The FDA has approved tebentafusp-tebn (Kimmtrak) for the indication of unresectable or metastatic uveal melanoma in adult patients whose disease harbors HLA-A*02:01.

 The regulatory decision represents both the first FDA-approved therapy to treat unresectable or metastatic uveal melanoma, as well as the first FDA-approved T-cell receptor therapeutic.

The approval is supported by findings from the phase 3 IMCgp100-202 trial (NCT03070392) which demonstrated that patients who received this drug achieved significantly improved overall survival at 1 year of follow-up compared with investigators choice of therapy (HR, 0.51; 95% CI, 0.37-0.71; 

Overall, 378 patients with previously untreated metastatic uveal melanoma were randomized 2:1 to receive either tebentafusp or investigators choice of pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine. At a 6-month follow-up, progression free survival (PFS) was also significantly higher among patients in the tebentafusp group than in the control group (31% vs 19%; HR, 0.73; 95% CI, 0.58-0.94; 

“Uveal melanoma is a devastating disease that has historically resulted in death within a year of metastasis for our patients,” John Kirkwood, MD, director of the Melanoma Center at the UPMC Hillman Cancer Center, said in a press release. “The approval of Kimmtrak [tebentafusp-tebn] represents a major paradigm shift in the treatment of metastatic uveal melanoma, and for the first time offers hope to those with this aggressive form of cancer.”

The most common grade 3 or worse adverse events (AEs) included rash (18%), pyrexia (4%), and pruritus (5%). Approximately less than 1% of patients experienced grade 3 cytokine release syndrome (CRS); however, this was reported to be well managed. A consequent warning for CRS will be included in the label due to its ability to become serious or life-threatening.

Manifestations for CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. Immediate access to mediations and resuscitative equipment is crucial for managing CRS. Patients should be euvolemic prior to beginning any infusions. Furthermore, patients should be monitored for fluid status, vital signs, and oxygen levels. In the event of persistent and severe CRS, tebentafusp should be withheld or discontinued.

Skin reactions and elevated liver enzymes were also frequently observed. If skin reactions occur, patients should be administered antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Providers should also monitor alanine aminotransferase (ALT), aminotransferase (AST), and total blood bilirubin prior to the start of and throughout treatment to watch for elevated liver enzymes.

No grade 4 or fatal events were observed throughout the phase 3 trial.

“Until now, effective treatment options for metastatic uveal melanoma patients were virtually non-existent,” concluded Kyleigh LiPira, MBA, CEO of the Melanoma Research Foundation. “The approval of Kimmtrak represents not only a new therapy but a new hope for the individuals and the families of those diagnosed with the deadliest form of eye cancer.”

Immunocore announces FDA approval of Kimmtrak (tebentafusp-tebn) for the treatment of unresectable or metastatic uveal melanoma. News release. Immunocore Holdings Limited; January 26, 2022. Accessed January 26, 2022. https://yhoo.it/3r1C3fk

Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. 

. 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485

Articles

Tebentafusp is now the first FDA-approved therapy to treat unresectable or metastatic uveal melanoma. 

FDA Approves Tebentafusp to Treat HLA-A*02:01 Positive Uveal Melanoma

LAG-3 represents a potentially relevant immune checkpoint pathway, according to Hussein A. Tawbi, MD, PhD.

®, Tawbi, who is a professor of melanoma medical oncology of The University of Texas MD Anderson Cancer Center, deputy chair of clinical research, co-director of MD Anderson Brain Metastases Clinic, as well as lead study author in a recent study published in the 

, discussed the results of the RELATIVITY-047 trial (NCT03470922), which found that the combination of the immune checkpoint inhibitors relatlimab and nivolumab (Opdivo) demonstrated safety and efficacy as a treatment for patients with untreated, advanced melanoma. 

Specifically, patients who received the combination achieved a median progression-free survival (PFS) of 10.1 months (95% CI, 6.4-15.7) compared with 4.6 months (95% CI, 3.4-5.6) among patients who received nivolumab as monotherapy (HR, 0.75; 95% CI, 0.62-0.92; 

Tawbi explained that “LAG-3 is one of several checkpoint inhibitors that are expressed on immune cells—in this case specifically on activated exhausted T cells. And as you know, you know, the immune checkpoint inhibitors have been you have revolutionized cancer in the last decade.”

“One of the challenges with the combination of PD-1 and CTLA-4 is that it's highly potent, highly effective, but it is also unfortunately highly toxic. We have about a 55% [rate of] grade 3/4 adverse events with that combination,” he explained. “Again, as we are looking for these checkpoints. There are several that are being studied. One of them is LAG-3; what we know about LAG-3 is that that is also co-expressed with PD-1 quite regularly on exhausted antigen specific exhausted T cells.”

“In preclinical models when you block PD-1 and you blocked LAG-3 with it that had shown quite a bit of synergy,” Tawbi continued. “The idea of being able to combine those in patients to improve their outcomes has been in study now for several years… there were definite durable response rates in patients that had already progressed on prior PD-1 or PD-1 and CTLA-4.”

“Based on that safety and clinical activity, RELATIVITY-047 was designed to study the same combination, but this time in patients with previously untreated metastatic melanoma: patients [who] are treatment naïve that have not experienced treatment with anti–PD-1 before.”

Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. 

 2022;386(1):24-34. doi: 10.1056/NEJMoa2109970

Videos

Dr. Hussein Tawbi, MD, PhD, explains the rationale behind the RELATIVITY-047 trial in melanoma and how the LAG-3 findings could further revolutionize immunotherapy. 



 Expert Explains Rationale Behind RELATIVITY-047 in Melanoma

Patients with cancer initiating immunotherapy treatment should be encouraged to adopt a fiber-rich diet, according to Jennifer McQuade, MD.

McQuade, an assistant professor of medical melanoma oncology at The University of Texas MD Anderson Cancer Center, recently spoke with 

® about recently published study findings, which suggest that high-fiber diets and lower probiotic use may be associated with improved immunotherapy response rates among patients with melanoma.

“I would avoid over-the-counter supplements, and then, as far as diet, [we looked at] our patients’ habitual diet,” McQuade explained. “The question now really is, ‘can we actually change a patient's diet and then change their microbiome and potentially influence their outcomes?’”

“That's the ongoing clinical intervention study that we have now—we actually are doing dietary interventions. In the meantime, the question is, ‘what do we tell our patients now?’ Fortunately, a diet that's high in fiber is the same diet that's recommended by the American Cancer Society, and by the American Institute for Cancer Research. We know that this diet is associated with a lower risk of cancer in general, it is associated with lower risks of cardiovascular disease, and it's really consistent with a diet that is recommended for the US population in general.”

“The recommendation is getting at least 20 to 25 grams of fiber per day, and most of the average US population consumes, on average, 15 to 17 grams of fiber per day,” she concluded.

An expert from The University of Texas MD Anderson Cancer Center offers advice on the best diet to enrich a patient’s microbiome and consequent immunotherapy response. 

Nurses May Advise Patients on Immunotherapy to Increase Fiber Intake

Diet and supplement use may influence the microbiome and subsequent responses to immunotherapy, according to Jennifer McQuade, MD.

McQuade, an assistant professor of medical melanoma oncology at The University of Texas MD Anderson Cancer Center, recently spoke with 

“We know that the microbiome is actually mostly not genetically determined, but shaped by our environment, and very specifically by things that we consume,” said McQuade. “What we did [was conduct] a cohort study where we asked our patients about diet and supplement use when they were starting immunotherapy, and we were collecting microbiome specimens.”

“We found that patients that were consuming a high-fiber diet were actually significantly more likely to respond to immunotherapy. This is consistent with the fact that the bacteria that have been associated with response are bacteria that have no roles in fiber fermentation.”

“We followed up that finding with preclinical studies,” she concluded. “In mice, we actually found that by doing fiber deprivation, and fiber manipulation, we are able to then change response to cancer immunotherapy. On the flip side, [when] we also looked at probiotic use, we found that 31% of our patients were actually taking over the counter probiotics—and that's probably driven by all of the attention that the microbiome has been getting—but those patients were actually less likely to respond to immunotherapy.”

An expert from The University of Texas MD Anderson Cancer Center highlights findings demonstrating the impact that diet and probiotics have in immunotherapy responses.

Diet and Probiotics Influence Immunotherapy Responses in Melanoma

A fiber-rich diet may help improve the efficacy of immunotherapy in patients with melanoma, according to data published in 

 Notably, this benefit was most pronounced among patients who were not taking probiotic supplements.

Specifically, patients who reported eating a sufficiently fiber rich diet experienced improved progression-free survival (PFS; n =37) compared with those who reported insufficient fiber intake (n = 91). The PFS between these 2 groups were not reached vs 13 months, respectively. Furthermore, data revealed that a daily fiber increase of 5 grams was linked to a 30% reduction in the risk of disease progression or death.

Similarly, 82% of patients who adhered to a sufficient fiber intake without probiotic use experienced a response to immunotherapy compared with 59% of patients who either had insufficient fiber intake or probiotic use.

“It definitely shows that we need to use caution with patients using over-the-counter probiotics,” first study author Jennifer McQuade, MD, assistant professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, said in an interview with 

®. “That doesn't mean that there's not a role for rationally designed probiotics, but it needs to be thoughtful, and we need to think about it. We need to [assess probiotics] within the context of clinical trials. Therefore, I would avoid over-the-counter supplements.”

Researchers assessed the gut microbiome profiles from 438 patients with melanoma. Eighty-seven percent of these patients were receiving immune checkpoint blockade (ICB) and the most common ICB were PD-1 inhibitors. In addition, 158 patients also completed a lifestyle survey regarding antibiotic and probiotic usage and, among these patients, 128 responded to a dietary questionnaire upon initiation of ICI therapy. Findings were compared against data from preclinical studies.

Furthermore, stratification between lower and higher fiber diets, along with probiotic use, revealed that, in multiple models, probiotic use drove impaired response to immune checkpoint blockade, and was associated with large tumors, reduced gut microbiome diversity, and a decrease in cytotoxic T cells in the tumor microenvironment. In contrast, a higher frequency of CD4+ T cells and slower tumor growth were associated with the high-fiber diet.

“As far as diet, [we looked at] our patients’ habitual diet,” McQuade explained. “The question now really is, ‘can we actually change a patient's diet and then change their microbiome and potentially influence their outcomes?’”

Fortunately, a diet that is high in fiber, or has around 20 to 25 grams of daily fiber, is the same diet that is current recommended by both the American Cancer Society and by the American Institute for Cancer Research, McQuade said.

“We know that this diet is associated with a lower risk of cancer in general, it is associated with lower risks of cardiovascular disease, and it's really consistent with a diet that is recommended for the US population in general,” she added. “While we don't yet have definitive data showing that if somebody makes a change in their diet, they can then influence outcomes, this is a diet that really has no real downsides, and is, again, consistent with what we would otherwise be promoting.”

In addition, the findings have propelled the design of a randomized clinical trial (

), which will seek to determine how a whole-food–based diet with high fiber can impact the microbiome and play a role in immune response. The trial is currently enrolling patients who have stage II to IV melanoma and who are receiving immunotherapy.

“We actually completed our phase 1 feasibility study in melanoma survivors, and we have shown already that the diet is well tolerated,” McQuade concluded. “Patients like the diet. They're able to comply with the diet and everybody was able to reach a target of 35 to 50 grams of fiber per day without issue. Our study now is [with] patients that are actively receiving immunotherapy and we're testing 2 different healthy diets with different fiber content.”

Spencer NC, McQuade JL, Gopalakrish V, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. 

. 2021;274(6575):1632-1640. doi:10.1126/science.aaz7015

New data support increased fiber consumption and decreased probiotic use among patients receiving immunotherapy.

High-Fiber Diets Strengthen Immunotherapy Responses in Patients With Melanoma

The combination of the immune checkpoint inhibitors relatlimab and nivolumab (Opdivo) demonstrated safety and efficacy as a treatment for patients with untreated, advanced melanoma, according to results of the RELATIVITY-047 trial (NCT03470922) that were published in the 

Moreover, the data indicate that lymphocyte-activation gene (LAG-3) inhibition with relatlimab may represent a third therapeutically relevant immune checkpoint pathway.

Findings from the double-blind, international, phase 2/3 RELATIVITY-047 trial revealed that patients who received the combination achieved a median progression-free survival (PFS) of 10.1 months (95% CI, 6.4-15.7) compared with a median PFS of 4.6 months (95% CI, 3.4-5.6) among patients who received nivolumab as monotherapy (HR, 0.75; 95% CI, 0.62-0.92; 

At a 12-month follow-up, the PFS between cohorts was 47.7% (95% CI, 41.8-53.2) among combination recipients compared with 36.0% (95% CI, 30.5-41.6) among those on nivolumab alone. Results were consistent across pre-defined subgroups, such as 

 status, tumor stage, and lactate dehydrogenase (LDH) levels, as well as LAG-3 and PD-1 expression.

LAG-3 is an immune checkpoint inhibitor located on the surface of T cells. Along with PD-1, this immune checkpoint is frequently upregulated in patients with melanoma. The findings from this study symbolize the first phase 2/3 trial to examine this immune checkpoint inhibitor.

“The results from this global effort advance the field of immunotherapy by establishing a third class of immune checkpoint inhibitors through the LAG-3 pathway and have the potential to be practice-changing,” lead study author Hussein Tawbi, MD, PhD, professor of melanoma medical oncology, of The University of Texas MD Anderson Cancer Center, said in a news release.

“We’ve seen historic developments in melanoma treatment over the last decade with the combination of PD-1 and CTLA-4 inhibitors, which work well but also carry substantial toxicity. This study represents a significant and long-awaited next step toward providing patients with effective and safer treatment options.”

RELATIVITY-047 enrolled a total of 714 patients with untreated, unresectable stage III or IV melanoma between May 2018 and December 2020. Participants were enrolled from over 111 international sites and randomized to receive either the combination or nivolumab alone once every 4 weeks.

A small percentage of patients (8.4%) had received prior neoadjuvant or adjuvant therapy prior to recurrence or had received interferon in the 6 weeks prior to randomization. In addition, 96% of participants were White, 41.7% were female, and the median age was 63 years (range, 20-94).

The median follow-up at the data cutoff point (March 9, 2021) was 13.2 months. At this follow-up, 470 patients overall reported treatment discontinuation (65.8%), the most cited reason being disease progression. In the combination arm, the rate of progression was 33.6% compared with 46.0% in the monotherapy arm.

Regarding safety, no new safety signals were detected. However, 18.9% of patients receiving the combination regimen reported grade 3 or 4 treatment-related adverse events (AEs) compared with 9.7% among those receiving nivolumab. Increased levels of pancreatic and liver enzymes, as well as fatigue, were the most cited severe AEs. There were also 3 reported deaths in the experimental arm and 2 deaths in the monotherapy arm, which were all determined to be treatment related.

Patients also reported immune-related AEs, including hypothyroidism/thyroiditis, rash, and colitis. Health-related quality of life was reported to be similar between the 2 groups.

“We now have evidence of a clear benefit for combination therapy compared to single-agent PD-1 inhibitors, and we’re looking forward to seeing response and overall survival data,” Tawbi concluded. “We’re also thinking about the populations that were excluded from this trial, including those with untreated brain metastases and uveal melanoma, so that all patients can have a chance to take advantage of the progress we are making against melanoma.”

Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. 

 2022;386(1):24-34. doi: 10.1056/NEJMoa2109970



Relatlimab plus nivolumab improves progression-free survival in metastatic melanoma. The University of Texas MD Anderson Cancer Center. News release. January 5, 2021. Accessed January 6, 2021. https://bit.ly/3q0xjX9

A novel regimen of relatlimab, an LAG-3 inhibitor, plus nivolumab doubled progression-free survival in patients with untreated, advanced melanoma.

Novel Immunotherapy Combination Shows Promise in Metastatic Melanoma

Fast-mimicking dieting (FMD) was found to be safe, feasible, and potentially beneficial for patients with various solid tumor types and who were receiving different anticancer therapies, according to a study published in 

. The diet, which involved short-term, severe caloric restriction was associated with a decrease in blood glucose and growth factor concentration, as well as a reduction in peripheral blood immunosuppressive cells, and enhanced intratumor T-cell infiltration, among this population.

Among 99 evaluable participants, the median plasma glucose concentration reduction was 18.6%, the serum insulin reduction was 50.7%, and the serum IGF-1 reduction was 30.3%. Throughout the 8 consecutive cycles, these results remained consistent.

“Our results from a first-in-human clinical trial showed that a scheme of severe short-term calorie restriction was safe and biologically active in patients, and that its activity likely involved the activation of immune responses,” said co-author Claudio Vernieri, MD, PhD, Fondazione IRCCS Istituto Nazionale dei Tumori and the director of the Metabolic Reprogramming in Solid Tumors program at the FIRC Institute of Molecular Oncology, in Milan, Italy, in a press release. “Since calorie restriction is a safe, inexpensive, and potentially effective approach that could be easily combined with standard antineoplastic therapies, we think these findings might have relevant implications for cancer therapy.”

The study assessed a total of 101 patients. These participants had a variety of tumor types and were receiving various standard anticancer therapies. The global compliance rate among these participants was 91.8%; compliance in this case was defined as observing all 8 FMD cycles.

The most common adverse event (AE) associated with the dieting technique was fatigue and was rarely severe (12.9%). Thus, the trial met its primary safety end point.

The diet itself involved the following cycle: 5-days of low-carbohydrate, low-protein, plant derived dieting amounting to a total of 1800 calories (600 calories on day 1 and 300 calories on the subsequent 4 days). This cycle was followed by a period or regular eating for about 3 to 4 weeks and followed by another cycle. The study period involved 8 total cycles. When patients were not observing the FMD cycle, they were not restricted to any dietary regulations, but were encouraged to adhere to a healthy diet and lifestyle.

The loss of body weight that occurred during the 5 days of severe calorie restriction was reversible in most of the patients during the refeeding period.

“This is an especially important finding, because it excludes the risk that patients might undergo progressive weight loss and/or malnourishment, which are associated with reduced efficacy of anticancer therapies and reduced survival,” added Filippo de Braud, MD, director of the Oncology and Hematology Department of Fondazione IRCCS Istituto Nazionale dei Tumori and professor of medical oncology at the University of Milan in Milan, Italy.

Researchers determined that at the conclusion of the 5-day restricted calorie diet, patients had a significant decrease in circulating immunosuppressive myeloid subpopulations and an increase of activated CD8+ T cells. Notably, the various concomitant antitumor therapies did not impact these results. Additionally, a group of cancer-free volunteers also produced the same effects.

To corroborate the findings, researchers also performed an interim analysis of another ongoing trial (DigesT; NCT03454282). Patients in this trial were asked to complete a 5

day FMD cycle 7 to 10 days before undergoing surgery for early-stage breast cancer or melanoma. The tumor-infiltrating immune cells and transcriptomic immune profiles revealed a significant increase in tumor-infiltrating CD8+ T cells and other changes, suggesting that FMD induces an antitumor immune microenvironment.

The study authors concluded that the experimental diet generated favorable immunomodulatory effects at both the systematic and the tumor level. These findings indicate that a coherent immune response originates in the blood and consequently propagates to the tumor.

The main study limitations are related to the heterogeneous nature of the participants; because the patients all had different tumor type and concomitant anticancer therapies, researchers could not conclude the antitumor efficacy of the caloric restriction.

Consequently, the authors have helped to launch a series of new clinical trials, including the BREAKFAST trial (NCT04248998), which will seek to better understand the antitumor effects of the FMD diet among patients with solid tumors. Researchers hope to uncover ways in which diet and caloric restrictions may improve the potency of antineoplastic therapies and potentially prolong the life expectancy of patients in this population.

Fasting-mimicking diet is safe, may modulate metabolism and boost antitumor immunity in cancer patients. American Association for Cancer Research. News release. November 17, 2021. Accessed November 29, 2021. https://bit.ly/3ELIaZS

Patients with various solid tumor types experienced improved antitumor immunity after adhering to a diet with severe caloric restrictions.

Fast-Mimicking Diet Is Potentially Beneficial for Patients With Solid Tumors

Pembrolizumab (Keytruda) has been granted an FDA approval on the indication of adults and pediatric patients (aged 12 and older) with stage IIB or IIIC melanoma following complete resection.

The regulatory agency also expanded the indication for the immunotherapy for adjuvant use in patients with stage III melanoma following CR to include pediatric patients aged 12 years and older.

The indication for the agent's use in patients with stage IIB and IIC melanoma is based on findings from the first interim analysis of the phase 3 KEYNOTE-716 trial (NCT03553836), in which pembrolizumab resulted in a statistically significant improvement in recurrence-free survival (RFS), reducing the risk of disease recurrence or death by 35% (HR, 0.65; 95% CI, 0.46-0.92; 

= .0132) vs placebo. Specifically, the median RFS was not reached in either treatment arm.

After a median follow-up of 14.4 months, 11% (n = 54/487) of patients who received the immunotherapy experienced a recurrence or died vs 17% (n = 82/489) of those who were given placebo.

Efficacy in pediatric patients, aged 12 years and older, who had stage IIB, IIC and III melanoma is supported by extrapolation of efficacy findings from adults, given similar biology, pharmacology of drug effect, as well as similar exposure-response for efficacy and safety.

“The standard of care for patients with resected stage IIB and IIC melanoma has been observation, despite the fact that for these patients, the risk of recurrence is nearly the same as for patients with later-stage disease for whom treatment is recommended,” Jason Luke, MD, director, Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center, stated in a press release. “Today’s approval of pembrolizumab for the adjuvant treatment of patients 12 years and older with stage IIB and IIC melanoma following complete resection is an important advance that provides these patients with a new option that can help reduce the risk of their cancer returning.”

The multicenter, double-blind, placebo-controlled phase 3 trial enrolled a total of 976 patients with completely resected stage IIB or IIC melanoma. Study participants were randomized to receive 200 mg of pembrolizumab or the pediatric dose of 2 mg/kg every 3 weeks or placebo for up to 1 year until either recurrence or intolerable toxicity. Patients were stratified based on AJCC eighth edition T Stage (> 2.0-4.0 mm with ulceration vs > 4.0 mm without ulceration vs > 4.0 mm with ulceration).

The main efficacy outcome measure for the trial was investigator-assessed RFS.

Regarding safety, adverse effects that were reported in those with stage IIB or IIC melanoma were comparable to those reported in 1011 patients with stage III melanoma from the phase 3 KEYNOTE-054 trial (NCT02362594) or the 2799 patients with melanoma or non–small cell lung cancer treated with the immunotherapy as a monotherapy.

FDA approves Merck's KEYTRUDA (pembrolizumab) as adjuvant treatment for adult and pediatric (≥12 years of age) patients with stage IIB or IIC melanoma following complete resection. News release. Merck; December 3, 2021. Accessed December 3, 2021. https://bit.ly/3DrqYal

This article was originally published on OncLive as “FDA Approves Adjuvant Pembrolizumab for Stage IIB or IIC Melanoma Following CR”

Pembrolizumab has been approved for the adjuvant treatment of adults and pediatric patients with stage IIB or IIC melanoma who have underwent complete resection.

FDA Oks Adjuvant Pembrolizumab for Adult and Pediatric Melanoma Following Complete Resection

Patients receiving immune checkpoint inhibitors (ICIs) for renal cell carcinoma (RCC) or melanoma were able to safely tolerate the COVID-19 vaccine, according to findings from a retrospective chart review presented during the 2021 SITC Annual Meeting.

COVID-19 poses a significant threat to patients with cancer or receiving anticancer treatment, commented study co-author Hannah Dzimitrowicz, MD, highlighting the importance of being able to safely vaccinate this population.

“In a solid tumor population at high risk for severe COVID-19 infections, vaccination is important to mitigate this risk,” said Dzimitrowicz, a medical instructor in the department of medicine at the Duke University School of Medicine in Durham, North Carolina. “In a heterogeneous population of patients with RCC and melanoma receiving immune checkpoint inhibitor therapy, COVID-19 vaccination appears to be well tolerated and safe.”

Vaccines appeared to be effective in this patient population. Two patients in the ICI group (n = 74) developed COVID-19 infection after 1 vaccine dose and no patients developed COVID-19 infection after 2 doses.

Although patients receiving active cancer treatment were excluded from COVID-19 vaccine trials, major oncologic organizations including the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend vaccination.

To evaluate the safety and tolerability of COVID-19 vaccines in this population, Dzimitrowicz and her colleagues used electronic medical records to identify all patients who received at least 1 dose of an FDA-authorized COVID-19 vaccine from December 1, 2020, to April 1, 2021, had received ICI at the time of vaccination, and had at least 3 months of documented follow up at Duke Cancer Center.

They then compared safety results for those who received ICIs (n = 74) vs those who did not (n = 74). Safety outcomes measured included adverse events (AEs) attributed to vaccination, immune-related AEs (irAEs) following vaccination, and incidence of subsequent COVID-19 infections.

The proportion of patients with RCC (49%) and melanoma (51%) was the same in both cohorts.

The median age was 70 years (range, 33 to > 90) in the ICI cohort compared with 73 years (range, 35-88) in the control group. The experimental group was primarily male (70%) while the control group was more balanced (51%).

Most patients in the ICI group received the Pfizer vaccine (62%), followed by Moderna (35%) and Johnson & Johnson (3%). In the control group, those numbers were 83%, 16%, and 1%, respectively.

Half of patients received nivolumab (Opdivo), 16% received pembrolizumab (Keytruda), 15% received nivolumab plus cabozantinib (Cabometyx), 10% received nivolumab plus ipilimumab (Yervoy), 7% received pembrolizumab plus axitinib (Inlyta), and 1% received ipilimumab.

One patient in the control group reported fatigue and arm pain. Twenty percent of patients in the ICI group reported at least 1 AE including fevers (7%), chills (7%), myalgias (7%), arm pain (5%), headache (5%), fatigue (5%), diarrhea (3%), erythema at the injection site (3%), and nausea and vomiting (1%).

“It is important to note that all of these symptoms reported by patients were mild and none resulted in hospitalizations or treatment interruption,” Dzimitrowicz said.

Investigators also recorded AEs that patients or clinicians thought could be attributed to vaccination. One patient in the ICI group developed porokeratoses following the second vaccine dose. One patient in the control group developed a stye and 1 developed premature ventricular contractions.

Nine (12%) patients in the ICI cohort developed a new or worsening irAE that required a treatment hold, systemic steroids, and/or hospital admission. The most common irAE was colitis (n = 4). Two patients developed hepatitis and 1 patient each developed pancreatitis, gastritis, dermatitis, and adrenal insufficiently.

Dzimitrowicz pointed out that these data reflect the experience at a single institution, and physicians saw patients undergoing active therapy more frequently, so those patients had more opportunities to report AEs. She also pointed out that the study did not include to patients receiving concurrent cytotoxic chemotherapy, thus limiting applicability to that group

“It’s important to note that larger cohort studies of patients receiving immune checkpoint inhibitors are needed to fully assess the safety and efficacy of COVID-19 vaccination in this population,” she said. “Despite these limitations, this study provides valuable information regarding the safety of COVID-19 vaccination in patients receiving immune checkpoint inhibitors in real world practice.”

Hwang JK, Dzimitrowicz H, Riddhishkumar S, et al. COVID-19 vaccination in patients with renal cancer or melanoma receiving immune checkpoint inhibitors. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 625. https://jitc.bmj.com/content/9/Suppl_2/A655

This article was originally published on OncLive as “Patients with RCC, Melanoma Taking ICIs Can Safely Receive COVID-19 Vaccination”

Patients receiving immune checkpoint inhibitors for renal cell carcinoma or melanoma responded well to the COVID-19 vaccine. 

COVID-19 Vaccine Appears Well Tolerated in Patients with RCC, Melanoma Receiving Immune Checkpoint Inhibitors 

Patients with resected high-risk stage II melanoma continued to experience superior relapse-free survival (RFS) following treatment with adjuvant pembrolizumab (Keytruda) compared with placebo after 6 months of additional follow-up, according to data from the second interim analysis of the phase 3 KEYNOTE-716 trial (NCT03553836).

Data, which were presented during the 2021 Society for Melanoma Research Congress, showed that the median RFS had not yet been reached (NR) with either pembrolizumab (95% CI, NR–NR) or placebo (95% CI, 29.9–NR; hazard ratio [HR], 0.61; 95% CI, 0.45-0.82). The 18-month RFS rates in the investigative and control arms were 85.8% and 77.0%, respectively.

Moreover, the HR for RFS at the time of the second interim analysis was further improved compared with that reported at the first analysis (HR, 0.65; 95% CI, 0.46-0.92; 

= .00658), and RFS continued to favor the immunotherapy across all key subgroups evaluated.

“With 6 months of additional follow-up, pembrolizumab continued to be associated with a reduction in the risk of disease recurrence or death compared with placebo and had a manageable safety profile,” lead study author Jason J. Luke, MD, of UPMC Hillman Cancer Center, said in a presentation on the data.

It is known that patients who have stage IIB and IIC melanoma are at increased risk of disease recurrence and experience outcomes that are comparable to what is seen in those with stage IIIA and IIIB disease. For those with stage II disease, current guidelines call for wide excision and observation or participation on a clinical trial examining adjuvant therapy.

KEYNOTE-716 enrolled patients with newly diagnosed, resected, high-risk stage II melanoma who were at least 12 years of age and who had an ECOG performance status of 0 or 1. In part 1 of the study, participants were randomized 1:1 to receive either intravenous (IV) pembrolizumab at 200 mg every 3 weeks or 2 mg/kg for pediatric patients (n = 487), or IV placebo every 3 weeks (n = 489). Treatment was administered for 17 cycles.

Upon recurrence, patients moved to the second portion of the trial. Those in the investigative arm were rechallenged with pembrolizumab, given at the same dose and schedule as part 1, and those in the control arm crossed over to receive the immunotherapy. Treatment was given until disease progression or recurrence or for up to 2 years.

Patients were stratified based on T category (3b vs 4a vs 4b) and pediatric status.

The primary end point of the trial was investigator-assessed RFS, and key secondary end points included distant metastasis-free survival, overall survival, and safety. Health-related quality of life (HRQoL) served as an exploratory end point.

Of the 487 patients allocated to receive pembrolizumab, 483 received treatment. At the time of data cutoff, 24 were still receiving treatment, 297 completed treatment, and 162 patients discontinued. The majority of those who discontinued did so because of adverse effects (AEs; n = 85), followed by patient withdrawal (n = 39), relapse or recurrence (n = 25), physician decision (n = 9), or a protocol violation (n = 4).

Of the 489 patients who were randomized to the control arm, 486 received treatment with 17 patients still on treatment and 353 having completed therapy. A total of 116 patients discontinued treatment on this arm, with most patients doing so because of relapse or recurrence (n = 60), followed by patient withdrawal (n = 26), toxicities (n = 23), physician decision (n = 4), and a protocol violation or another reason (n = 3).

The median time from randomization to date of death or database cutoff was 20.5 months (range, 4.6-32.7). The median treatment duration was 11.1 months with pembrolizumab (range, 0.0-16.4) and 11.1 months (range, 0.0-15.6) with placebo.

Across the arms, the median age was 60.5 years, and most patients were between the ages of 18 years and 64 years. Moreover, most patients were male, White, not from the United States, had an ECOG performance status of 0, a T category of 3b, and had stage IIB disease.

Results from the first interim analysis showed that the immunotherapy significantly reduced the risk of disease recurrence or death vs placebo in this patient population.2 At a median follow-up of 14.4 months, the proportion of patients with distant recurrence was 4.7% with pembrolizumab vs 7.8% with placebo. The rates of grade 3 or 4 treatment-related AEs (TRAEs) in the investigative and control arms were 16.1% and 4.3%, respectively. No grade 5 toxicities were reported, and HRQoL was noted to be maintained with the immunotherapy.

Additional updated data from a sensitivity analysis including primary melanoma showed that the median RFS had not yet been reached for either the pembrolizumab arm (95% CI, NR–NR) or the placebo arm (95% CI, 29.9–NR; HR, 0.60; 95% CI, 0.45-0.79).

Among those with T3b disease, the median RFS had not yet been reached in the investigative arm (95% CI, NR–NR) and in the control arm (NR–NR; HR, 0.40; 95% CI, 0.23-0.69). The 18-month RFS rates in the pembrolizumab and placebo arms were 91.1% and 77.4%, respectively.

In the subgroup of patients with T4a disease, the median RFS had not yet been reached (95% CI, 24.9–NR) with the immunotherapy vs 29.9 months (95% CI, 28.2–NR) with placebo (HR, 0.49; 95% CI, 0.24-1.00). The 18-month RFS rates in the investigative and control arms were 90.4% and 81.8%, respectively.

In those with T4b disease, the median RFS had not yet been reached (95% CI, 24.2–NR) with pembrolizumab or placebo (95% CI, 25.2–NR; HR, 0.82; 95% CI, 0.54-1.26). The 18-month RFS rate in the investigative arm was 78.9% vs 74.1% in the control arm.

When looking at patterns of recurrence, 85.2% of patients who received pembrolizumab (n = 487) did not experience a RFS event vs 76.5% of those who were given placebo (n = 489). Conversely, 14.8% of those on the investigative arm and 23.5% of those on the control arm experienced an RFS event.

Among those who did have an event and received the immunotherapy, 7.8% had local or regional or locoregional recurrence and 6.4% experienced distant recurrence; these rates were 10.2% and 12.3%, respectively, in those who were given placebo. Three patients on the investigative arm died vs 5 on the control arm.

Regarding safety, 95.4% of those on the pembrolizumab arm (n = 483) experienced any-grade AEs vs 91.4% of those on the placebo arm (n = 486); 28.2% and 19.1% of patients, respectively, reported grade 3 to 5 toxicities. Moreover, 82.8% of those who received the immunotherapy experienced treatment-related AEs (TRAEs) vs 63.4% of those who received placebo; 17.0% and 4.3% of patients, respectively, experienced grade 3 to 5 TRAEs.

Moreover, 16.4% of patients on the immunotherapy experienced a toxicity that resulted in treatment discontinuation vs 2.5% of those on placebo. No toxicities resulted in death.

Additionally, 37.7% of those on the investigative arm and 9.1% of those on the control arm reported immune-mediated AEs. Grade 3 or 4 immune-mediated AEs occurred in 10.1% of those who received pembrolizumab and 1.2% of those given placebo.

AEs of special interest included hypothyroidism, hyperthyroidism, severe skin reactions, colitis, hypophysitis, adrenal insufficiency, hepatitis, pneumonitis, thyroiditis, myositis, nephritis, sarcoidosis, infusion reactions, myasthenic syndrome, pancreatitis, T1DM, uveitis, myelitis, and myocarditis.

Among the 107 patients who had an event of interest in the investigative arm, 20.3% received hormonal therapy. Among the 18 patients with an event of interest in the control arm, 1.2% received hormonal therapy.

Luke JJ, Long GV, Khattak MA, et al. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: updated results from the KEYNOTE-716 trial. Presented at: 2021 Society for Melanoma Research Congress; October 28-31, 2021; virtual.

Luke JJ, Rutkowsi P, Queirolo P, et al. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. 

. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741

This article was originally published on OncLive as “Adjuvant Pembrolizumab Maintains RFS Benefit in Resected High-Risk Stage II Melanoma”

After 6 months of additional follow-up, patients with resected high-risk stage II melanoma continued to experience improved relapse-free survival following treatment with adjuvant pembrolizumab. 

Skin Cancer/Melanoma