Adjuvant pembrolizumab (Keytruda) was associated with better quality of life (QOL) outcomes compared with ipilimumab (Yervoy) or high-dose interferon α 2b (HDI) in patients with resected melanoma, according to a secondary analysis of the randomized SWOG S1404 trial (NCT02506153).

, showed that patient-reported outcomes collected at cycle 3 of treatment using the Functional Assessment of Cancer Therapy Biological Response Modifiers Trial Outcome Index (FACT-BRM TOI) score were 9.6 points higher with pembrolizumab than comparators (95% CI, 7.9-11.3; 

 < .001). Investigators hypothesized that a difference of 5.0 points would signal clinically meaningful difference in QOL with pembrolizumab.

In the linear-mixed models, pembrolizumab surpassed ipilimumab and HDI by over 5 points through cycle 7, and in the post hoc analysis, the FACT-BRM TOI scores favored the pembrolizumab arm against both the ipilimumab (difference, 6.0 points; 95% CI, 4.1-7.8;

 < .001) and HDI arms (difference, 17.0 points; 95% CI, 14.6-19.4;

“We found that QOL end points for patients randomized to receive treatment with pembrolizumab were superior than those of patients randomized to treatment with ipilimumab/HDI,” wrote Joseph Unger, PhD, MS, associate professor, biostatistician, and health services researcher with the Cancer Prevention Program and Public Health Sciences Division of Fred Hutch Cancer Center, and coinvestigators, in the study.

Immune checkpoint blockade has repeatedly demonstrated its benefit in the adjuvant setting for high-risk melanoma; in 2015, ipilimumab outperformed placebo in prolonging recurrence-free survival (RFS), although patients in the experimental arm experienced worse QOL and patient-reported symptoms were higher for diarrhea, and insomnia.

In the KEYNOTE-054 trial (NCT02362594), pembrolizumab also extended RFS compared with placebo; but again was associated with detriments to QOL. However, in both trials, the worse QOL outcomes were deemed clinically insignificant and therefore supported widespread adoption of immune checkpoint inhibitor adjuvant therapy in melanoma.

The CheckMate 238 trial (NCT02388906) found that the PD-1 inhibitor nivolumab (Opdivo), elicited superior RFS than the CTLA-4 inhibitor, ipilimumab; however, the differences in QOL outcomes between the 2 immune checkpoint inhibitors were not considered meaningful.

“An important issue in the adjuvant treatment of patients with high-risk melanoma is how patients weigh the benefits of RFS, overall survival, and QOL,” study authors noted. “Adjuvant high-dose interferon improves RFS for this patient population but is known to be associated with major grade 3 to 4 toxic effects and impaired QOL. Ipilimumab, a cytotoxic T-lymphocyte antigen 4–blocking antibody, has been shown to provide longer RFS in resectable high-risk melanoma, but to result in potentially dose-limiting toxic effects.”

The S1404 trial was a randomized, phase 3 clinical trial, which was conducted across 211 community and academic sites in the US, Canada, and Ireland. The trial enrolled patients with high-risk melanoma to assess the clinical efficacy of pembrolizumab in this setting.

Patients were enrolled between December 2015 to October 2017 and randomly assigned 1:1 to adjuvant treatment with either pembrolizumab or standard of care (ipilimumab/DHI). The QOL analysis captured responses from 832 evaluable patients. Previous reports form the trial showed that pembrolizumab resulted in a significantly longer RFS than standard of care with a 23% reduction in risk of relapse (HR, 0.77; 99.62% CI, 0.59-0.99; 

Patients were assessed for QOL at baseline, and again at cycles 1, 3, 5, 7, and 9. QOL outcomes was assessed via the FACT-BRM TOI ,FACT-General, Functional Assessment of Chronic Illness Therapy–Diarrhea, and the European QOL 5-Dimension 3-Level scales. However, the FACT-BRM TOI scores at the end of cycle 3 were the primary comparison point.

At cycle 3, 267 (32.1%) were receiving standard of care treatment and 565 (67.9%) were receiving pembrolizumab. The rates of FACT-BRM TOI compliance were similar (ipilimumab/HDI, 96.0% vs pembrolizumab, 98.3%; 

Overall, adverse events (AEs) occurred in over 90% of patients in the intention-to-treat population—including 91% (n = 585) of patients receiving pembrolizumab, 95% of patients receiving ipilimumab (n = 401), and 99% (n = 143) of patients receiving HDI. The rates of grade 3 or worse AEs in these 3 groups were 17%, 43%, and 66%, respectively.

Fatigue (59%) and maculo-papular rash (29%) represented the 2 most common AEs linked to pembrolizumab, fatigue (51%) and nausea (48%) were most common with ipilimumab, and fatigue (88%) and aminotransferase increase (70%) were most prevalent with HDI.

Unger JM, Darke A, Othus M, et al. Effectiveness of adjuvant pembrolizumab vs high-dose interferon or ipilimumab for quality-of-life outcomes in patients with resected melanoma: a secondary analysis of the SWOG S1404 randomized clinical trial. 

 Published online November 23, 2022. doi:10.1001/jamaoncol.2022.5486

Articles

Adjuvant pembrolizumab demonstrated significantly better quality of life outcomes for patients with resected melanoma vs standard care. 

Adjuvant Pembrolizumab Offers Patients With Resected Melanoma Better QOL Outcomes Than Ipilimumab, High-Dose Interferon 

All checkpoint inhibitor-naïve patients with Merkel cell carcinoma demonstrated an objective response with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), according to data from a phase 2 trial (NCT03071406). Notably, the addition of stereotactic body radiation therapy (SBRT) did not impact the objective response rate (ORR), which was 100% (95% CI, 82%-100%).

Among all 24 patients who did not receive prior treatment with a checkpoint inhibitor, 13 received nivolumab/ipilimumab alone and 11 were administered nivolumab/ipilimumab with SBRT. Data presented at the 2022 ESMO Congress showed that 41% of all checkpoint inhibitor–naïve patients achieved a complete response (CR) and 59% had a partial response (PR). Nine percent of patients experienced disease progression following an initial response.

In patients who received prior treatment with a checkpoint inhibitor (n = 26), nivolumab/ipilimumab with or without SBRT produced an ORR of 31% (95% CI, 15%-52%), with a CR rate of 15% and a PR rate of 15%. Additionally, 1 patient had stable disease, 65% of patients experienced progressive disease, and 50% of responders progressed following an initial response. Those given nivolumab/ipilimumab alone and a prior checkpoint inhibitor (n = 12) achieved an ORR of 42% (95% CI, 16%-71%), and those who received nivolumab/ipilimumab plus SBRT and a prior checkpoint inhibitor had an ORR of 21% (95% CI, 6%-51%).

“[The] addition of SBRT did not improve the efficacy of nivolumab/ipilimumab,” Sungjune Kim, MD, PhD, the director of Radiation Oncology Translational Research and an associate member of the Department of Radiation Oncology and Department of Immunology at Moffitt Cancer Center, wrote in a presentation of the data.

The open-label, randomized, phase 2 trial investigated the combination of nivolumab and ipilimumab with or without SBRT in patients aged at least 18 years with recurrent or metastatic MCC who had at least 2 distinct lesions to assess response in the non-irradiated lesion. Patients were also required to have an ECOG performance status of 0 to 1. Patients could not have active brain metastases. Patients were stratified based on prior immunotherapy.

Patients in arm A (n = 25) received 240 mg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks. Those in arm B (n = 25) received the same nivolumab/ipilimumab regimen plus 24 Gy/3 fx of SBRT at week 2. Treatment continued until disease progression, unacceptable toxicity, or withdrawn consent.

ORR served as the trial’s primary end point. Secondary end points included overall survival (OS), progression-free survival (PFS), local control, and exploratory biomarkers.

Among all enrolled patients (n = 50), the median age was 73 years (interquartile range, 67-81), 78% of patients were male, and all patients were White. Patients either had an ECOG performance status of 0 (46%) or 1 (54%). Patients had stage IIIB (24%) or IV (76%) disease. Forty-eight percent of patients were naïve to checkpoint inhibitors and 90% were chemotherapy naïve.

Additional data showed that the median duration of response (DOR) was not evaluable (NE; 95% CI, 34-NE) in all patients who were naïve to checkpoint inhibitors. For those with prior exposure to checkpoint inhibitors, the median DOR was 11 months (95% CI, 5-NE). In arm A, the median DORs in the checkpoint inhibitor–naïve and–exposed populations were NE (95% CI, 34-NE) and 15 months (95% CI, 7-NE), respectively. In arm B, the median DOR in these populations were NE and 5 months (95% CI, 3-NE), respectively.

The median PFS was NE among checkpoint inhibitor–naïve patients in both arms. Those with prior checkpoint inhibitor treatment in arms A and B experienced a median PFS of 4.2 months and 2.7 months, respectively. The median OS was NE for both arms among patients without prior checkpoint inhibitor exposure. Those in arm A with prior checkpoint inhibitor treatment achieved a median OS of 14.9 months compared with 9.7 months for those in arm B.

Regarding safety, 54% of all patients experienced at least 1 grade 1/2 treatment-related adverse effect (TRAE). The rates of grade 1/2 TRAEs in arm A and arm B were 44% and 64%, respectively. Grade 3 TRAEs occurred in 26% of all patients, including 28% of those in arm A and 24% of those in arm B. Grade 4 TRAEs were reported in 10% of all patients, including 12% of those in arm A and 8% of those in arm B.

Overall, 8 patients discontinued treatment due to toxicity.

Kim S, Wuthrick E, Blakaj DM, et al. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma. 

. 2022;33(suppl 7):S1409-S1410. doi:10.1016/j.annonc.2022.08.041

All 24 patients with Merkel cell carcinoma who received nivolumab plus ipilimumab responded to treatment, and 41% achieved complete responses. 

Nivolumab/Ipilimumab Induces Stark Overall Response Rate in Checkpoint Inhibitor–Naïve Merkel Cell Carcinoma

Camsirubicin, a doxorubicin analogue, combined with pegfilgrastim (Neulasta) led to promising clinical activity with manageable tolerability in patients with advanced soft tissue sarcoma, according to phase 1b findings from a clinical trial (NCT05043649).

Findings showed that among 10 evaluable patients, 5 achieved stable disease at 12 weeks. The remaining 5 patients experienced progressive disease. Notably, an 11th patient met the criteria for stable disease at 6 weeks but died due to COVID-19 prior to the week 12 evaluation.

Doxorubicin is approved by the FDA as first-line monotherapy for the treatment of patients with advanced soft tissue sarcoma. However, due to its risk of irreversible, life-threatening cardiotoxicity, treatment with doxorubicin is stopped once a lifetime cumulative dose is reached in approximately 4 to 6 months.

Camsirubicin was designed via chemical modification to mitigate cardiotoxicity while retaining antitumor activity. Data from a previous phase 1 dose-escalating trial suggested a recommended phase 2 dose (RP2D) of 265 mg/m2 due to concerns of acute neutropenia. The phase 1b trial added pegfilgrastim with camsirubicin to address neutropenia toxicity to determine a higher maximum tolerated dose (MTD) for future studies.

The ongoing phase 1b trial is enrolling patients at least 18 years of age with a locally confirmed histological diagnosis of advanced unresectable or metastatic soft tissue sarcoma including leiomyosarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma, undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumor, or synovial sarcoma who were not amenable to curative treatment with surgery or radiotherapy.

Other key inclusion criteria include measurable disease, an ECOG performance status of 0 or 1, no previous treatment with anthracyclines, and no prior systemic cytotoxic therapies for advanced/metastatic sarcoma, left ventricular ejection fraction of at least 50% assessed within 28 days prior to enrollment, and adequate hepatic, renal, cardiac, and hematologic function.

All previous anticancer treatments must be completed at least 21 days prior to first dose of study drug.

Key exclusion criteria include intolerance to pegfilgrastim, known active central nervous system or leptomeningeal metastasis, prior treatment with doxorubicin, epirubicin, idarubicin, and/or other anthracyclines or anthracenediones, or prior radiotherapy of the mediastinal/pericardial area or whole pelvis radiation.

In the 3+3 trial design, patients received pegfilgrastim plus escalating doses of camsirubicin, starting at 265 mg/m2 (n = 3). Other doses of camsirubicin included 330 mg/m2 (n = 3), 410 mg/m2 (n = 3), and 520 mg/m2 (n = 2). The trial has advanced to the fourth cohort without any dose-limiting toxicity. Treatment with camsirubicin consists of 6, 21-day cycles, with an extension of up to 16 cycles.

The co-primary end points of the trial are to determine the MTD and RP2D.

Among the 11 enrolled patients, the median age was 49 years (range, 26-81). Eight patients were male, and all 11 had an ECOG performance status of 1. One patient had a localized tumor, 5 patients had locally advanced disease, and 5 patients had metastatic disease.

No drug-related cardiotoxicity was observed up to current dose level of 520 mg/m2 per cycle.

Monopar announces encouraging clinical data from ongoing camsirubicin phase 1b trial. News release. Monopar Therapeutics Inc. November 16, 2022. Accessed November 18, 2022. 

Chua VS, Chawla S, Gordon E. Phase 1b trial of camsirubicin, a novel doxorubicin analog, with concomitant pegfilgrastim for advanced soft tissue sarcoma to identify a new maximum tolerated dose/recommended phase 2 dose. Presented at: 2022 Connective Tissue Oncology Society (CTOS) Annual Meeting; November 16-19, 2022; Vancouver, BC, Canada. 

Camsirubicin + pegfilgrastim to determine MTD in ASTS. ClinicalTrials.gov. Updated September 20, 2021. Accessed November 18, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05043649

Combining the doxorubicin analogue camsirubicin with pegfilgrastim yielded encouraging clinical activity in patients with advanced soft tissue sarcoma. 

Camsirubicin Demonstrates Efficacy, Tolerability in Advanced Soft Tissue Sarcoma

Frontline treatment with sotigalimab (APX005M) plus pembrolizumab (Keytruda) led to promising antitumor activity in patients with metastatic melanoma, according to updated phase 1/2 findings that that were presented at the 2022 SICT Annual Meeting. Moreover, the combination was found to be well tolerated.

Sotigalimab is a humanized IgG1 monoclonal antibody against human CD40.

As of October 28, 2022, the overall response rate (ORR) by RECIST 1.1 criteria among 32 patients on the study (NCT02706353) was 47%, which consisted of a 16% complete response rate and a 31% partial response rate; the stable disease rate was 22% and 31% of patients had progressive disease. The disease control rate was 69%.

The ORR at the recommended phase 2 dose (RP2D) of 10 mg sotigalimab was 50%.

“[The combination] showed oncologic activity, and from our biomarker analysis we demonstrated that the combination of sotigalimab with pembrolizumab can induce broad innate and adaptive immune activation in both local and distant lesions,” lead study author Salah-Eddine Bentebibel, PhD, of the Department of Melanoma Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center (MD Anderson), said in a presentation.

“Biomarker analysis demonstrates that the combination of sotigalimab with pembrolizumab can induce broad innate and adaptive immune activation in both local and distant lesions.”

Intratumoral immunotherapy operates on the principal of using the tumor as its own vaccine; local intratumoral injection of immunostimulatory agents is designed to trigger tumor-specific immunity. This leads to distant effects of systemic antitumor immunity against non-injected tumor sites.

Although immune checkpoint inhibitors are an important modality for the treatment of patients with metastatic melanoma, physicians need new combinations to improve benefit-risk profiles. Adi Diab, MD, the study’s principal investigator and an associate professor in the Department of Melanoma Medical Oncology at MD Anderson, explained that many patients are unresponsive to immune checkpoint inhibitors or develop resistance after initial tumor regression.

“Results from the ongoing phase 2 trial of intratumoral sotigalimab and the PD-1 inhibitor pembrolizumab showed a promising ORR including responses achieved in PD-L1–negative tumors,” he said in a news release.

 “Moreover, this encouraging anti-tumor activity correlated with treatment-induced immunologic changes, such as activated myeloid dendritic cells and macrophages, which support the mechanism of action and differentiated activity of sotigalimab—ultimately leading to inflammatory immune responses in the local injected tumor as well as distant non-injected lesions.”

In the phase 1/2 dose-escalation/dose-expansion study, investigators assessed the safety and tolerability of sotigalimab plus pembrolizumab in the frontline setting of patients with metastatic melanoma. The primary end point was maximum-tolerated dose and RP2D; additional outcome measures were ORR by RECIST 1.1 criteria and biomarker assessment in blood and tumor samples.

To be eligible for enrollment, patients had histologically or cytologically confirmed cutaneous or mucosal stage III/IV melanoma that was measurable and unresectable. Patients had to have an ECOG performance status of 0 or 1, adequate organ function, and fresh biopsy and archival tissue.

The phase 1 dose-escalation portion (n = 14) included checkpoint inhibitor–naïve patients who received intravenous pembrolizumab at 2 mg/kg plus sotigalimab at 0.1 mg, followed by increasing doses of sotigalimab at 0.5 mg, 1 mg, 3 mg, and 10 mg. Sotigalimab was given every 3 weeks for a total of 4 injections.

The RP2D was sotigalimab was at 10 mg, which was used in the phase 2 portion (n = 18).

In the total population of 32 patients, 84% were male, the median age was 64.5 years (range, 32-81), and 44% of patients had an ECOG performance status of 1. Thirty-four percent of patients had 

-positive disease, lactate dehydrogenase (LDH) levels at baseline were below the upper limit of normal in half of patients, and 25% of patients had PD-L1­–positive disease. Fifty-three percent of patients had stage IV M1a or M1b disease, 22% had stage MI1c disease, and 25% had stage III disease.

Additional findings showed that clinical responses were reported in both PD-L1–negative tumors and patients with elevated LDH.

Safety data demonstrated that the combination is well tolerated, Bentebibel said, adding that there were no study discontinuations or deaths due to treatment-related adverse events (TRAEs). The most common TRAEs were injection-site reactions, and 18% of patients (n = 6) had grade 3 immune-related adverse events. No dose-limiting toxicities were reported at any of the dose levels, and no dose-limiting toxicities were needed.

Through NanoString gene expression, investigators noted that sotigalimab engaged CD40 activation, macrophage activation, and up-regulation of genes that was associated with antigen-presenting cells. Additionally, it was found that pre-existing interferon-gamma mediated immune activation in baseline tumor tissue did not correlate with response to the combination regimen.

Bentebibel also pointed out that patients who did respond to pembrolizumab plus sotigalimab appeared to have high pre-existing CD11c

 DC cells. Furthermore, the combination also activates the DC and increases macrophage signature in both local and distant tumors.

Finally, patients who responded to treatment experienced an on-treatment increase in CD8

 T, cytotoxic, and Th1 scores in the tumor, as well as an increase in CD8

 T-cell proliferation. Bentebibel also noted that, through T-cell receptor sequencing in tumor samples, the combination can lead to an increase in T-cell infiltration and clonality, as well a new clone expansion shared between local and distal lesions.

Data from a phase 2 trial (NCT03123783) presented during the 2021 SITC Annual Meeting showed that the combination of sotigalimab plus the PD-1 inhibitor nivolumab (Opdivo) elicited durable responses with a reasonable safety profile in patients with melanoma who were refractory to anti–PD-1 therapy.

The ORR was 15.2% (95% CI, 6.2%-29.3%) among 33 evaluable patients; this included a partial response (PR) rate of 15.2% and a stable disease rate of 33.3%.

Bentebibel S-E. Intatumoral sotigalimab with pembrolizumab activates antigen-presenting cells and induces local and distant anti-tumor responses in first-line metastatic melanoma: results of a phase I/II study. Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. Abstract 782.

Apexigen announces new data from a phase 1/2 trial evaluating its CD40 antibody, sotigalimab, in combination with pembrolizumab in patients with first-line metastatic melanoma at the SITC 2022 Annual Meeting. News release. November 11, 2022. Accessed November 16, 2022. https://bit.ly/3EBf2H7

Weiss SA, Sznol M, Shaheen M, et al. Phase II of CD40 agonistic antibody sotigalimab (APX005M) in combination with nivolumab in subjects with metastatic melanoma with confirmed disease progression on anti-PD-1 therapy. 

. 2021;9. doi:10.1136/jitc-2021-SITC2021.389

Sotigalimab, a humanized IgG1 monoclonal antibody against human CD40, may hold value in the frontline treatment of patients with metastatic melanoma. 

Sotigalimab/Pembrolizumab Displays Promising Response Rate in Metastatic Melanoma

A significant portion of patients with resected stage IIIA melanoma were alive and recurrence free at a median follow-up of over 20 months following treatment with adjuvant nivolumab (Opdivo), according to a real-world analysis presented at the 19th International Congress of the Society for Melanoma Research.

Patients treated with adjuvant nivolumab (n = 171) achieved a 12-month recurrence-free survival (RFS) rate of 97.1% (95% CI, 93.1%-98.8%) compared with 81.6% (95% CI, 65.2%-90.8%) for patients who underwent observation (n = 38).The RFS rates at 18 months were 91.4% (95% CI, 85.6%-94.9%) vs 78.6% (95% CI, 61.6%-88.7%), respectively. The median RFS was not reached in either arm.

Additionally, treatment with neoadjuvant nivolumab improved 12- and 18-month overall survival (OS) rates; 98.2% (95% CI, 94.6%-99.4%) and 94.2% (95% CI, 89.1%-96.9%) compared with 94.7% (95% CI, 80.6%-98.7%) and 91.8% (95% CI, 76.6%-97.3%) in the observation group, respectively. The median OS was 34.6 months and not reached, respectively.

“In 2 real-world studies that have been published, nivolumab was shown to provide benefit, however the numbers were small,” Anna C. Pavlick, BSN, MSc, DO, MBA, a medical oncologist at Weill Cornell Medicine, in New York, New York, said in a presentation of the data. “Therefore, we’re presenting the real-world Cardinal Health database [for patients] with resected stage IIIA melanoma treated with nivolumab or observation. This is the largest real-world database to be presented to date.”

The real-world study collected data from Cardinal Health’s propriety Oncology Provider Extended Network.2 Data from the phase 3 CheckMate 238 trial (NCT02388906), led to the approval of nivolumab monotherapy for the adjuvant treatment of patients with resected stage III/IV melanoma in 2017.3 However, per AJCC-7 staging criteria, patients with stage IIIA melanoma were excluded and a minimal number of patients per AJCC-8 were enrolled.

Patients in the adjuvant nivolumab cohort (n = 171) and an observation cohort were aged 18 years and older with stage IIIA melanoma per AJCC-8 and had complete surgical resection between January 1, 2018, and December 31, 2019.

The mean age of patients was 57.4 years in the adjuvant nivolumab cohort and 68.1 years in the observation group; both cohorts had a majority White male population. Year of resection was 30% in 2018 and 70% in 2019 vs 47% in 2018 and 53% in 2019, respectively.

Most patients in both cohorts had a lymph node involvement of 1, but 33% of patients in the nivolumab arm had an involvement of 2 or 3 nodes vs 26% in the observation arm. Only 1 patient had 4 or more and was in the nivolumab arm.

In patients with known or available data, most in both arms had an sentinel lymph node tumor burden of 1 mm to 4 mm. Primary lesion sites were similar in the cohorts: trunk, (25% vs 24%), extremities (55% vs 53%), head/neck (20% vs 21%), and external genitalia (1% vs 3%), in the nivolumab and observational groups, respectively. Although ulcers were mostly absent, 22% of patients in the nivolumab arm and 18% patients in the observation arm had ulcers present. The median Breslow thickness of tumors at the time of resection was 1.80 vs 1.90, respectively. ECOG performance status ranged from 0 to 3 with most patients having a score of 0.

The median duration of treatment with nivolumab was 12.0 months (95% CI, 11.8-12.0). Three patients continued treatment and 91% of patients completed the scheduled duration of nivolumab therapy, with the most common reasons for discontinuation being patient choice, toxicity, and disease progression.

Additional data from the study showed that distant metastasis–free survival was examined as well and was 98.2% and 91.3% vs 94.7% and 88.8%, respectively.

The median time to first recurrence was 18.9 (range, 3.9-29.1) months in the nivolumab arm and 9.4 months (range, 2.6-30.6) in the observation arm with the most frequent sites being lungs and lymph nodes. Any first recurrence occurred in 11% vs 26% of patients, respectively. There were 11 deaths (6%) in the nivolumab group and 6 deaths (16%) in the observation group and the most common cause was disease progression. Cardiovascular disease, infectious disease, and unspecified were also cited as fatal events.

Regarding safety, endocrine, dermatologic, gastrointestinal, and hepatic, treatment-related adverse events (TRAEs) of any grade occurred in the adjuvant nivolumab group at rates of 13%, 11%, 8%, and 5%, respectively. Grade 3 or 4 events were observed in the endocrine and gastrointestinal categories in 1% and 2% of patients, respectively, and 2% of patients discontinued treatment due to TRAEs. The data was collected from patient charts and may be underreported as the data is real-world, investigators noted.

Although the study used a nationwide databased to assess real-world data from this subgroup of patients that may be able to give more accurate date than randomized control trial population data, the analysis was retrospective. Further limitations included the shorter follow-up of the survival outcomes data, as stage IIIA melanoma patients have a relatively good prognosis, errors that could have occurred in data entry, and differences in the cohort’s baseline characteristics.

A lack of adjustment for heterogeneity between the 2 cohorts when reporting Kaplan–Meier curves was as a challenge, study authors wrote.

When asked if removing the IIIA less than 1 mm patients would result in the curves looking more like one would expect, Pavlick explained, “The number of measurements that were done there are very few patients that had a numerical measurement in their sentinel lymph node [and because] it was mostly reported as positive or negative that would be difficult to do.”

Pavlick AC, Amin A, Moser JC, et al. Outcomes in patients with resected stage IIIA melanoma treated with adjuvant nivolumab or monitored with observation: a real-world study. Presented at: 19th International Congress of the Society for Melanoma Research. October 17-20, 2022. Edinburgh, Scotland.

Pavlick AC, Amin A, Moser JC, et al. Outcomes in patients with resected stage IIIA melanoma treated with adjuvant nivolumab or monitored with observation: a real-world study. 

. 2022;40(suppl 16): e21534. doi:10.1200/JCO.2022.40.16_suppl.e21534

FDA grants regular approval to nivolumab for adjuvant treatment of melanoma. FDA. December 20, 2017. Accessed November 7, 2022. bit.ly/3WYnDe6

A significant portion of patients with resected stage IIIA melanoma were alive and recurrence free at a median follow-up of over 20 months following treatment with adjuvant nivolumab. 

Real-World Study Demonstrates Benefits with Adjuvant Nivolumab in Resected Stage IIIA Melanoma

Different sequencing strategies may help improve outcomes and mitigate toxicities for patients with metastatic melanoma, according to Jeffrey S. Weber, MD, PhD. Moreover, while the dual immunotherapy combination of nivolumab (Opdivo) and ipilumumab (Yervoy) continues to demonstrate long-term benefit for this patient population, newer regimens are also starting to show promise—potentially expanding the growing number of effective therapies in this setting.

For instance, the phase 3 CheckMate 067 trial (NCT01844505), which randomly assigned patients with previously untreated, unresectable or metastatic melanoma 1:1:1 to receive the combination of nivolumab/ipilimumab, nivolumab alone, or ipilimumab alone, now has available data from 6.5 years of follow-up. “There are not a lot of studies out there in melanoma—in fact, I would say there are none—that have this kind of follow-up,” Weber, the deputy director of the Perlmutter Cancer Center at New York University Langone Health in New York, New York, noted, duing a presentation at the 

The combination elicited a median overall survival [OS] of 72.1 months (95% CI, 38.2-not reached [NR]), compared with 36.9 months (95% CI, 28.2-58.7) for nivolumab alone (HR, 0.84; 95% CI, 0.67-1.04) and 19.9 months (95% CI, 16.8-24.6) for ipilimumab alone (HR, 0.52; 95% CI, 0.43-0.64).2 The 78-month OS rates were 49% for nivolumab/ipilimumab, 42% for nivolumab alone, and 23% for ipilimumab alone.

However, 59% of patients treated in the combination arm (n=313) experienced at least 1 grade 3/4 treatment-related adverse effect (TRAE). “Yes, of course, there is more toxicity [with the combination of nivolumab/ipilimumab], but my feeling is that in routine practice, every patient who has metastatic disease deserves a shot at nivolumab/ipilimumab,” Weber said.

Ways to mitigate the toxicities of the combination of nivolumab and ipilimumab were addressed in the phase 3b/4 CheckMate 511 trial (NCT02714218), which evaluated a flipped dose of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks, compared with the regimen of 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks used in CheckMate 067.

At 3 years of follow-up in CheckMate 511, grade 3 to 5 TRAEs occurred in 34% of patients given the flipped dose regimen, compared with 48% for those administered the regular regimen. Notably, the 2 regimens elicited numerically similar OS, with 3-year OS rates of 59% in the flipped-dose arm and 61% in the control arm.

“Given that OS curve, you tell me which [regimen] you would rather get. If I were the patient, I would rather have [the] flipped dose,” Weber said. “Flipped dose nivolumab/ipilimumab has thus entered common practice, certainly at my institution and in the community. The likelihood that you are going to sacrifice a survival benefit would seem incredibly low.”

Weber noted that the full dose of nivolumab plus ipilimumab still has a place in practice for patients with brain metastases or those with rapidly progressive disease.

Sequencing Immunotherapy and Targeted Therapy in 

CheckMate 067 and CheckMate 511 both evaluated nivolumab/ipilimumab in patients with metastatic melanoma, irrespective of the presence of 

 mutations. The phase 3 DREAMseq trial (NCT02224781) helped address sequencing questions of nivolumab/ipilimumab vs BRAF-targeted therapy for patients with metastatic melanoma harboring 

DREAMseq randomly assigned patients with 

-mutant metastatic melanoma to receive nivolumab/ipilimumab induction and nivolumab maintenance, followed by continuous dabrafenib (Tafinlar) plus trametinib (Mekinist) at disease progression, or continuous dabrafenib plus trametinib followed by nivolumab/ipilimumab induction and nivolumab maintenance at disease progression.

Weber noted that data from the trial showed an early OS benefit for patients who received dabrafenib/trametinib first, but the survival curves crossed around month 8 or 9. Ultimately, patients who received nivolumab/ipilimumab first achieved a 3-year OS rate of 66.2% (95% CI, 56.0%-74.6%) compared with 42.8% (95% CI, 32.9%-52.4%) for those given dabrafenib/trametinib first (log rank 

“This essentially puts to rest the idea that you could either give a BRAF [inhibitor] plus a MEK [inhibitor] or immunotherapy first. In my practice, I will continue to prefer to give immunotherapy first,” Weber explained. “The one caveat...if someone presents with high lactate dehydrogenase, rapidly progressive bulky disease, and they are 

 mutated, I will probably give them 8 to 12 weeks of BRAF/MEK, then I’ll switch them to nivolumab/ipilimumab [irrespective of disease progression. However], that is a different question not addressed in this trial.”

Role of Nivolumab Plus Relatlimab in Metastatic Melanoma

Following the positive data from the phase 2/3 RELATIVITY-047 trial (NCT03470922) and the FDA approval of relatlimab plus nivolumab (Opdualag) for the treatment of adult and pediatric patients who are 12 years or older and who have unresectable or metastatic melanoma

in March 2022, the combination may replace single-agent PD-1 blockade, according to Weber.

RELATIVITY-047 randomly assigned patients with previously untreated, unresectable or metastatic melanoma 1:1 to receive 480 mg of nivolumab once every 4 weeks with or without 160 mg of relatlimab. The combination elicited a median progression-free survival (PFS) of 10.22 months (95% CI, 6.51-14.75) compared with 4.63 months (95% CI, 3.48-6.44) for nivolumab alone (HR, 0.78; 95% CI, 0.64-0.94).

Additionally, the combination produced a median OS that was NR (95% CI, 34.20-NR) vs 34.10 months (95% CI, 25.23-NR) for nivolumab alone (HR, 0.80; 95% CI, 0.64-1.01; 

“TRAEs of grade 3/4 are [approximately] doubled from 11.% [with nivolumab alone] to 21.1% [for relatlimab/nivolumab], and the discontinuation rate goes up [with relatlimab],” Weber said. “So yes, [relatlimab plus nivolumab] is more toxic, but it is still within what I would consider reasonable bounds.”

Tumor-Infiltrating Lymphocytes on the Horizon

Weber pointed to tumor-infiltrating lymphocytes (TILs)as the next possible advancement in the treatment paradigm for metastatic melanoma. Data from the phase 2 C-144-01 trial (NCT02360579) showed that among 62 patients treated with lifileucel (LN-44), 81% experienced a reduction in tumor burden.7

Furthermore, data from the phase 3 M14TIL trial (NCT02278887), which evaluated patients with metastatic melanoma who received no more than 1 prior line of therapy and no prior ipilimumab, showed that those treated with TIL therapy experienced a median PFS of 7.2 months (95% CI, 4.2-13.1) and a 6-month PFS rate of 52.7% (95% CI, 42.9%-64.7%).8 Those given single-agent ipilimumab had a median PFS of 3.1 months (95% CI, 3.0-4.3) and a 6-month PFS rate of 21.4% (95% CI, 14.2%-32.2%).

“This has gone to the FDA. We hope that this will get approved in the next few months, and the survival curve of TIL [therapy] vs ipilimumab is also better, but again, very immature without a real 

Weber JS. Advances in metastatic melanoma. Presented at: 

 CFS®; November 9-11, 2022; New York, NY and virtual.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. 

. 2022;40(2):127-137. doi:10.1200/JCO.21.02229

Lebbe C, Meyer N, Mortier L, et al. Two dosing regimens of nivolumab (NIVO) plus ipilimumab (IPI) for advanced (adv) melanoma: three-year results of CheckMate 511. 

. 2021;39(suppl 15):9516. doi:10.1200/JCO.2021.39.15_suppl.9516

Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq (doublet, randomized evaluation in advanced melanoma sequencing): a phase III trial—ECOG-ACRIN EA6134. 

. 2021;39(suppl 36):356154. doi:10.1200/JCO.2021.39.36_suppl.356154

U.S. Food and Drug Administration approves first LAG-3-blocking antibody combination, Opdualag (nivolumab and relatlimab-rmbw), as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb; March 18, 2022. Accessed November 10, 2022. 

Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab vs 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

Larkin J, Sarnaik A, Chesney JA, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced melanoma: evaluation of impact of prior anti-PD-1 therapy. 

. 2021;39(suppl 15):9505. doi:10.1200/JCO.2021.39.15_suppl.9505

Haanen JBAG, Rohaan M, Borch TH, et al. Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: results from a multicenter, randomized phase III trial. 

. 2022;33(suppl 7):S1406. doi:10.1016/j.annonc.2022.08.036

During the 40th Annual Chemotherapy Foundation Symposium, Jeffrey S. Weber, MD, PhD, discussesed best sequencing practices in metastatic melanoma. 

Evolving Immunotherapy Data Shed Light on Best Practices in Metastatic Melanoma 

Brain metastases have historically been associated with dismal outcomes. However, while former treatment approaches were centered around surgery or radiation, in the past decade and a half, investigators have made transformative advances in unlocking the scientific understanding of the genomic drivers behind cancer, according to Manmeet Ahulwalia, MD, MBA. Consequently, the oncology community has made great strides in precision medicine and immunotherapy: 2 approaches which are significantly improving outcomes for patients with brain metastases.

Ahulwalia, the Fernandez Family Foundation Endowed Chair in Cancer Research, Chief of Medical Oncology, and Chief Scientific Officer & Deputy Director, Miami Cancer Institute, Baptist Health South Florida, recently presented on the management of brain and leptomeningeal metastases across tumor types during the 

, he underscored how the evolution of treatment directions across tumor types have unlocked promising opportunities to penetrate the blood brain barrier.

Some of the cancers which have a greater tendency to metastasize to the brain include lung cancer, breast cancer, and melanoma. According to Ahulwalia, all of these subtypes have seen tremendous progress in the past 2 decades in terms of treatment options and outcomes According to Ahulwalia, patients with lung cancer and brain metastases in 2010 had, on average, an estimated overall survival of 9 to 12 months . However, today, patients with 

-mutant lung cancer which has metastasized to the brain are generally expected to survive an average of 2 to 3 years, and for patients with translocation lung cancer with brain metastases, the average survival has been prolonged to approximately 5 years. Small molecular inhibitors with promising blood brain barrier penetration have played a larger part in boosting survival in this arena.

Moreover, drugs like tucatinib (Tukysa) and, more recently, trastuzumab deruxtecan-nxki (Enhertu), have yielded encouraging results for patients with breast cancer and brain metastases. In the melanoma realm, a mere decade or 2 ago, the average survival was approximately 6 months—today immunotherapy advances are helping these patients achieve survival for nearly 4 or 5 years.

Unfortunately, patients with leptomeningeal disease still face dismal prognoses, Ahulwalia says. The good news is that certain patients with leptomeningeal disease now have promising treatments. For instance, osimertinib (Tagrisso) has shown promising benefit in patients with 

-mutant lung cancer, and patients with breast cancer have also experienced promising results with intrathecal based approaches. Ahulwalia expresses hope that the advances being made in this space will continue to ramp up in the coming decades and that new treatment approaches will open doors for patients with brain metastases and leptomeningeal disease.

“There have been transformative changes in the last decade or so, which make people like me extremely excited for our patients [and excited] about the progress that we're going to make in the next decade or two,” he concludes.

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Manmeet Ahulwalia, MD, MBA, underscores how novel treatment approaches in oncology are proving effective in managing brain metastases. 

Ahulwalia on Targeting the Blood Brain Barrier With Novel Immunotherapies and Precision Oncology 

Several immunotherapy agents have received FDA approval across numerous malignancies since ipilimumab (Yervoy) a decade ago and, in many ways, the effect of immunotherapy in certain populations is equitable to magic, according to Melinda S. Weber, DNP, APN, AOCN-C. However, the unique mechanism of action associated with immunotherapy is also linked to adverse events (AEs) for patients receiving treatment.

In a presentation during the Nursing track at the 

 Weber who is the director of care transformation and a charge APN in the Skin and Sarcoma Division at John Theurer Cancer Center at Hackensack University Medical Center Weber, touched on the marked success of the treatment in the field in melanoma and outlined the tenets of early recognition, appropriate grading, and best management practices for these immune-related adverse events (irAEs).

Immunotherapeutic Agents Usher in a Wave of Hope

“Prior to the advent of ipilimumab [Yervoy] in 2011, [a diagnosis of] metastatic melanoma was a death sentence,” said Weber in an interview with 

 ahead of a presentation. “No radiation touched [the melanoma], no chemotherapy touched it, [and approximately] less than 1% of patients might survive [treatment with] high-dose IL-2 therapy, but that was very rare.”

In November 2022, approved immune-checkpoint inhibitors include atezolizumab (Tecentriq), avelumab (Bavencio), cemiplimab-rwlc (Libtayo), dostarlimab-gxly (Jermperli), durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda). Each of these regiments are approved across multiple indications.

Weber said that the efficacy that immunotherapy wielded in certain populations has been nothing short of astounding, and that it drastically changed her clinical practice.

“They’ve changed the face of oncology…I never thought in a million years that I would see PET scans, that were once lit up like a Christmas tree, become normal and stay normal over months, and then years. Now we have people that are survivors 10 years [or longer]….Our focus for those patients [with] late-stage disease was about palliative care, preserving their dignity, and optimizing their comfort. It was very sad.”

Weber said that the availability of these drugs is exciting because they are helping many patients achieve remission, and for those who do not, immunotherapeutic agents may help individuals reach partial remission, prolonged duration of responses, and superior overall survival rates.

“I never take for granted when we bring in our patients for follow-up visits, because I will never forget what it was like before these drugs,” Weber said. “To see people now go on to live their lives, enjoy their families, watch their children and grandchildren grow, is incredible.”

However, Weber noted the start of the immunotherapy integration was not a smooth journey and shared that when immunotherapy first hit the scene, she had patients who chose not to continue treatment because the irAEs were so severe. According to Weber, as clinicians, you must do everything in your power to avoid that possibility, because patients could be forfeiting a chance at a partial or full remission.

The most common irAEs associated with immune-checkpoint inhibitors include fatigue, asthenia, musculoskeletal pain, decreased appetite, diarrhea, nausea, vomiting, pyrexia, cough, dyspnea, constipation, abdominal pain, rash, peripheral neuropathy, mucosal inflammation, alopecia and stomatitis.

Additionally, immune-checkpoint inhibition is also associated with pneumonitis, colitis, hepatitis, encephalitis, endocrinopathies, dermatologic adverse events, nephritis, renal dysfunction, solid organ transplant rejection, infusions-related reactions, and embryo-fetal toxicity.

According to the National Comprehensive Cancer Network (NCCN), a comprehensive baseline assessment of a patient’s current emotional, physical, and spiritual status, with attention to a patient’s social determinants of health, financial toxicity burden, and health literacy are important for early recognition and prompt intervention for irAEs. These factors may influence how and when patients report irAEs, and can influence whether a patient needs to be admitted following the emergence of irAEs. 

According to Weber, the key with irAEs is to catch them early and intervene as soon as possible, because the sooner that the reactions dissolve and therapy can continue, the greater the outcome the patient can expect to achieve.

Weber noted that nurses today may be able to leverage novel technologies such as mobile applications or software programs to track irAEs. Prior to the advent of these applications, research nurses would carry around binders with the common terminology criteria for adverse events (CTCAE) information when assessing patients.

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only, intervention not indicated.

Gradw 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL).

Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Although CTCAE provides this broad overview of irAE grading, Weber also provided an example of what the clinical presentation looks like for a common irAE, diarrhea.

Grade 1: Increase of < 4 stools per day over baseline; mild increase in ostomy output compared with baseline.

Grade 2: Increase of 4 to 6 stools per day over baseline; moderate increase in ostomy output compared with baseline; limiting instrumental ADL.

Grade 3: Increase of > 7 stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared with baseline limiting self-care ADL.

According to Weber, CTCAE criteria offer clear guidance into appropriate handling of various irAEs, and with early intervention, management is possible. However, she repeatedly stressed that these irAEs are not to be taking lightly, as they can represent a serious barrier to treatment for many patients.

“If I can get anything across, it is that irAEs represent real suffering. [They are] different from chemotherapy adverse reactions,” Weber said. “For example, immunotherapy-induced colitis is horrific, and patients, depending on the grade, may be frightened to leave their homes. Besides the abdominal cramping, the discomfort, the risk of dehydration malnutrition, for many patients, there may be embarrassment or fear of living a normal life, and they may not want to leave their house.”

Moreover, irAEs are different from chemotherapy-related toxicities, because they can occur at unexpected time intervals. These toxicities have varying onset times—they can appear as early as within the first 2 weeks of treatment, or 12 weeks in, they can even occur over 22 months past the last cycle of immunotherapy. Thus, the gravity of these toxicities, the threat they pose to patients, and the need for patient education, cannot be overemphasized.

“irAEs are profoundly debilitating for many, many patients,” she added. “Our job as nursing professionals, besides [providing] great patient education, must be knowing the patient’s baseline to where they are right now, teaching patients to call us early when anything is out of ordinary that’s didn’t not occur before these drugs to call us, and intervening as swiftly as possible.”

Nurses Play a Vital Role in irAE Management

Therefore, when a patient is embarking on immunotherapy, the oncology nurse adopts a unique role as a patient cheerleader.

“We have to be the person who provides knowledge and comfort to that patient,” Weber said. She noted that patients are often afraid of the AEs of their treatments, but nurses can help reassure them and let them know that there is a plan to manage their irAEs.…We tell patients ‘We are going to get you through this,’” Weber said. She added that she likes to tell patients that immunotherapy makes their immune system similar to hungry sharks.

“It’s important for patients to understand what’s happening to them and how we are going to intervene,” she said. “We use a multidisciplinary group, we need our nutritionist, our psychotherapist, we need [individuals] that can provide globally comprehensively care for that patient.”

When it comes to symptom management, there is an arsenal of strategies that clinicians can utilize to help their patients; however, the most important thing, according to Weber, is recognizing the effect these symptoms can have on a patient’s quality of life and reassure them that it can be diminished.

“You can do old-fashioned things. For example, with diarrhea you can [advise patients] to use the BRAT diet, given its within your institutions policies. You can give Imodium [loperamide], Lemotil [atropine and diphenoxylate], Bentyl [dicycloverine], etc. Teach them appropriate dosing of prednisone as ordered, and to get the [irAE] behind them so they can move on.

Weber stressed that there must be awareness alongside action. Nurses have a responsibility to recognize the anguish, pain, and sometimes embarrassment, that patients experienced with these therapies. In managing the patients’ physical symptoms, it is important to recognize the turmoil they can induce on the whole person.

“They are not just clinical symptoms; they really change the face of the patient’s and the family member’s perception of their treatment,” Weber emphasized. “We have to really inspire hope that it's not going to be this way forever,” she said.

Immunotherapy has changed the face of cancer treatment, but requires appropriate irAE management to reach full potential. 

Skin Cancer/Melanoma