (n = 66) of the nivolumab arm. Additionally, 17.2% of the combination arm achieved stable disease (n = 61) vs 16.4% (n = 59) of the nivolumab arm.

No new safety signals were reported at this second analysis. Any-grade adverse effects (AEs) were experienced by 99.2% (n = 352) of the combination arm and 95.8% (n = 344) of the nivolumab arm. Grade 3 or 4 AEs were experienced by 43.4% (n = 154) of the combination arm and 35.1% (n = 126) of the nivolumab arm.

Notably, any-grade myocarditis occurred in 6 patients (1.7%) and 2 patients (0.6%) in the combination and nivolumab arms, respectively. The first 2 months of treatment included troponin monitoring, per protocol.

Common treatment-related AEs (TRAEs) included pruritis, fatigue, rash, hypothyroidism, arthralgia, diarrhea, and vitiligo. Any-grade TRAEs were experienced in 83.7% (n = 297) of the combination arm and 72.4% (n = 260) of the nivolumab arm, leading to treatment discontinuation in 15.2% (n = 54) and 7.2% (n = 26) of the combination and nivolumab arms, respectively. Grade 3 or 4 TRAEs were experienced in 21.1% (n = 75) of the combination arm and 11.1% (n = 40) of the nivolumab arm, leading to discontinuation in 9.0% (n = 32) and 3.6% (n = 13) of the combination and nivolumab arms, respectively.

A total of 4 (1.1%) and 2 (0.6%) treatment-related deaths occurred in the combination and nivolumab arms, respectively.

Going forward, more research, including studies across clinical subgroups, is needed to discern the best placement for fixed-dose nivolumab plus relatlimab among the current treatment options available for melanoma. More information is also necessary regarding the intercranial activity of nivolumab plus relatlimab, as well as the role of biomarkers for this combination therapy.

“These data further validate nivolumab plus relatlimab as a treatment option for patients with advanced melanoma and support the benefit of dual checkpoint inhibition [in the first-line setting],” Long concluded.

Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047). 

2022;40(suppl 36)360385. doi:10.1200/JCO.2022.40.36_suppl.360385

Relatlimab, a human LAG-3 blocking antibody, plus nivolumab, elicited superior progression-free survival in patients with advanced melanoma compared to nivolumab alone. 

Updated PFS Data Continue to Support Nivolumab Plus Relatlimab in Advanced Melanoma

Treatment with the CD40 agonist sotigalimab (APX005M) in addition to pembrolizumab (Keytruda) elicited immunologic changes that yielded positive clinical responses in patients with unresectable stage III or IV metastatic melanoma, according to phase 1/2 findings (NCT02706353) presented during the 2022 AACR Annual Meeting.

Furthermore, the agent was found to have a favorable safety profile. Investigators also identified broad immune activity in both local and distant lesions through biomarker analysis.

In addition to evaluating the safety of sotigalimab, investigators determined the maximum-tolerated dose, the recommended phase 2 dose (RP2D), and objective response rate (ORR).

Among the total evaluable patients (n = 30), the ORR was 50% and was comprised of complete (17%) and partial responses (33%). Seventeen percent reported stable disease and 33% reported disease progression. The disease control rate was 67% and the response rate at the RP2D was 55%, said Bentebibel. Responses were also seen across PD-L1 and lactate dehydrogenase (LDH) levels.

By the data cutoff of December 30, 2021, 30 patients had been enrolled, said lead author Salah-Eddine Bentebibel, PhD. In the phase 1 portion of the study, 14 patients who were immune checkpoint inhibitor–naïve received an initial dose of intratumoral sotigalimab (0.1 mg) and intravenous pembrolizumab (2.0 mg/kg). This was followed by 4 increasing doses of sotigalimab at 0.5 mg, 1.0 mg, 3.0 mg, and 10 mg. Pembrolizumab was administered at 2.0 mg/kg across the escalation.

At the conclusion of phase 1, it was determined that the RP2D should be sotigalimab at 10 mg and pembrolizumab at 2 mg/kg. The phase 2 portion of the study is underway and will seek to enroll approximately 20 patients.

Investigators had hypothesized that sotigalimab could harness the CD40 pathway and activate innate and adaptive immunity. This is especially important because “many patients do not respond to [checkpoint inhibitor] therapy or develop resistance after initial tumor regressions, and new combinations are needed to improve the benefit risk profiles,” Bentebibel, an instructor in the Department of Melanoma Medical Oncology–Research at The University of Texas MD Anderson Cancer Center in Houston, Texas, said during the presentation of the data.

The majority of patients were male (n = 26; 87%) and were a median age of 65 years (range, 32-81). ECOG performance status was either 0 (57%) or 1 (43%). Fifty-seven percent had stage IV disease and 54% were 

 negative. Most patients (47%) had low LDH levels but 30% had very high LDH levels. PD-L1 status was unknown or negative in 37% of patients, respectively, and 8 patients (27%) were PD-L1 positive.

Biomarker analysis was conducted using blood and tumor samples obtained from local and distant lesions at baseline and at 24 hours post sotigalimab. Upregulation of genes and CD40 activation were noted by the investigators. “We saw robust upregulation of genes associated with antigen-presenting cells [APCs] and also engagement of MAP kinase and nuclear factor ĸB, a regulator of innate immunity,” Bentebibel said. In addition to the early time points of upregulated APCs, the investigators also reported T-cell response at later time points. “So [taken] together, these data suggest that sotigalimab engages the CD40 pathway,” Bentebibel said.

Further immune activity observed included an increase in macrophage, T cells, CD8+ T, and cytotoxic gene signatures in responding patients and the combination resulted in an increase in T-cell infiltration and clonality in local and distant lesions.

Regarding safety, investigators reported zero study discontinuations or death due to treatment-related adverse events (TRAEs). The most common TRAEs were injection-site reactions and 6 patients (20%) reported grade 3 immune-related AEs. Zero dose-limiting toxicities were observed for any dose level of sotigalimab.

Investigators concluded that the combination of sotigalimab and pembrolizumab showed encouraging antitumor activity and that the combination could induce immune activity in both local and distant lesions.

Bentebibel S-E, Johnson D, Amariae R, et al. Intratumoral CD40 agonist sotigalimab with pembrolizumab induces broad innate and adaptive immune activation in local and distant tumors in metastatic melanoma. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT039.

The CD40 agonist sotigalimab in combination with pembrolizumab yielded promising outcomes in patients with unresectable stage III or IV metastatic melanoma.

Sotigalimab/Pembrolizumab Jumpstarts Immune Activity, Ignites Clinical Responses in Metastatic Melanoma

Second-line treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) outperformed ipilimumab alone by statistically improving progression-free survival (PFS) in previously treated patients with stage III unresectable or stage IV melanoma, according to findings from the phase 2 SWOG S1616 trial (NCT03033576) that were presented during the 2022 AACR Annual Meeting.

At a median follow-up of 28.3 months, the median PFS was 3.0 months (90% CI, 2.8-5.3) with the combination vs 2.7 months (90% CI, 2.5-2.9) with ipilimumab alone (HR, 0.63; 90% CI, 0.41-0.97; 

 = .037). The estimated 6-month PFS rates were 34% (90% CI, 25%-44%) and 13% (90% CI, 4%-27%), respectively.

“Subgroups that appear to have done particularly well with the combination therapy include patients with stage IV disease, patients with no prior adjuvant therapy, and patients who received less than 6 months of anti–PD-1 therapy prior to enrollment,” lead study author Ari VanderWalde, MD, MPH, vice president of Clinical Development, Precision Oncology Alliance, Caris Life Sciences, and research faculty at the West Cancer Center & Research Institute, said in the presentation.

The optimal use of immunotherapy is not well defined in melanoma. Available frontline options, such as the combination of ipilimumab and nivolumab, may be too toxic for all patients, and although PD-1 inhibitors have a high response rate, patients will ultimately develop resistance.

As such, the SWOG S1616 trial was designed to understand whether treatment with a CTLA-4 inhibitor alone or in combination with continued PD-1 inhibition can couldreverse primary resistance to PD-1/PD-L1 inhibition in metastatic melanoma.

The study enrolled patients with unresectable stage III or IV melanoma with disease progression on prior PD-1/PD-L1 inhibition. Patients must have achieved a confirmed partial response (PR) or complete response (CR) prior to progression. Patients who progressed on a PD-1/PD-L1 inhibitor in the adjuvant setting were not excluded from enrollment.

Additional eligibility criteria stipulated that patients must have measurable disease per RECIST version v1.1 criteria; a Zubrod performance status of 2 or belowlower; no prior exposure to a CTLA-4 inhibitor;, no history of clinically significant autoimmune disease; and no active central nervous system metastases.

Patients underwent a pretreatment biopsy and were randomized 1:3 to 3 mg/kg of ipilimumab every 3 weeks for 4 doses (n = 24) or the same schedule of ipilimumab plus 1 mg/kg of nivolumab every 3 weeks for 4 doses followed by 480 mg of nivolumab every 4 weeks (n = 70). Additional blood samples and biopsies were taken on days 28 through 35.

Patients underwent tumor assessment every 12 weeks for 1 year. Treatment was continued with clinical benefit, and patients were followed for 2 years.

PFS served as the primary end point of the study. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and the difference in T-cell infiltrate between on-study biopsy samples of responders vs nonresponders.

Between July 2017, and July 2020, 91 eligible patients were treated across 35 sites in the United States.

A total of 23 patients received ipilimumab and 68 received ipilimumab plus nivolumab.

The study arms were well balanced for significant baseline factors. Most patients were male, White, had a performance status of 0, less than 6 months of prior PD-1 therapy, no prior adjuvant therapy, and prior PD-1 therapy only for metastatic disease.

Additional results demonstrated that the ORR was 9% (n = 2; 90% CI, 2%-25%) with ipilimumab alone vs 28% (n = 19; 90% CI, 19%-38%) with the combination (

 = .05). In the ipilimumab arm, there were 0 CRs, 2 PRs (9%), 3 cases of stable disease (13%), and 18 cases of progressive disease (78%). In the combination arm, there were 6 CRs (9%), 13 PRs (18%), 14 cases of stable disease (20%), and 35 cases of progressive disease (51%); 1 patient was not evaluable for response.

The median duration of response was not reached (NR) with ipilimumab vs 18.9 months with the combination. Response was ongoing in 9% of patients on ipilimumab (100% of responders) vs 12% of patients on the combination (42% of responders).

Post-progression therapy for patients from both arms included pembrolizumab (Keytruda; n = 6; 8%), a PD-1 inhibitor (n = 5; 6%), ipilimumab (n = 6; 8%), another immunotherapy (n = 16; 21%), targeted therapy (n = 12; 15%), cytotoxic chemotherapy (n = 4; 5%), and radiation (n = 12; 15%). No significant differences were seen in post-progression therapy between treatment arms; any differences were above the threshold for significance (

At a median follow-up of 27.3 months, the median OS was 21.7 months (90% CI, 15.4-32.4) with the combination vs 25.7 months (90% CI, 8.1-NR) with ipilimumab, failing to reach the threshold for statistical significance (HR, 0.93; 90% CI, 0.54-1.60; 

 = .408). The 12-month OS rates were 63% (90% CI, 52%-72%) and 57% (90% CI, 38%-71%), respectively.

Regarding safety, any-grade adverse effects (AEs) were reported in 87% (n = 20) of patients on ipilimumab vs 93% (n = 63) of patients on the combination. Grade 1 through 3 AEs occurred in 74% (n = 17) of patients in the ipilimumab arm vs 85% (n = 58) of patients in the combination arm. Grade 4 and 5 AEs occurred in 13% (n = 3) of patients vs 7% (n = 5) of patients, respectively.

Grade 3 or greater higher AEs that occurred in at least 5% of patients in the ipilimumab and/or combination arms, respectively, included diarrhea (13% each), aspartate aminotransferase increase (7% each), alanine aminotransferase (7% each), rash (4% vs 6%), fatigue (4% vs 6%), anemia (0% vs 6%), hypotension (0% vs 6%), and hyponatremia (4% vs 6%).

A total of 16% (n = 4) and 23% (n = 16) of patients in the ipilimumab and combination arms, respectively, did not complete all 4 doses of ipilimumab because of an AE.

Correlative analysis demonstrated that the combination led to an increase in CD8+ cells in the tumor and at the boundary in responsive tumors.

“Nivolumab plus ipilimumab is an appropriate next-line treatment in patients without response to anti–PD-1 alone,” VanderWalde concluded.

VanderWalde A, Moon J, Bellasea S, et al. Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT013.

An improved progression-free survival benefit was observed in patients with stage III unresectable or stage IV melanoma who received nivolumab plus ipilimumab.

Nivolumab/Ipilimumab Elicits Promising PFS in Second-Line Metastatic Melanoma

 the fixed dose of relatlimab plus nivolumab (Opdivo; Opdualag) on the indication of unresectable or metastatic melanoma for adults of at least 12 years of age and who weigh at least 40 kg.

This approval is particularly novel because relatlimab, a LAG-3 inhibitor, is the first approved checkpoint inhibitor of its class, according to Hussein A. Tawbi, MD, PhD.

The FDA approval was primarily supported by findings from the 

 (NCT03470922), which showed that the fixed combination yielded a progression-free survival (PFS) that was double of that reached with nivolumab alone.

Specifically, patients with unresectable or metastatic melanoma who received the combination experienced a median PFS of 10.2 months (95% CI, 6.37-15.74). In comparison, patients who received nivolumab alone reached a median PFS of 4.63 months (95% CI, 3.38-5.62; HR, 0.75; 95% CI, 0.62-0.92, 

Oncology Nursing News® speaks with Hussein A. Tawbi, MD, PhD, principal investigator of the phase 2/3 RELATIVITY-046 trial, about the significance of the relatlimab/nivolumab approval for patients with unresectable or metastatic melanoma. 

Skin Cancer/Melanoma