A rolling biologics license application (BLA) seeking the approval of lifileucel (LN-44) in patients with advanced melanoma who progressed on or after previous anti–PD-1/PD-L1 therapy, and if 

 mutation positive, also previous BRAF or BRAF/MEK inhibitor therapy, has been submitted to the FDA.

The application is based on findings from the phase 2 C-144-01 trial (NCT02360579).

In cohort 4 (n = 87), the tumor-infiltrating lymphocyte therapy elicited an objective response rate (ORR) of 29% (95% CI, 19.5%-39.4%) per independent review committee (IRC) assessment and by RECIST v1.1 criteria.

 Among those who responded to treatment, 3 achieved complete responses (CRs) and 22 experienced partial responses (PRs). At a median follow-up of 23.5 months, the median duration of response (DOR) in this cohort was 10.4 months by IRC.

These data are supported by findings from cohort 2 (n = 66), in which lifileucel produced an ORR of 35% (95% CI, 23.5%-47.6%) per IRC; this included 5 CRs and 18 PRs. The median DOR was not yet reached at a median follow-up of 36.6 months.

In pooled patients from cohorts 2 and 4 (n = 153), lifileucel induced an ORR of 31% (95% CI, 24.1%-39.4%) by IRC. At a median follow-up of 27.6 months, the median DOR was not yet reached.

“Initiating our rolling BLA submission for lifileucel is a significant step toward our goal to deliver the first individualized, one-time cell therapy for melanoma patients with significant unmet need,” Frederick Vogt, PhD, JD, interim president and chief executive officer of Iovance Biotherapeutics, Inc., stated in a press release. “In parallel, we are executing our on-boarding and personnel training at authorized treatment centers, education and awareness initiatives, internal capacity planning, and launch readiness activities to prepare for commercialization. The FDA is supportive of our regulatory approach, and we look forward to continuing this collaboration throughout the submission and review process.”

The trial enrolled patients with unresectable or metastatic melanoma that was stage IIIC or IV who had confirmed radiologic progression.

 Patients must have progressed after 1 or more previous systemic therapies, including a PD-1 inhibitor, and if 

 positive, a BRAF inhibitor with or without a MEK inhibitor.

Study participants received a nonmyeloablative lymphodepletion regimen comprised of cyclophosphamide at 60 mg/kg once daily for 2 days followed by fludarabine at 25 mg/m

 once daily for 5 days. Lifileucel was thawed and administered as a single infusion about 24 hours from the last dose of fludarabine. A short course of bolus interleukin-2 at 600,000 IU/kg was infused every 8 to 12 hours for up to 6 doses, starting within 3 to 24 hours of completing the infusion.

The primary objective of the trial was investigator-assessed objective response rate using RECIST v1.1 criteria. Secondary end points comprised DOR, overall survival, and safety.

Patients in cohort 4 were noted to have higher disease burden at baseline vs those in cohort 2.2 For example, a substantially higher proportion of patients had elevated lactate dehydrogenase levels at baseline in cohort 4 vs cohort 2, at 64.4% and 40.9%, respectively, and more baseline tumor lesions, at 83.9% vs 65.2%, respectively.

Those in cohort 2 also had about half of the cumulative duration of PD-1 therapy prior to lifileucel vs those in cohort 4; a reduced duration of previous PD-1 therapy was linked with an increase in DOR with lifileucel.

Regarding safety, the treatment-emergent adverse effects experienced in both cohorts were noted to align with the underlying disease and the known safety profiles of nonmyeloablative lymphodepletion and IL-2. Safety findings also proved to be consistent between cohorts 4 and 2.

Iovance shared plans to present additional data from C-144-01 at a medical conference later this year.

Iovance Biotherapeutics initiates biologics license application (BLA) submission for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics, Inc. August 25, 2022. Accessed August 25, 2022. 

Iovance Biotherapeutics announces positive clinical data for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics, Inc. May 26, 2022. Accessed August 25, 2022. 

Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. 

. 2021;39(24):2656-2666. doi:10.1200/JCO.21.00612

Articles

A rolling biologics license application has been submitted to the FDA seeking the approval of lifileucel in patients with advanced melanoma who progressed on or after previous anti–PD-1/PD-L1 therapy, and if BRAF mutation positive, also previous BRAF or BRAF/MEK inhibitor therapy.

FDA Approval Sought for Lifileucel in Advanced Melanoma

The addition of talimogene laherparepvec (T-VEC) to pembrolizumab (Keytruda) did not significantly improve progression-free survival (PFS) or overall survival (OS) over pembrolizumab alone in patients with advanced melanoma, according to data from a phase 2 trial (NCT02263508) published in the 

In the planned PFS primary analysis, which had a median follow-up of 25.58 months (range, 0.3-45.8), the doublet did not improve PFS over pembrolizumab alone per blinded independent central review (BICR) and RECIST 1.1 criteria (overall stratified HR, 0.86; 95% CI, 0.71-1.04; 

However, the PFS favored the combination arm over the monotherapy arm in those who were enrolled to the United States (overall HR, 0.59; 95% CI, 0.37-0.92), those with baseline lactate dehydrogenase (LDH) less than or equal t o the upper limit of normal (overall HR, 0.76; 95% CI, 0.59-0.99), and in those with a baseline sum of the longest diameters of target lesions of less than or equal to the median (overall HR, 0.70; 95% CI, 0.51-0.96).

In the second OS interim analysis, which had a median follow-up of 31.0 months (range, 0.3-53.0), T-VEC plus pembrolizumab did not significantly improve OS vs pembrolizumab alone (HR, 0.96; 95% CI, 0.76-1.22; 

= .74). Moreover, no OS improvement was observed with the doublet over the monotherapy in any of the predefined subgroups.

“There is a continuing unmet need in the field for combination strategies to improve the efficacy of currently available therapies without added toxicities,” Jason A. Chesney, MD, PhD, of the University of Louisville School of Medicine, and colleagues, wrote in the paper. “Although the combination of T-VEC [and] pembrolizumab did not result in OS benefit compared with placebo [and] pembrolizumab in the frontline treatment of advanced melanoma, this combination is still under active investigation in patients who are refractory to anti–PD-1 inhibitor therapy for melanoma and other tumor types.”

T-VEC is an oncolytic viral intratumoral therapy designed to produce granulocyte-macrophage colony-stimulating factor. When combined with pembrolizumab, it is hypothesized that T-VEC may have the potential to overcome immunotherapy failure.

Data from the single-arm, phase 1b MASTERKEY-265 trial (NCT02263508) showed that T-VEC plus pembrolizumab elicited an objective response rate (ORR) of 62%, which included a complete response rate (CRR) of 43%, in 21 patients with advanced melanoma.

 The combination was also found to be well tolerated, with no dose-limiting toxicities reported.

Based on these data, investigators launched the randomized, double-blind, placebo-controlled, multicenter, international phase 3 trial, which enrolled those with histologically confirmed stage IIIB to IV M1c, unresectable melanoma. To be eligible, patients were required to be at least 18 years of age, have an ECOG performance status of 0 or 1, and at least 1 visceral or nodal/soft tissue melanoma lesion that could be measured in at least 1 dimension and for which the longest diameter was at least 10 mm.

If patients had active untreated brain metastases or primary uveal or mucosal melanoma, or if they previously received T-VEC or any other oncolytic viruses, previous PD-1/PD-L1/PD-L2 agents, previous tumor vaccine in the neoadjuvant setting, or had a history of autoimmune diseases, they were excluded.

Study participants (n = 692) were randomly assigned 1:1 to receive the combination of T-VEC and pembrolizumab (n = 346) or placebo plus pembrolizumab (n = 346). T-VEC/placebo was given via intratumor injection once at 10

 PFU/mL for up to 4 mL on day 1 of week 0, followed by up to 4 mL of 10

 PFU/mL on day 1 of week 3, and once every 2 weeks until the fifth injection at week 9. Every 3 weeks thereafter, T-VEC plus placebo was then given synchronously with pembrolizumab, which was administered at 200 mg once every 3 weeks.

PFS per modified RECIST (mRECIST) v1.1 criteria and BICR and OS served as the dual primary end points of the trial. Important secondary end points comprised CRR, PFS per modified immune-related response criteria (irRC)–RECIST and BICR, and OS in those with stage IIIB to IVM1b disease.

Other end points included ORR, best overall response, durable response rate (DRR), duration of response, and disease control rate per BICR and both mRECIST v1.1 and modified irRC-RECIST criteria, and safety.

Baseline patient characteristics were noted to be balanced between the treatment arms. Across the arms, the median age was 64 years (range, 19-94). In the investigative and control arms, most patients were White (94.5% vs 96.8%, respectively), had an ECOG performance of 0 (74.9% vs 72.0%), were enrolled in a non-US region (74.9% vs 79.5%), had negative 

 mutational status (61.0% vs 62.1%), had a baseline LDH ≤ ULN (61.8% vs 69.7%), were PD-L1 positive at baseline (66.8% vs 63.0%), and have IVM1c disease (41.9% vs 41.3%).

Additional data from the primary analysis showed that the ORR achieved with the doublet was 48.6% (95% CI, 43.3%-53.8%) by BICR and per RECIST v1.1 criteria; the CRR was 17.9% (95% CI, 13.9%-22.0%) and the DRR was 42.2% (95% CI, 37.0%-47.4%). The median DOR was 43.7 months (95% CI–not estimable [NE]). In the monotherapy arm, the ORR was 41.3% (95% CI, 36.1%-45.5%), the CRR was 11.6% (95% CI, 8.2%-14.9%), and the DRR was 34.1% (95% CI, 29.1%-39.1%). The median DOR was not NE with pembrolizumab alone.

Regarding safety, treatment-related toxicities were reported by 88.4% of those who were given T-VEC plus pembrolizumab vs 74.6% of those given pembrolizumab alone. The most common adverse effects (AEs) reported in the investigative and control arms were pyrexia (35.1% vs 5.0%, respectively) and fatigue (31.3% vs 22.2%).

Grade 3 or higher treatment-related AEs were experienced by 20.3% of those in the doublet arm and 15.7% of those in the monotherapy arm. Five patients on the investigative arm and 42 patients on the control arm had a fatal AE. Five of these effects were determined to be related to treatment. In the T-VEC/pembrolizumab arm, 1 patient experienced atypical pneumonia, 1 had cardiac arrest, and 1 had delirium, and 1 had pulmonary sepsis; in the pembrolizumab-alone arm, 1 patient had respiratory failure.

Any-grade immune-related AEs (irAEs) were reported in 27.5% of patients who received the doublet and 24.8% of those who were given the monotherapy. The most common irAEs in the investigative and control arms were hypothyroidism (12.5% vs 13.4%) and hyperthyroidism (5.8% vs 5.0%).

Chesney JA, Ribas A, Long GV, et al. Randomized, double-blind, placebo-controlled, global phase III trial of talimogene laherparepvec combined with pembrolizumab for advanced melanoma. 

. Published online August 23, 2022. doi:10.1200/JCO.22.00343

Long G, Dummer R, Johnson D, et al. 429 Long-term analysis of MASTERKEY-265 phase 1b trial of talimogene laherparepvec (T-VEC) plus pembrolizumab in patients with unresectable stage IIIB-IVM1c melanoma. 

. 2020;8(suppl 3). doi:10.1136/jitc-2020-SITC2020.0429

The addition of talimogene laherparepvec to pembrolizumab did not significantly improve progression-free survival or overall survival over pembrolizumab alone in patients with advanced melanoma.

Talimogene Laherparepvec Plus Pembrolizumab Misses Mark in Advanced Melanoma

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of the fixed-dose combination of nivolumab (Opdivo) and relatlimab (Opdualog) for the frontline treatment of adult and adolescents who are 12 years of age or older with advanced melanoma and a tumor cell PD-L1 expression of less than 1%.

The proposed indication was supported by findings from an exploratory analysis of patients with a PD-L1 expression of less than 1% who were examined in the phase 2/3 RELATIVITY-047 trial (NCT03470922).

Data presented during the 2022 ASCO Annual Meeting showed that the hazard ratio (HR) for progression-free survival (PFS) by blinded independent central review (BICR) in those with a PD-L1 expression of less than 1% (n = 209) was 0.68 (95% CI, 0.53-0.86). The HR for overall survival (OS) in this subset was 0.78 (95% CI, 0.59-1.04).

“We are very proud of the role we have played in progressing the treatment of advanced melanoma over the years. As part of our mission to deliver new medicines for patients, we have continued to develop new dual immunotherapy combinations,” Paul Basciano, development lead of relatlimab at Bristol Myers Squibb (BMS), stated in a press release. “This positive CHMP opinion marks the first step toward the potential approval of the first LAG-3–blocking antibody combination – and the third distinct checkpoint inhibitor for BMS – for advanced melanoma patients in the European Union.”

The global, randomized, double-blind, gated, phase 2/3 RELATIVITY-047 trial enrolled patients with previously untreated, unresectable, or metastatic melanoma who had an ECOG performance status of 0 or 1.

A total of 714 study participants were randomized 1:1 to receive the fixed-dose combination of nivolumab at 480 mg plus relatlimab at 160 mg intravenously (IV) every 4 weeks (n = 355) or IV nivolumab at 480 mg every 4 weeks (n = 359).

Patients were stratified by LAG-3 expression on immune cells in the tumor microenvironment, PD-L1 expression on tumor cells, 

 mutational status, and AJCC v8 metastatic stage.

The primary end point of the trial was PFS by BICR, and secondary end points included OS and objective response rate (ORR) by BICR. Moreover, end points were hierarchically tested starting with PFS, followed by OS, and then ORR.

The median age of patients was 63 years (range, 20-94), and 41.7% were female. Regarding AJCC v8 M stage, 25.8% had M1A stage, 24.2% had M1B stage, 38.9% had M1C stage, and 2.4% had M1D stage. Additionally, 66.9% of patients had an ECOG performance status of 0, 36.1% had a serum lactate dehydrogenase level above the upper limit of normal, and 8.4% previously received neoadjuvant or adjuvant treatment.

Regarding LAG-3 expression, 75.2% of patients had expression of 1% or higher and 24.8% had expression of less than 1%. Forty-one percent of patients had a PD-L1 expression of 1% or higher and 59% had an expression of less than 1%. Regarding 

 mutational status, 38.5% had mutated disease, and 61.5% had wild-type disease. Moreover, 65.7% of patients had AJCC M stage of M0/M1any[0] and 34.3% had M1any[1].

 for the treatment of adult and pediatric patients aged 12 years and older with unresectable or metastatic melanoma.

 The decision was supported by earlier findings from the trial, which showed that the doublet resulted in a median PFS of 10.1 months (95% CI, 6.4-15.7) compared with 4.6 months (95% CI, 3.4-5.6) with standard nivolumab monotherapy (HR, 0.75; 95% CI, 0.62-0.92; 

Updated data showed that at a median follow-up of 19.3 months, the PFS benefits achieved with the combination were maintained.

 The median PFS with nivolumab/relatlimab was 10.22 months (95% CI, 6.51-14.75) vs 4.63 months (95% CI, 3.48-6.44) with single-agent nivolumab (HR, 0.78; 95% CI, 0.64-0.94).

The 12-month PFS rates in the investigative and control arms were 48.0% (95% CI, 42.5%-53.4%) and 36.9% (95% CI, 31.7%-42.1%), respectively; at 24 months, these rates were 38.5% (95% CI, 32.7%-44.2%) and 29.0% (95% CI, 23.8%-34.4%), respectively.

With 19.3 months of follow-up, the doublet resulted in a clinically meaningful improvement in OS vs nivolumab monotherapy, although this improvement was not determined to be of statistical significance. In those who received the doublet, the median OS had not yet been reached (NR; 95% CI, 34.20-NR) vs 34.10 months (95% CI, 25.23-NR) in those who received nivolumab alone (HR, 0.80; 95% CI, 0.64-1.01; 

The 12-month OS rates in the investigative and control arms were 77.0% (95% CI, 72.2%-81.1%) and 71.6% (95% CI, 66.6%-76.0%), respectively, and the 24-month OS rates were 63.7% (95% CI, 58.1%-68.7%) and 58.3% (95% CI, 52.7%-63.4%), respectively. The 36-month OS rates in these arms were 55.8% (95% CI, 49.8%-61.4%) and 48.8% (95% CI, 42.7%-54.7%), respectively.

Additionally, the doublet elicited an ORR of 43.1% (95% CI, 37.9%-48.4%) per BICR vs 32.6% (95% CI, 27.8%-37.7%) with nivolumab monotherapy, translating to a 10.3% difference between the arms (95% CI, 3.4-17.3) with an odds ratio of 1.6 (95% CI, 1.2-2.2). In the combination arm, 16.3% achieved a complete response (CR), 26.8% had a partial response (PR), and 18.2% achieved stable disease; in the monotherapy arm, the CR rate was 14.2%, the PR rate was 18.4%, and the stable disease rate was 16.4%. Those in the investigative arm experienced a lower rate of progressive disease than those in the control arm, at 29.6% vs 41.5%, respectively.

Common treatment-related toxicities included pruritus, fatigue, rash, hypothyroidism, arthralgia, diarrhea, and vitiligo. Any-grade treatment-related adverse effects (TRAEs) were reported in 83.7% of those in the combination arm and 72.4% of those in the monotherapy arm; they led to discontinuation in 15.2% and 7.2% of patients, respectively.

Grade 3 or 4 TRAEs were reported in 21.1% and 11.1% of those in the investigative and control arms, respectively; these effects resulted in discontinuation in 9.0% and 3.6% of patients, respectively. Treatment-related deaths occurred in 4 patients in the investigative arm and 2 patients in the control arm.

Bristol Myers Squibb receives positive CHMP opinion recommending approval for LAG-3-blocking antibody combination Opdualag (nivolumab and relatlimab) for treatment of patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb. July 22, 2022. Accessed July 22, 2022. 

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

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

US Food and Drug Administration approves first LAG-3-blocking antibody combination, Opdualag (nivolumab and relatlimab-rmbw), as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb; March 18, 2022. Accessed July 22, 2022. 

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of the fixed-dose combination of nivolumab and relatlimab for the frontline treatment of adult and adolescents who are 12 years of age or older with advanced melanoma and a tumor cell PD-L1 expression of less than 1%.

Relatlimab Plus Nivolumab Approaches EU Approval for Advanced Melanoma With PD-L1 of <1%

The European Commission (EC) has approved pembrolizumab (Keytruda) for adjuvant treatment of adult and adolescent patients 12 years and older with stage IIB or IIC melanoma who have undergone a complete resection.

Furthermore, the EC expanded the indications for pembrolizumab to included adolescent patients aged 12 years and older with advanced unresectable or metastatic melanoma and stage III melanoma as an adjuvant treatment following complete resection.

“When melanoma recurs, patients often have a significantly worse long-term prognosis, especially if the cancer returns or spreads to distant sites,” Alexander Eggermont, MD, PhD, chief scientific officer of the Princess Máxima Center for Pediatric Oncology in the Netherlands, stated in a press release. “This approval further reinforces the important role of adjuvant therapy for patients 12 years and older with completely resected stage IIB and IIC melanoma who now have a treatment option that has demonstrated the potential to significantly reduce the risk of their cancer returning.”

The commission based its approval on findings from the phase 3 KEYNOTE-716 trial (NCT03553836) in which pembrolizumab significantly prolonged recurrence-free survival (RFS) vs placebo. At a median follow-up of 20.5 months, pembrolizumab reduced the risk of recurrence or death by 39% (HR, 0.61; 95% CI, 0.45-0.82; 

= .00046). Additionally, at a median follow-up of 26.9 months, pembrolizumab lowered the risk of distant metastasis by 36% vs placebo (HR, 0.64; 95% CI, 0.47-0.88; 

the FDA approved pembrolizumab for the adjuvant treatment of adult and pediatric patients with stage IIB or IIC melanoma

 following complete resection based on data from KEYNOTE-716.

The trial enrolled 976 patients who were at least 12 years old with newly diagnosed, resected, high-risk, stage II melanoma with a negative sentinel lymph node biopsy. Patients were also required to have an ECOG performance status of 0 or 1.

Patients were randomly assigned to 200 mg of intravenous (IV) pembrolizumab (n = 487) or IV placebo (n = 489) once every 3 weeks for 17 cycles. Stratification factors included T-category (3b, 4a, and 4b) and pediatric status.

The primary end point of the trial was RFS per investigator assessment. Secondary end points included distant metastasis–free survival, overall survival, and safety.

Additional data presented at the 2022 ASCO Annual Meeting

 showed that at a median follow-up of 37.2 months, patients in the pembrolizumab arm continued to see a benefit in RFS (HR, 0.64; 95% CI, 0.50-0.84).3The 24-month RFS rates in the pembrolizumab and placebo arms were 81.2% and 72.8%, respectively.

Investigators have evaluated single-agent pembrolizumab for safety in 7631 patients across multiple tumor types. The rate of any-grade immune-related adverse effects (IRAEs) in the adjuvant setting was 36.1% and the rate of grade 3-5 IRAEs was 8.9%. Investigators observed no new IRAEs with adjuvant pembrolizumab.

“Melanoma continues to be a public health burden in Europe, claiming more than 26,000 lives in 2020, with rates rising annually,” Scot Ebbinghaus, MD, vice president of Global Clinical Development at Merck Research Laboratories, said in a press release. “[Pembrolizumab] has become the first anti-PD-1 adjuvant treatment option approved in the EU for patients 12 years and older across stage IIB, IIC and III melanoma following complete resection, based on data that show the potential of [pembrolizumab] to help reduce the risk of recurrence, including as distant metastases, in these patients. This approval furthers our commitment to finding new effective options for even more patients with melanoma.”

European Commission approves KEYTRUDA® (pembrolizumab) as adjuvant treatment for adult and adolescent patients (≥12 years of age) with stage IIB or IIC melanoma following complete resection. News release. Merck. June 24, 2022. Accessed June 24, 2022. 

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 June 24, 2022. 

Long GV, Luke JJ, Khattak M, et al. Distant metastasis-free survival with pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: The phase 3 KEYNOTE-716 study. 

. 2022;40(suppl 17):LBA9500. doi:10.1200/JCO.2022.40.17_suppl.LBA9500

The European Commission has approved pembrolizumab for adjuvant treatment of adult and adolescent patients 12 years and older with stage IIB or IIC melanoma who have undergone a complete resection.

Dermatologists in Cancer Care®: September 2022 | Supplements and Featured Publications

FDA Approval Sought for Lifileucel in Advanced Melanoma

Talimogene Laherparepvec Plus Pembrolizumab Misses Mark in Advanced Melanoma

Relatlimab Plus Nivolumab Approaches EU Approval for Advanced Melanoma With PD-L1 of <1%

Adjuvant Pembrolizumab Wins European Approval for Stage IIB/IIC Melanoma Following Complete Resection