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Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

In this episode of Targeted Talks, Omid Hamid, MD, chief of translational research and immunotherapy and director of melanoma therapeutics at The Angeles Clinic and Research Institute in Los Angeles, California, delves into the mechanism of action, supporting data, and approval of lifileucel (LN-44; Amtagvi).

Lifileucel is a tumor infiltrating lymphocyte (TIL) therapy used for the treatment of patients with advanced melanoma who progressed on at least 1 systemic therapy, including a PD-1 inhibitor, and if 

 V600 mutation-positive, a BRAF inhibitor with or without a MEK inhibitor.

“The way it works is we harvest a tumor from a patient, and then we obtain those T cells that are there in the tumor. We think that the majority of those T cells are tumor-directed, and they recognize multiple tumor neoantigens, so we take them out," Hamid explains.

The FDA granted an accelerated approval to lifileuce

 in February 2024 for the treatment of patients with advanced melanoma who have progressed after receiving an anti-PD-1 antibody and, if 

 inhibitor with or without a MEK inhibitor.

 The regulatory decision was supported by data from an efficacy population of 73 patients enrolled in cohort 4 of the phase 2 C-144-01 trial (NCT02360579). These patients were treated with lifileucel at the recommended dose.

In the study, the objective response rate among these patients was 31.5%, comprising 3 (4.1%) complete responses and 20 (27.4%) partial responses. Of the patient responders, 56.5% of patients maintained their response at 6 months, 47.8% at 9 months, and 43.5% at 12 months.

"After 4 years of follow-up from the cohorts that received lifileucel...we have seen a response rate of 31.4%...the responses were not only rapid...but they were durable," says Hamid.

With the clinically meaningful antitumor activity observed with this autologous TIL cell therapy in patients with advanced melanoma, this approval marks a significant development for clinicians and patients.

1. Wermke M, Chesney J, Whitman E, et al. Long-term efficacy and patterns of response of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: a 4-year analysis of the C-144-01 study. Ann Oncol. 2023;34(suppl 2):100589. doi:10.1016/iotech/iotech100589

2. FDA approves first cellular therapy to treat patients with unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed July 9, 2024. 

In this episode of Targeted Talks, Omid Hamid, MD, discusses data supporting the use of lifileucel for the treatment of advanced melanoma.

Advancing Melanoma Treatment: Hamid on Lifileucel's Role

In season 4, episode 4 of Targeted Talks, Richard D. Carvajal, MD, deputy physician in chief and director of Medical Oncology, Northwell Health Cancer Institute, discusses mucosal melanoma and treatment options for the disease.

The prognosis of mucosal melanoma is difficult to treat, and outcomes for patients are not as satisfactory as with other melanoma types, like cutaneous melanoma, according to Carvajal. One factor contributing to poor prognosis in patients with mucosal melanoma is the fact that the disease is often diagnosed in the later stages, Carvajal explains.

Carvajal also notes that there has been an increasing interested in studying the biology of mucosal melanoma, which may lead to better therapies in the future. However, despite clinical trials that investigated chemotherapy vs interferon therapy and the use of checkpoint blockade, there have been no recent FDA approvals for mucosal melanoma.

As clinical trials continue in the mucosal melanoma space, an important question to address will be that neoadjuvant vs adjuvant therapy. Carvajal notes that in the phase 2 SWOG 1801 clinical trial (NCT03698019), neoadjuvant pembrolizumab (Keytruda) showed event-free survival benefit when compared with adjuvant pembrolizumab in patients with stage III-IV disease. Studies looking further into the potential benefit of treatment in the adjuvant setting are ongoing. Moreover, there are novel targeted therapies under investigation for the treatment of mucosal melanoma.

Carvajal explains that while oncologists wait for result from clinical trials that may provide better information regarding treatment, mucosal melanoma treatment should be approached in a multidisciplinary fashion. Oncologists should also strongly consider enrolling their patients onto clinical trials. Outside of the clinical trial setting, Carvajal notes that checkpoint blockade gas been proven effective for the treatment of mucosal melanoma. Still, whether to use an immune checkpoint inhibitor combination like nivolumab (Opdivo) plus ipilimumab (Yervoy) remains an unsewered question in the field.

In season 4, episode 4 of Targeted Talks, Richard D. Carvajal, MD, discusses mucosal melanoma and treatment options for the disease. 

Understanding and Treating Mucosal Melanoma 

In season 2, episode 7 of Targeted Talks, Jeff Yorio, MD, a physician and hematology and medical oncology specialist with Texas Oncology-Austin Central and Douglas Johnson, MD, MSCI, an assistant professor of Medicine and Hematology/Oncology at Vanderbilt University Medical Center, joins us for a talk around recent advances in immunotherapy for melanoma.

First, Yorio discusses how the use of immunotherapy in melanoma has changed in his own practice over the past 5 to 10 years, considering tha there were limited options for these patients in the beginning. For patients with stage IV melanoma or high-risk stage III melanoma, clinical trials were the only option. Chemotherapy was also an option but had very little activity.

According to Yorio, checkpoint inhibitors made a dramatic change in the melanoma landscape. There are even some patients who were enrolled in the initial checkpoint inhibitor trials who are still alive 6 years later.

Johnson has had a similar experience with melanoma immunotherapy in community practice. Compared with years ago when survival rates were low, data has now shown an over 50% survival rate for patients treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

In season 2, episode 7 of Targeted Talks, Jeff Yorio, MD, and Douglas Johnson, MD, MSCI, talk about recent advances in immunotherapy for melanoma.

Recent Developments in Immunotherapy for Melanoma

A phase 3 trial plans to further assess neoadjuvant darovasertib for the potential treatment of patients with primary uveal melanoma.

FDA Grants Breakthrough Therapy Designation to Darovasertib in Melanoma

Tilsotolimod plus ipilimumab did not show benefit vs ipilimumab alone in anti–PD-1 refractory melanoma, despite prior positive phase 1/2 trial data.

Tilsotolimod Combo Does Not Improve Outcomes in Refractory Melanoma

During a live event, James W. Smithy, MD, MHS, and other oncologists discussed how their experience with immune-related adverse events in metastatic melanoma has developed over time.  

Experience Managing irAEs Vital for Both Oncologists and Specialists

The anti–PD-1/VEGF combination of pembrolizumab and bevacizumab elicited strong clinical activity in patients with melanoma brain metastases.

Pembrolizumab Plus Bevacizumab Shows Promise for Melanoma Brain Metastases

Georgina V. Long, MD, MSc, discussed the long-term follow-up data for the combination of adjuvant dabrafenib and trametinib in stage III BRAF-mutated melanoma.

Dr Long Highlights Long-Term Benefit of Dabrafenib/Trametinib in Melanoma 

The Promise of OBX-115, a Novel TIL Therapy, in Melanoma

Rodabe Amaria, MD, medical oncologist in the Department of Melanoma Medical Oncology, Division of Cancer Medicines, at MD Anderson Cancer Center, discusses the current role of OBX-115, a novel engineered tumor infiltrating lymphocyte (TIL) therapy, and how it compares with other agents being developed and designed for the treatment of patients with checkpoint inhibitor-resistant metastatic melanoma.

Traditional TIL therapies typically require toxic high-dose interleukin-2 (IL2). However, 

uses a regulated IL15 system and eliminates the need for this harmful cytokine. According to Amaria, this offers an improved safety profile.

OBX-115 is currently being investigated in a phase 1 study (NCT05470283). Findings were previously presented at the 2024 American Society of Clinical Oncology Annual Meeting, showing that in patients with unresectable or metastatic melanoma resistant to immune checkpoint inhibitors (n = 9), the combination of OBX-115 plus acetazolamide led to an objective response rate (ORR) of 44.4%, including complete response and partial response rates of 22.2% each. For patients given 30 billion cells at OBX-115 infusion (n = 6), the ORR was 50%.

A total of 55.6% of patients had stable disease that lasted for at least 12 weeks, and no patients had progressive disease, translating to a disease control rate of 100%. Additionally, the progression-free survival (PFS) rate at 24 weeks was 75%.

For safety, findings showed that at a median follow-up of 29.5 weeks (range, 13.0-69.3), no treatment- or disease-related mortality were reported. No patients required admission to an intensive care unit, no dose-limiting toxicities were reported, and no cases of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or capillary leak syndrome were seen.

In the interview, Amaria notes that when compared with other TIL therapies, OBX-115 is engineered and does not require the use of interleukin-2, which offers an improved safety profile.

Amaria RN, McQuade JL, Davies MA, et al. OBX-115, an interleukin 2 (IL2)-sparing engineered tumor-infiltrating lymphocyte (TIL) cell therapy, in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma. 

. 2024;42(suppl 16):9515. doi:10.1200/JCO.2024.42.16_suppl.9515

Videos

Rodabe Amaria, MD, discusses the current role of OBX-115 for the treatment of patients with checkpoint inhibitor-resistant metastatic melanoma. 


News

Amaria Highlights Phase 1 Trial of OBX-115 in Melanoma

Rodabe N. Amaria, MD, medical oncologist in the Department of Melanoma Medical Oncology, Division of Cancer Medicines, at MD Anderson Cancer Center, explains a trial of OBX-115 (NCT05470283), a novel engineered tumor infiltrating lymphocyte (TIL) therapy, for the treatment of patients with checkpoint inhibitor-resistant metastatic melanoma.


According to Amaria, early data from the phase 1 study, including findings presented at the 2024 American Society of Clinical Oncology Annual Meeting were encouraging, as OBX-115 was shown to be well-tolerated and did not lead to any severe adverse events.

The agent also demonstrated significant antitumor activity, leading to durable responses in half of the patients studied, including 2 complete remissions and 1 partial remission.

FDA granted a regenerative medicine advanced therapy designation to OBX-115

 for the treatment of patients with unresectable or metastatic melanoma that has been resistant to immune checkpoint inhibitor therapy. In July 2024, the FDA also granted the agent fast track designation.

 This is a trial specifically focusing on patients with immune checkpoint inhibitor-refractory melanoma. There has been a lot of research in this space. And honestly, it is a bit of an open area, we do not really have a clear directive of how to treat these patients. And so this represents a really active area of research in melanoma. So, my trial specifically is focusing on that patient population because it's the biggest unmet need.

 This is an early phase study, it really helped us get a sense of what we were dealing with and how we can tweak the regimen to make it better. So currently, there is ongoing optimization of this regimen in a clinical trial, a multicenter clinical trial that's currently enrolling in melanoma, as well as non–small cell lung cancer, where we are doing a little bit more digging into the dosing of the OBX TIL, as well as the duration and dosing of the FDA-approved small molecule inhibitor acetazolamide [Diamox], that turns the cells on.

Rodabe N. Amaria, MD, explains a trial of OBX-115, a novel engineered tumor infiltrating lymphocyte therapy, in checkpoint inhibitor-resistant metastatic melanoma.


Melanoma Treatment Advances: Fianlimab and Cemiplimab Show Promise

A longer-term follow-up of a study evaluating fianlimab, an anti-LAG-3 agent, and cemiplimab (Libtayo), an anti-PD-1 agent, is being presented as a poster at this year's European Society for Medical Oncology (ESMO) Congress. Meredith McKean, MD, director of melanoma and skin cancer research at the Sarah cannon Research Institute in Nashville, TN, discusses findings from this analysis. 

Investigators observed that the combination therapy achieved a 57% overall response rate with a median progression-free survival of 24 months. Immune-mediated adverse events were similar to those seen with PD-1 monotherapy. Further, a significant number of patients maintained responses for over a year, with some completing 2 years of treatment, and the combination therapy was effective regardless of PD-L1 or LAG-3 expression levels.

Overall, fianlimab and cemiplimab demonstrated promising efficacy and safety in patients with melanoma, suggesting it may be a valuable treatment option.

the American Society of Clinical Oncology (ASCO) Annual Meeting] in 2023

. There were 3 different cohorts that were evaluated: the initial frontline cohort in the metastatic melanoma setting, and patients that were anti-PD-1 naive, and there was a confirmatory cohort of additional patients, and then a third cohort of patients that had previously received either neoadjuvant or adjuvant anti-PD-1. 

And so in those initial results presented last year, we saw response rates between 56 to 63%. This additional follow-up, with a median follow up of 23 months for patients, we saw with the evaluation of the blinded independent central review, we saw a relatively preserved objective response rate of 57%, and we really saw ongoing durability of those initial responses that patients had. Additionally, the complete response rate was 25% and so we saw that deepening with time, which is really, really exciting for our patients.

Meredith McKean, MD, discusses a longer-term follow-up study investigating fianlimab and cemiplimab immunotherapy in advanced melanoma. 

Conference News

OBX-115 is a novel engineered tumor infiltrating lymphocyte (TIL) therapy designed to treat patients with checkpoint inhibitor-resistant metastatic melanoma. Unlike traditional TIL therapies that require toxic high-dose interleukin-2 (IL2), OBX-115 incorporates a regulated IL15 system, eliminating the need for this harmful cytokine.

Early results from a phase 1 study (NCT05470283) are encouraging. OBX-115 was well-tolerated with no severe adverse effects. Importantly, it demonstrated significant antitumor activity, leading to durable responses in half of the patients studied. This includes 2 complete remissions and 1 partial remission. The therapy also showed no sign of promoting brain metastases, a common concern with cancer treatments.

These findings suggest that OBX-115 has the potential to be a safe and effective treatment option for patients with advanced melanoma who have failed other therapies. Further studies are ongoing to confirm these promising results.

Here, Rodabe Amaria, MD, medical oncologist in the Department of Melanoma Medical Oncology, Division of Cancer Medicines, at MD Anderson Cancer Center, discusses the background and findings of this study. 

 We are using in the study a novel T-cell therapy called OBX-115. So a little bit of background here: TIL is basically stands for tumor infiltrating lymphocytes. The idea is we take a patient with metastatic melanoma, subject them to some kind of surgery to remove a piece of melanoma tissue, that tissue gets sent to a lab. From there, we grow lots and lots of T cells that can be engineered to be really active, antimelanoma, little fighters. And then we infuse them back into the patient after giving them a course of chemotherapy. Traditionally, we use a medication called high-dose IL2 after the T cells are infused to make an environment where the T cells can grow and thrive. But that's really associated with toxicity. And what we're doing with OBX-115 is totally changing the way that we're doing TIL. We still have the component of taking tumor out; we still grow them in a lab. But our lab has the technique to basically genetically manipulate these T cells to make them better and to prevent them from having to use IL2. So basically, we can turn those T cells on after we infuse them into the patient, we can give an FDA-approved small molecule inhibitor, turn the T cells on, and when we turn those T cells on, it makes its own cytokines. So instead of having to use IL2, we can regulate the expression of the cytokine. And in that way, we think it's safer, we think we can offer this to a bigger pool of patients. And we think the T cells are just better overall. 


This is a first-in-human study, and we're really only presenting data on the first 10 patients, specifically 9 patients included in the per protocol efficacy analysis. And here we found a response rate of 44%, including 22% of patients having a complete response. Additionally, there were no patients with primary progressive disease. So 100% disease control rate. 75% of the patients were progression-free at 24 weeks. And because this was a dose escalation, if we specifically look at the group of patients that received over 30 billion TIL, response rate is 50%. Additionally, we did a lot of analysis on safety. We really didn't see any unexpected safety profiles. We saw expected side effects from the chemotherapy. And otherwise we saw a low-level rash, right, as from the actual T cell infusion.

OBX-115: A Promising TIL Therapy for Melanoma

A study explored a new approach to treating melanoma that has spread to the meninges, the membranes surrounding the brain and spinal cord (leptomeningeal disease or LMD). LMD is a rare but aggressive form of metastasis with very limited treatment options and poor prognosis.

The main hurdle in developing new therapies has been the lack of good models to study the disease. This research addresses this by establishing methods to grow melanoma cells from patient spinal fluid samples (CSF-CTCs) in the lab and in mice.

Using these models, researchers at the Moffitt Cancer Center screened a library of existing drugs and identified several with promising activity against the melanoma cells. One drug, homoharringtonine, showed good results in mice, significantly extending their survival.

This study demonstrates a groundbreaking approach for developing targeted therapies for melanoma-associated LMD. It provides valuable insights into the disease biology and paves the way for potential new treatment options for patients with this aggressive cancer.

Here, Vincent Law, research associate at Moffitt Cancer Center, discusses the key takeaways and implications of this research.

Vincent Law, research associate at Moffitt Cancer Center, discusses the key takeaways and implications of this research.

Melanoma

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