Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) experienced significantly improved overall survival (OS) and progression-free survival (PFS) following frontline treatment with liposomal irinotecan (Onivyde) plus 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (NALIRIFOX) compared with nab-paclitaxel (Abraxane), according to findings from the phase 3 NAPOLI 3 trial (NCT04083235).

Findings presented at the 2023 Gastrointestinal Cancers Symposium showed that at a median follow-up of 16.1 months (95% CI, 15.3-16.8), patients in the intent-to-treat (ITT) population who were administered liposomal irinotecan plus NALIRIFOX (n = 383) experienced a median OS of 11.1 months (95% CI, 10.0-12.1) compared with 9.2 months (95% CI, 8.3-10.6) for those given nab-paclitaxel plus gemcitabine (n = 387; HR, 0.83; 95% CI, 0.70-0.99; 

“These results support the NALIRIFOX regimen as a new regimen for the first-line treatment of patients with metastatic PDAC. [The regimen represents] something we can hopefully build off in the future,” lead study author Zev A. Wainberg, MD, a professor of medicine at University of California, Los Angeles (UCLA) and co-director of the UCLA GI Oncology Program, said in a presentation of the data.

Based on the findings of NAPOLI 3, Ipsen plans to file a supplemental new drug application seeking the approval of liposomal irinotecan plus NALIRIFOX in this patient population in the United States.

 In October 2015, the FDA approved liposomal irinotecan plus 5-FU/leucovorin for the treatment of patients with metastatic PDAC after progression with gemcitabine-based treatment.

The randomized, open-label NAPOLI 3 study evaluated the efficacy and safety of liposomal irinotecan plus NALIRIFOX vs nab-paclitaxel plus gemcitabine in patients with confirmed metastatic PDAC who were previously untreated in the metastatic setting. Patients were required to have metastatic disease diagnosed no more than 6 weeks prior to screening, at least 1 metastatic lesion measurable by MRI or CT scan per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.

Enrolled patients were randomly assigned 1:1 to 50 mg/m

 of oxaliplatin on days 1 and 15 of each 28-day cycle, or 1000 mg/m

 of nab-paclitaxel on days 1, 8, and 15 of each 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal. Tumor assessment was conducted every 8 weeks per RECIST v1.1 criteria, and follow-up continued until death or study conclusion.

Stratification factors included ECOG performance status (0 vs 1), region, and presence or absence of liver metastases.

OS served as the trial’s primary end point. Secondary end points included investigator-assessed PFS, overall response rate (ORR) per RECIST v1.1 criteria, and safety. Health-related quality of life and biomarker assessments were exploratory end points.

Statistical analysis consisted of a stratified long-rank test with a 2-sided alpha of 0.05 and 90% power. Analysis occurred after at least 543 OS events in the ITT population in a stepwise hierarchical test for efficacy. The 

 boundary for efficacy at the final analysis was < .048.

At the July 23, 2022, data cutoff, 85.1% of patients in the experimental arm discontinued treatment compared with 96.1% in the control arm. The primary reasons for discontinuation in the liposomal irinotecan/NALIRIFOX arm were progressive disease (48%), adverse effects (AEs; 14.1%), death (8.4%), or other (14.7%). In the nab-paclitaxel/gemcitabine arm, those rates were 45.7%, 23.8%, 6.7%, and 19.9%, respectively.

Baseline characteristics were similar across both treatment arms. The median age was 64 years (range, 20-85) and 65 years (range, 36-82) in the liposomal irinotecan/NALIRIFOX and nab-paclitaxel/gemcitabine arms, respectively. The majority of patients in both arms were male (53.3% and 59.4% for the experimental and control arms, respectively), White (82.2% and 83.7%), had an ECOG performance status of 1 (58.0% and 56.6%), had liver metastases (80.2% and 80.4%), were treated in the rest of the world outside of North America and East Asia (65.8% and 65.6%), had their main tumor located outside the head of the pancreas (61.6% and 59.7%), and had a baseline CA 19-9 level of at least 37 U/mL (83.8% and 81.7%).

The median time from metastatic diagnosis at study entry was 3.00 weeks (range, 0.6-9.1) for the liposomal irinotecan/NALIRIFOX group and 3.57 weeks (range, 0.4-10.9) for the nab-paclitaxel/gemcitabine group.

Additional data showed the patients in the liposomal irinotecan/NALIRIFOX arm achieved a median PFS of 7.4 months (95% CI, 6.0-7.7) compared with 5.6 months (95% CI, 5.3-5.8) for the nab-paclitaxel/gemcitabine arm (HR, 0.69; 95% CI, 0.58-0.83; 

Liposomal irinotecan/NALIRIFOX elicited an ORR of 41.8% (95% CI, 36.8%-46.9%) vs 36.2% (95% CI, 31.4%-41.2%) for nab-paclitaxel/gemcitabine. The complete response rate was 0.3% in both arms. In the liposomal irinotecan/NALIRIFOX arm, the rates of partial response, stable disease, and progressive disease were 41.5%, 25.8%, and 9.9%, respectively. In the nab-paclitaxel/gemcitabine arm, those rates were 35.9%, 26.1%, and 14.5%, respectively. Additionally, 22.5% and 23.3% of patients from the liposomal irinotecan/NALIRIFOX and nab-paclitaxel/gemcitabine arms, respectively, were not evaluable for response.

In the experimental arm, 50.5% of patients underwent subsequent anticancer therapy, including 50.5% who had systemic anti-neoplastic therapy, 0.3% who had surgery, and 0.5% who received radiotherapy. In the nab-paclitaxel/gemcitabine arm, 54.4% of patients received subsequent anticancer therapy, including 54.1% who had systemic anti-neoplastic therapy, 0.5% who had surgery, and 1.1% who had radiotherapy.

Among patients evaluable for safety, patients treated with liposomal irinotecan/NALIRIFOX (n = 370) had a median treatment duration of 24.29 weeks (range, 0.4-100.9) compared with 17.57 weeks (range, 0.7-81.7) for those in the nab-paclitaxel/gemcitabine arm (n = 379).

Any-grade treatment-emergent AEs (TEAEs) occurred in 99.7% and 99.2% of patients in the experimental and control arms, respectively, and 95.1% and 92.9% had any-grade TEAEs related to the treatment regimen. Grade 3 or higher TEAEs were reported in 87% of patients in the liposomal irinotecan/NALIRIFOX arm and 86% of patients in the nab-paclitaxel/gemcitabine arm, and 70.8% and 68.1%, respectively, had grade 3 or higher TEAEs related to treatment.

Serious TEAEs occurred in 54.3% of patients given liposomal irinotecan/NALIRIFOX, and 26.5% experienced a serious TEAE related to treatment. In those administered nab-paclitaxel/gemcitabine, 51.5% had serious TEAEs, and 19% had serious TEAEs related to treatment. TEAEs leading to death occurred in 5.9% of patients in the liposomal irinotecan/NALIRIFOX group, including 1.6% of patients who died due to a TEAE related to treatment. In the nab-paclitaxel/gemcitabine group, 6.1% of patients experienced a TEAE leading to death, and 2.1% of patients died due to TEAEs related to treatment.

“When one looks at the nuances in the patients and the toxicity profiles, we can see these 2 regimens have very different toxicity profiles,” Wainberg said.

The most common hematologic TEAEs in the experimental and control arms, respectively, included neutropenia (any grade, 29.5% vs 31.9%; grade 3/4, 14.1% vs 24.5%), decreased neutrophil count (20.5% vs 18.7%; 9.7% vs 13.5%), febrile neutropenia (2.4% vs 2.6%; 2.4% vs 2.4%), anemia (26.2% vs 40.4%; 10.5% vs 17.4%), thrombocytopenia (13.5% vs 22.7%; 0.8% vs 3.7%), and decreased platelet count (10.5% vs 17.9%; 0.8% vs 2.4%).

The most common non-hematologic TEAEs in the liposomal irinotecan/NALIRIFOX and nab-paclitaxel/gemcitabine groups, respectively, included diarrhea (any grade, 70.5% vs 36.7%; grade 3/4, 20.3% vs 4.5%), nausea (59.5% vs 42.7%; 11.9% vs 2.6%), vomiting (39.7% vs 26.4%; 7.0% vs 2.1%), hypokalemia (31.6% vs 12.9%; 15.1% vs 4.0%), peripheral neuropathy (17.8% vs 17.4%; 3.2% vs 5.8%), peripheral sensory neuropathy (15.1% vs 13.5%; 3.5% vs 2.9%), paresthesia (11.9% vs 8.7%; 0.3% vs 0.5%), and pyrexia (10.5% vs 23.0%; 0.8% vs 1.6%).

In a discussion of the presentation, Laura Goff, MD, MSCI, an associate professor of medicine, and the executive medical director for the Cancer Patient Care Center at Vanderbilt Ingram Cancer Center, in Nashville, Tennessee, referenced the phase 2 SWOG S1505 trial (NCT02562716) of mFOLFIRINOX vs nab-paclitaxel/gemcitabine in patients with resectable PDAC. She noted that the resectable setting is clinically different from the metastatic setting, and although the randomized SWOG S1505 study was not designed as a head-to-head trial, the similar outcomes between the arms led to the belief that there was not a difference between the regimens.

“I would argue that this randomized trial of NAPOLI 3 should supersede our opinion about the efficacy of these regimens [mFOLFIRINOX and nab-paclitaxel/gemcitabine] in the metastatic setting,” Goff said.

Goff also pointed to safety findings observed with both liposomal irinotecan/NALIRIFOX and nab-paclitaxel/gemcitabine during NAPOLI 3. “High rates of toxicity were seen in both arms, despite the reputation that gemcitabine/nab-paclitaxel is a significantly easier regimen to tolerate. I would argue that the data do not necessarily support that,” Goff said.

Wainberg ZA, Melisi D, Macarulla T, et al. NAPOLI 3: a randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma. 

. 2023;41(suppl 4):LBA661. doi:10.1200/JCO.2023.41.3_suppl.LBA661

Onivyde regimen demonstrated statistically significant improvement in overall survival in previously untreated metastatic pancreatic ductal adenocarcinoma. News release. Ipsen Biopharmaceuticals, Inc. November 9, 2022. Accessed January 20, 2023. 

FDA approves irinotecan liposome to treat pancreatic cancer. News release. National Cancer Institute. November 24, 2015. Accessed January 20, 2023. 

Articles

The median overall survival with frontline liposomal irinotecan/NALIRIFOX was 11.1 months vs 9.2 months with nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma.

Frontline Liposomal Irinotecan/NALIRIFOX Confers OS Benefit in Metastatic Pancreatic Ductal Adenocarcinoma

AstraZeneca has announced that they will be permanently discontinuing Moxetumomab pasudotox-tdfk (Lumoxiti) for the treatment of relapsed/refractory hairy cell leukemia (HCL) in the United States.

The CD22-directed cytotoxin is currently indicated for the treatment of adult patients with relapsed/refractory HCL who have received at least 2 prior lines of therapy, including treatment with a purine nucleoside analog.

The company plans to remove moxetumomab pasudotox from the market in July 2023 and has informed the FDA of its decision. In August 2023, AstraZeneca will advise distributors to halt distribution of the agent and request the return of moxetumomab pasudotox packs.

The company wrote that the decision to withdraw the agent is not related to efficacy or safety.

“There has been very low clinical uptake of [moxetumomab pasudotox] since FDA approval on September 23, 2018, due to the availability of other treatment options and possibly due to the specialized complexity of administration, toxicity prophylaxis, and safety monitoring needs for patients,” the company wrote in the letter.

AstraZeneca advised that physicians should not initiate treatment with moxetumomab pasudotox with immediate effect. Patients currently undergoing treatment with moxetumomab pasudotox had time to complete 6 cycles of therapy as of the November 18, 2022, letter.

Additionally, the company will terminate the PROXY trial (NCT04125290). Investigators initiated the study to satisfy a post-marketing requirement to provide evidence characterizing the safety of moxetumomab pasudotox in patients aged 65 years and older and/or the safety of moxetumomab pasudotox in patients who have moderate renal impairment defined as an estimated glomerular filtration rate of 30-59 ml/min.

The 2018 FDA approval of moxetumomab pasudotox was based on findings from a pivotal phase 3 trial (NCT01829711) that showed the CD22-directed recombinant immunotoxin elicited an objective response rate of 75%. Additionally, 30% of patients experienced a complete remission (CR) lasting more than 180 days.

The trial enrolled patients with relapsed/refractory HCL who received at least 2 prior systemic therapies, including at least 1 purine nucleoside analog. Moxetumomab pasudotox was administered at 40 µg/kg intravenously on days 1, 3, and 5 of each 28-day cycle.

Fifty patients (62.5%) completed a full 6 cycles of treatment. Patients most commonly discontinued treatment due to CR with minimal residual disease (MRD) negativity (15%) and adverse effects (AEs; 15%).

Updated findings from the trial showed that at a median follow-up of 24.6 months, moxetumomab pasudotox the durable CR rate (CR with hematologic remission [HR] of more than 180 days) of 36% (95% CI, 26%-48%), a CR with HR of at least 360 days of 33%, and an overall CR of 41%.

 Twenty-seven complete responders (82%) were MRD-negative, and 61% of complete responder achieved a CR lasting at least 60 months. The median progression-free survival without the loss of HR was 71.7 months.

The FDA approved the agent with a Boxed Warning regarding the potential for grade 3/4 capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS), which occurred in 2.5% and 5% of patients, respectively. Updated data also showed that hemolytic uremic and capillary leak syndromes were each reported in no more than 10% of patients, and no more than 5% of patients experienced grade 3 or 4 adverse effects [AEs], and AEs were generally reversible. No treatment-related deaths were reported.

 (moxetumomab pasudotox-tdfk) for injection, for intravenous Use – permanent withdrawal of LumoxitiI from the US market. Astrazeneca. November 18, 2022. Accessed January 13, 2023. 

FDA approves moxetumomab pasudotox-tdfk for hairy cell leukemia. News release. FDA. September 13, 2018. Accessed January 13, 2023. 

US post-marketing safety study of moxetumomab pasudotox-tdfk (Lumoxiti) (PROXY). ClinicalTrials.gov. Updated December 9, 2022. Accessed January 13, 2023. 

https://clinicaltrials.gov/ct2/show/NCT04125290

Kreitman RJ, Dearden C, Zinzani PL, et al. Moxetumomab pasudotox in heavily pretreated patients with relapsed/refractory hairy cell leukemia: Results of a pivotal international study. 

. 2018;32(8):1768-1777. doi:10.1038/s41375-018-0210-1

Kreitman RJ, Dearden C, Zinzani PL, et al. Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial. 

. 2021;14(1):35. doi:10.1186/s13045-020-01004-y

Moxetumomab pasudotox-tdfk, a treatment for patients with relapsed/refractory hairy cell leukemia, will be permanently discontinued.  

Moxetumomab Pasudotox Will Be Removed From US Market for Hairy Cell Leukemia

Patients with cutaneous melanoma whose disease did not response to anti–PD-1 therapy achieved encouraging initial responses with a combination of vusolimogene oderparepvec (RP1) and nivolumab (Opdivo) in the phase 2 IGNYTE trial (NCT03767348).

At a median follow-up of 9.96 months, the first 75 patients enrolled on the trial achieved an overall response rate (ORR) over 36%, including a complete response (CR) rate of 20% and a partial response rate of 16.0%.

Furthermore, 17.3% of patients had stable disease, and 42.7% experienced progressive disease. The disease control rate (DCR) was 53.3%.

The findings were consistent with previously reported data for 16 patients with melanoma who failed prior anti–PD-1 therapy, where the combination elicited an ORR of 37.5% and a DCR of 43.8%.

“The rate, depth, and durability of responses seen across a range of anti–PD1 failed melanoma settings with RP1 combined with nivolumab suggests broad utility of RP1 in this difficult to treat patient population,” Mark Middleton, MD, PhD, FRCP, professor of Experimental Cancer Medicine, consultant medical oncologist at the Oxford Cancer Centre, head of the Department of Oncology at the University of Oxford, and principal investigator on the IGNYTE study, stated in a press release.

“Based on the growing body of clinical data with RP1, I believe it has the potential to become a new treatment paradigm across multiple skin cancers, including in melanoma patients who have failed anti–PD-1 therapy. I look forward to seeing the primary analysis data from the full 125 patients in the anti–PD-1 failed cohort from the IGNYTE clinical trial, and of the registration-directed [phase 2] CERPASS clinical trial [NCT04050436] in cutaneous squamous cell carcinoma in 2023.”

RP1 is based on a proprietary new strain of herpes simplex virus engineered and genetically armed with a fusogenic protein and granulocyte-macrophage colony-stimulating factor to maximize tumor killing potency, the immunogenicity of tumor cell death, and the activation of a systemic antitumor immune response.

IGNYTE is evaluating RP1 monotherapy and in combination with nivolumab across cohorts of patients with advanced or metastatic non-neurological solid tumors without treatment options. Key overall eligibility criteria for the trial include at least 1 measurable and injectable lesion of at least 1 cm, adequate organ function, no prior treatment with an oncolytic therapy, and an ECOG performance status of 0 or 1.

In the cohort of those with melanoma who failed prior anti–PD-1 therapy, patients were required to have at least 8 weeks of prior anti–PD-1 therapy and have confirmed progression while on anti–PD-1 therapy. Anti–PD-1 therapy must have been the last therapy prior to enrollment on IGNYTE. Patients on prior adjuvant therapy must have progressed while on prior adjuvant treatment, with confirmation from a biopsy.

In the anti–PD-1 failed cutaneous melanoma cohort, patients received the first dose of RP1 at 1 x 10

 cells during the first 2-week cycle. In cycles 2 through 8, patients were given RP1 at 1 x 10

 cells plus 240 mg of nivolumab. In cycle 9, patients received 240 mg of nivolumab alone, and in cycles 10 to 30, nivolumab was administered at 480 mg every 4 weeks.

Radiographic imaging occurred at baseline and every 8 weeks from the first dose, plus every 12 weeks after confirmation of response. A 100-day safety follow-up was also conducted.

The co-primary end points of the trial were safety and tolerability, plus ORR. Secondary end points included duration of response, CR rate, DCR, progression-free survival (PFS), and 1- and 2-year overall survival (OS).

Among the 75 patients enrolled in the anti–PD-1 failed melanoma cohort, the median age was 60 years (range, 31-91), and 70.7% of patients were male. Regarding prior therapy, 69.3% of patients had failed anti–PD-1 therapy but not anti–CTLA-4 therapy, 29.3% of patients failed both anti–PD-1 and anti–CTLA-4 therapy, 9.3% also failed BREF/MEK inhibition, and 12.0% also failed other therapy. Notably, 34.7% of patients received prior anti–PD-1 therapy only as adjuvant therapy.

Disease stage included IIIB (4.0%), IIIC (34.7%), IVM1a (16.0%), IVM1b (18.7%), and IVM1c (26.7%). Most patients had lactate dehydrogenase at or below the upper limit of normal (65.3%) and an ECOG performance status of 0 (64.0%).

Additional data showed that 85% of responses were ongoing at data cutoff, and most responses were observed in patients who did not respond to prior anti–PD-1 therapy. A clinically meaningful ORR was seen across all subgroups analyzed, including prior adjuvant anti–PD-1 therapy only (n = 30; ORR, 50.0%), prior anti–PD-1 therapy other than adjuvant (n = 61; ORR, 29.5%), prior anti–PD-1 and anti–CTLA4 therapy (n = 31; ORR, 29.0%), stage IIIB/IIIC/IVa disease (n = 44; ORR, 45.4%), and stage IVB/IVC disease (n = 47; ORR, 27.7%).

More than 50% of patients experienced target tumor reduction, per RECIST v1.1 criteria. PFS and OS data are immature, although a plateau appears to be developing on the PFS curve, and OS data are promising.

Regarding safety data for all patients with skin cancer who have received RP1 plus nivolumab during IGNYTE (n = 187), treatment-related adverse effects (TRAEs) were generally grade 1/2. The most common any-grade TRAEs included fatigue (34.2%), chills (28.9%), pyrexia (25.1%), nausea (20.9%), influenza-like illness (13.9%), and pruritus (13.4%). One grade 5 event of immune-mediated myocarditis occurred.

“We are pleased to be providing an initial data snapshot from the first 75 patients from the IGNYTE clinical trial being conducted with registrational intent for the treatment of anti–PD1 failed cutaneous melanoma,” Philip Astley-Sparke, chief executive officer of Replimune, said.

“The data confirm the prior signal seen in anti–PD-1 failed melanoma in a smaller earlier cohort of patients, with the data from the first 75 patients in the new cohort showing an overall 36% ORR, a 20% CR rate, and clinically meaningful activity across all subgroups analyzed, including the most advanced stage IVM1b/c patients. This highly encouraging data, taken together with the compelling and durable data with RP1 we have previously shared from our prior IGNYTE cohorts, give us high confidence we will be able to realize our ambition of establishing a broad skin cancer franchise with RP1.”

Replimune announces positive initial data from the anti-PD1 failed melanoma cohort of the IGNYTE clinical trial & an RP2/3 program update. News release. Replimune. December 7, 2022. Accessed December 7, 2022. 

Igniting a systemic immune response to cancer. Replimune. December 7, 2022. Accessed December 7, 2022. 

A combination of vusolimogene oderparepvec and nivolumab elicited early clinical activity in patients with cutaneous melanoma whose disease did not response to anti-PD-1 therapy.

RP1 Plus Nivolumab Generates Activity in Pretreated Cutaneous Melanoma 

Patients with primary advanced or recurrent endometrial cancer experienced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) following treatment with dostarlimab-gxly (Jemperli) plus standard-of-care chemotherapy, followed by dostarlimab alone, thus meeting the primary end point of the phase 3 RUBY trial (NCT03981796).

Findings from a planned interim analysis showed that the PFS benefit was observed in the prespecified mismatch repair deficient (dMMR)/microsatellite instability–high (MSI-H) patient subgroup and in the overall population. Additionally, a clinically relevant benefit in PFS was observed in the mismatch repair proficient (MMRp)/microsatellite stable (MSS) patient subgroup.

Although overall survival (OS) data were immature at the time of the interim analysis, a trend favoring the dostarlimab regimen was observed in the overall population, including the dMMr/MSI-H and MMRp/MSS subgroups.

Full results from the trial will be published in a medical journal and presented at an upcoming medical meeting. GSK intends to seek regulatory approvals for a potential new indication for dostarlimab in the treatment of primary advanced or recurrent endometrial cancer, and submission based on the results of RUBY are anticipated in the first half of 2023.

“Patients with primary advanced or recurrent endometrial cancer have limited treatment options. Long-term outcomes remain poor, and new treatment options are urgently needed to evolve the current standard of care, which is platinum-based chemotherapy,” Hesham Abdullah, senior vice president, global head of Oncology Development at GSK, stated in a press release. “Based on these positive headline results from the RUBY trial, GSK intends to seek regulatory approvals for a potential new indication for dostarlimab in the treatment of primary advanced or recurrent endometrial cancer.”

The 2-part global, randomized, double-blind, multicenter RUBY trial investigated the use of dostarlimab in patients with primary advanced or recurrent endometrial cancer. Part 1 examined dostarlimab plus carboplatin and paclitaxel, followed by dostarlimab alone, compared with carboplatin and paclitaxel plus placebo, followed by placebo alone. In part 2, patients were administered dostarlimab plus carboplatin and paclitaxel, followed by dostarlimab plus niraparib (Zejula), compared with carboplatin and paclitaxel plus placebo, followed by placebo alone.

To enroll in either part of the trial, patients were required to by at least 18 years of age with histologically or cytologically proven endometrial cancer with recurrent or advanced disease.

 Stage III or IV disease or first recurrent endometrial cancer with a low potential for cure by radiation therapy or surgery alone was required. Patients also needed to have an ECOG performance status of 0 or 1 and adequate organ function.

Key exclusion criteria included patients who received neoadjuvant/adjuvant systemic anticancer therapy for primary stage III or IV disease and did not have a recurrence or progressive disease prior to first dose on the study or did have a recurrence or progressive disease within 6 months of completing systemic anticancer therapy treatment prior to first dose on the study; more than 1 recurrence of endometrial cancer prior anti–PD-(L)1 therapy; anticancer therapy within 21 days of study treatment; or uncontrolled central nervous system metastases or carcinomatosis meningitis.

The co-primary end points of part 1 were investigator-assessed PFS per RECIST v1.1 criteria and OS. Investigator-assessed PFS was the primary end point of part 2. Secondary end points for both parts of the trial include PFS per blinded independent central review, overall response rate, duration of response, disease control rate, patient-reported outcomes, safety, and tolerability.

Regarding safety, the toxicity profile of dostarlimab in RUBY was consistent with clinical trials of similar regimens. The most common treatment-emergent adverse effects in patients receiving dostarlimab plus chemotherapy included nausea, alopecia, fatigue, peripheral neuropathy, anemia, arthralgia, constipation, and diarrhea.

Jemperli (dostarlimab-gxly) RUBY phase III trial met its primary endpoint in a planned interim analysis in patients with primary advanced or recurrent endometrial cancer. News release. GSK. December 2, 2022. Accessed December 2, 2022. 

A study to evaluate dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel in participants with recurrent or primary advanced endometrial cancer (RUBY). ClinicalTrials.gov. Updated August 12, 2022. Accessed December 2, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03981796

Dostarlimab plus standard-of-care chemotherapy, followed by dostarlimab alone, met a predetermined progression-free survival end point in the phase 3 RUBY trial.

Dostarlimab Improves Progression-Free Survival in Advanced or Recurrent Endometrial Cancer

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

Adding pembrolizumab (Keytruda) to chemotherapy yielded superior overall survival (OS) in patients withHER2-negative, locally advanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to findings from the phase 3 KEYNOTE-859 trial (NCT03675737), which assessed the regimen against placebo plus chemotherapy. 

OS benefits were present irrespective of PD-L1 expression. Additionally, pembrolizumab plus chemotherapy generated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall response rate (ORR) compared with chemotherapy alone.

Merck said in a news release detailed findings from the prespecified interim analysis conducted by an independent data monitoring committee will be presented at an upcoming medical meeting and submitted to regulatory authorities.

“Despite improvements in cancer care, advanced gastric cancer continues to have one of the lowest 5-year survival rates, and new interventions are urgently needed. The results from KEYNOTE-859 show the potential of [pembrolizumab] plus chemotherapy to improve survival beyond chemotherapy alone for patients with HER2-negative, locally advanced, unresectable or metastatic gastric or GEJ adenocarcinoma, regardless of PD-L1 expression,” Eliav Barr, MD, senior vice president, head of global clinical development, and chief medical officer, Merck Research Laboratories, stated in a press release.

“We are excited by these new results that demonstrate our commitment to exploring new treatment options for patients fighting gastrointestinal cancers with [pembrolizumab] and thank all investigators and patients who participated in this trial.”

The randomized, double-blind KEYNOTE-859 trial enrolled patients with a histologically or cytologically confirmed diagnosis HER2-negative, locally advanced, unresectable or metastatic gastric or GEJ adenocarcinoma with a known PD-L1 expression status.

 Patients were also required to have measurable disease per RECIST v1.1 criteria, provide a tissue sample for PD-L1 and microsatellite biomarker analysis, have an ECOG performance status of 0 or 1, and have adequate organ function.

Previous therapy for locally advanced, unresectable or metastatic gastric or GEJ adenocarcinoma was not permitted, although prior neoadjuvant and/or adjuvant therapy was allowed if completed at least 6 months prior to randomization.

Other key exclusion criteria included squamous cell or undifferentiated gastric cancer; major surgery, open biopsy, or significant injury within 28 days of randomization; preexisting peripheral neuropathy greater than grade 1; or known active central nervous system metastases and/or carcinomatous meningitis.

Enrolled patients were randomly assigned to 200 mg of intravenous (IV) pembrolizumab or placebo once every 3 weeks for up to 35 cycles, plus physician’s choice of chemotherapy. Chemotherapy consisted of IV cisplatin at 80 mg/m

 once every 3 weeks plus 5-fluorouracil at 800 mg/m

 via continuous IV on days 1 to 5 of every 3-week cycle, or IV oxaliplatin at 130 mg/m

 once every 3 weeks plus oral capecitabine at 1000 mg/m

 twice daily on days 1 to 14 of every 3-week cycle. Patients in the pembrolizumab arm who achieved a complete response but progressed after discontinuation were permitted to begin a second course of pembrolizumab for up to 17 cycles.

Along with the primary end point of OS, secondary end points included PFS, ORR, duration of response, and safety.

Regarding safety, the safety profile of pembrolizumab was consistent with data from previously reported studies, and no new safety signals were identified.

Merck announces phase 3 KEYNOTE-859 trial met primary endpoint of overall survival in patients with HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. News release. Merck. November 22, 2022. Accessed November 22, 2022. 

Pembrolizumab (MK-3475) plus chemotherapy versus placebo plus chemotherapy in participants gastric or gastroesophageal junction (GEJ) adenocarcinoma (MK-3475-859/KEYNOTE-859). ClinicalTrials.gov. Updated August 17, 2022. Accessed November 22, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03675737

Pembrolizumab plus physician’s choice of chemotherapy bested placebo plus chemotherapy in improving overall survival rates in patients with HER2-negative gastric cancer or gastroesophageal junction adenocarcinoma, regardless of PD-L1 expression.

Pembrolizumab Combination Delivers Overall Survival Benefit in HER2-Negative Gastric/GEJ Adenocarcinoma

GlaxoSmithKline (GSK) intends to pull out its marketing authorization for belantamab mafodotin-blmf (Blenrep) in the United States. The agent had been approved for adult patients with multiple myeloma who had received at least 4 prior lines of therapy, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

The decision to withdraw the US indication for belantamab mafodotin stems from a request from the FDA following the results of the phase 3 DREAMM-3 trial (NCT04162210), which showed that the study did not meet its primary end point of a progression-free survival (PFS) benefit with belantamab mafodotin vs the combination of pomalidomide (Pomalyst) plus low-dose dexamethasone.

At a median follow-up of 11.5 months for the belantamab mafodotin arm and 10.8 months for pomalidomide plus low-dose dexamethasone arm, patients treated with belantamab mafodotin experienced a median PFS of 11.2 months compared with 7.0 months for pomalidomide plus dexamethasone (HR, 1.03; 95% CI, 0.72-1.47).

GSK announced that patients already enrolled in the Blenrep Risk Evaluation and Mitigation Strategy program will have the option to enroll in a compassionate use program to continue access to treatment.

“We respect the [FDA’s] approach to the accelerated approval regulations and associated process. Multiple myeloma is a challenging disease, with poor outcomes for patients whose disease has become resistant to standard-of-care treatments. We will continue the DREAMM clinical trial program and work with the FDA on a path forward for this important treatment option for patients with multiple myeloma,” Sabine Luik, MD, MBA, chief medical officer of GSK, stated in a news release.

In August 2020, the FDA granted accelerated approval to belantamab mafodotin for the treatment of patients with relapsed/refractory multiple myeloma who have received 4 prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody.

 The regulatory decision was based on results of the phase 2 DREAMM-2 trial (NCT03525678).

The open-label, randomized DREAMM-3 study investigated the efficacy and safety of belantamab mafodotin monotherapy vs pomalidomide plus dexamethasone in patients at least 18 years old with histologically or cytologically confirmed relapsed/refractory multiple myeloma who had undergone autologous stem cell transplant (ASCT) or were considered transplant ineligible, and had received at least 2 prior lines of anti-myeloma treatments, including at least 2 consecutive cycles of both lenalidomide (Revlimid) and a PI. Patients were required to have documented disease progression on, or within 60 days of, completion of the last treatment or must be non-responsive while on last treatment.

Patients were required to have an ECOG performance status of 0 to 2, adequate organ function, and resolution of all prior treatment-related toxicities to grade 1 or lower, except for alopecia or grade 2 peripheral neuropathy. For patients who underwent prior ASCT, transplant must have been completed more than 100 days prior to initiating study treatment, and no active infections were permitted.

Enrollment was not permitted for patients with symptomatic amyloidosis, active POEMS syndrome, or active plasma cell leukemia; any systemic anti-myeloma therapy or use of an investigational drug within 14 days or 5 half-lives, whichever was shorter, before the first dose of study treatment; prior treatment with an anti–multiple myeloma monoclonal antibody within 30 days prior to first study treatment; prior BCMA-targeted therapy or prior pomalidomide treatment; prior allogeneic stem cell transplant; or any major surgery within 4 weeks of the start of study treatment.

DREAMM-3 randomly assigned patients 2:1 to 2.5 mg/kg of belantamab mafodotin once every 3 weeks, or pomalidomide administered daily on days 1 to 21 of each 28-day cycle plus dexamethasone given once weekly on days 1, 8, 15, and 22 of each cycle.

Along with the primary end point of PFS, secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), assessment of minimal residual disease, and safety.

Additional data from the phase 3 trial showed belantamab mafodotin generated an ORR of 41% compared with 36% for pomalidomide plus dexamethasone. Twenty-five percent of patients in the belantamab mafodotin arm achieved a very good partial response or better, vs 8% of those in the experimental arm. The DOR was not yet reached (95% CI, 17.9–not estimable [NE]) for belantamab mafodotin vs 8.5 months (95% CI, 7.6-NE) for pomalidomide plus low-dose dexamethasone. The 12-month DOR rates were 76.8% and 48.4% for belantamab mafodotin and pomalidomide plus low-dose dexamethasone, respectively.

OS data reached 37.5% overall maturity at the time of data cutoff. The median OS was 21.2 months for belantamab mafodotin compared with 21.1 months for pomalidomide plus dexamethasone (HR, 1.14; 95% CI, 0.77-1.68).

Regarding safety, findings for belantamab mafodotin were similar to the known safety profile of the agent, with no new safety signals being identified. Rates of grade 3 keratopathy were consistent with previously reported data.

Belantamab mafodotin remains under investigation in multiple phase 3 trials exploring the agent’s efficacy and safety in combination with other agents. The DREAMM-7 trial (NCT04246047) is investigating belantamab mafodotin plus bortezomib (Velcade) and dexamethasone vs daratumumab (Darzalex) plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma who received at least 1 prior multiple myeloma therapy.

The DREAMM-8 trial (NCT04484623) in examining belantamab mafodotin plus pomalidomide and dexamethasone vs bortezomib plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma who had at least 1 prior line of multiple myeloma therapy including a lenalidomide-containing regimen.

GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. News release. GlaxoSmithKline. November 22, 2022. Accessed November 22, 2022. 

GSK provides update on DREAMM-3 phase III trial for Blenrep in relapsed/refractory multiple myeloma. News release. GlaxoSmithKline. November 7, 2022. Accessed November 22, 2022. 

FDA approves GSK’s BLENREP (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. News release. GlaxoSmithKline. August 6, 2020. Accessed November 22, 2022. 

Study of single agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone (pom/dex) in participants with relapsed/refractory multiple myeloma (RRMM) (DREAMM-3). ClinicalTrials.gov. Updated September 30, 2022. Accessed November 22, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04162210

Evaluation of efficacy and safety of belantamab mafodotin, bortezomib and dexamethasone versus daratumumab, bortezomib and dexamethasone in participants with relapsed/refractory multiple myeloma (DREAMM 7). ClinicalTrial.gov. Updated September 26, 2022. Accessed November 22, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04246047

Belantamab mafodotin plus pomalidomide and dexamethasone (Pd) versus bortezomib plus Pd in relapsed/refractory multiple myeloma (DREAMM 8). ClinicalTrial.gov. Updated October 14, 2022. Accessed November 22, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04484623

In light of findings from the phase 3 DREAMM-3 trial, manufacturers have elected to withdraw belantamab mafodotin-blmf from the United States market.  

Belantamab Mafodotin Will No Longer Be Available For Multiple Myeloma

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

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.

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

Chris Ryan