Dr Kluger on the FDA Approval of Lifileucel in Advanced Melanoma

Harriet Kluger, MD, Harvey and Kate Cushing Professor of Medicine (Oncology) and of Dermatology; director, Yale SPORE in Skin Cancer; vice chair, Translational Research, Internal Medicine; chief, Division of Skin and Kidney Cancer; associate cancer center director, Education, Training and Faculty Development; deputy section chief, Medical Oncology, Yale Cancer Center, discusses 

 of the tumor infiltrating lymphocyte (TIL) therapy lifileucel (Amtagvi) for patients with advanced melanoma.

On February 16, 2024, the FDA approved lifileucel for the treatment of adult patients with unresectable or metastatic melanoma whose disease has been previously treated with a PD-1 inhibitor, as well as a BRAF inhibitor with or without a MEK inhibitor for 

 V600–mutated disease This regulatory decision was supported by findings from cohorts 2 and 4 of the phase 2 C-144-01 trial (NCT02360579). Patients who received lifileucel at the recommended dose (n = 73) achieved an overall response rate of 31.5%, including complete response and partial response rates of 4.1% and 27.4%, respectively.

This FDA approval is important because it marks the first cellular and TIL therapy product to be approved by the FDA for patients with solid tumors, Kluger says. Unlike CAR T-cell products, which have been used in patients with liquid tumors, TIL products use cells from patients’ tumors that will theoretically recognize multiple tumor antigens, Kluger explains. TILs are expanded, then reinfused into patients, which is different from the process of administering CAR T-cell therapy, wherein T cells are leukapheresed, engineered into CAR T-cells, then reinfused into patients, Kluger notes.

The use of TILs for the treatment of patients with solid tumors is a unique treatment paradigm, and lifileucel is likely the first of several TIL products that will be available for patients with melanoma, as well as those with other solid tumors, according to Kluger. As science and cell engineering technology becomes more sophisticated, increasingly targeted cell therapy products will emerge that will be better equipped against tumor cells than the bystander antigens present in patients’ bodies, Kluger concludes.

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Harriet Kluger, MD, discusses the FDA approval of the tumor infiltrating lymphocyte therapy lifileucel for patients with advanced melanoma.

Harriet Kluger, MD, professor of medicine, associate cancer center director for education and training, deputy section chief, Medical Oncology, Yale Cancer Center, discusses the progression of treatment for patients with melanoma who have brain metastases. 

Prior to 2011, though not a standard of any other organ, patients with brain metastases had been excluded from clinical trials with the exception of patients whose metastases had been stabilized for many weeks. 

It has since been discovered that other organs with a similar prognosis have a worse prognosis than in the brain. These patients had been excluded due to concerns about side effects in the brain and whether these drugs could penetrate the blood-brain barrier. 

A number of trials have since been conducted, mainly with melanoma, but are starting to be used in other diseases as well. Research suggests responses in the brain are similar to those in extra cerebral sites. Though stereotactic surgery has had a high success rate in treating patients with brain metastases, systemic therapy is now becoming an integral part of therapy for patients whose diseases have metastasized to the brain. 

Harriet Kluger, MD, professor of medicine, associate cancer center director for education and training, deputy section chief, Medical Oncology, Yale Cancer Center, discusses the progression of treatment for patients with melanoma who have brain metastases.

Dr. Kluger on Systemic Management of Melanoma With Brain Metastases

Harriet Kluger, MD, associate professor of medicine, Yale Cancer Center, talks about the toxicity of nivolumab and ipilimumab for the treatment of patients with advanced melanoma.

The trial showed extremely promising results, including one-and two- year overall survival rates of 85% and 79%, respectively. However, there was a grade 3/4 adverse event rate of over 50%. Increased communication and early-intervention when toxicities were identified resulted in improved quality of life for the patient, says Kluger.

If the toxicities were treated early with immune suppressants, most were reversible.

Dr. Kluger on Toxicity of Nivolumab/ Ipilimumab for Advanced Melanoma

Harriet Kluger, MD, associate professor of medicine, Yale Cancer Center, discusses the results from a phase I trial of nivolumab and ipilimumab for the treatment of patients with advanced melanoma.

The overall response rate of patients on the trial was over 40%, Kluger says, while one- and two- year overall survival rates were 85% and 79%, respectively. This type of survival has never been seen before in metastatic melanoma.

Kluger notes that many patients had a poor prognosis prior to the trial — many had elevated LDH and 53% of patients were M1c.

Dr. Kluger on a Phase I Trial of Concurrent Nivolumab and Ipilimumab

Harriet Kluger, MD, associate professor of medicine (medical oncology), associate director, Hematology/Oncology Fellowship Program, Yale Cancer Center, discusses the changes and challenges of treating patients with melanoma.

Kluger says things are changing in the field of melanoma treatment. Ten years ago, a newly-diagnosed metastatic patient would be told that the median survival is approximately 6-9 months. However, patients and physicians now do not talk about survival rates with newly diagnosed patients, Kluger say, because of new anti-PD-1 agents, like nivolumab and lambrolizumab (MK-3475).

A recent phase I trial of nivolumab has shown a median duration of response was almost 2 years and patients with metastatic melanoma can now work, exercise, and live their lives.

Though these agents can have extremely durable responses, there is currently no way of predicting who will respond and how long they will respond for, which makes treating the disease very challenging.

Dr. Kluger on the Challenges of Treating Melanoma

Harriet Kluger, MD, associate professor of medicine (medical oncology), associate director, Hematology/Oncology Fellowship Program, Yale Cancer Center, discusses the effectiveness of immunotherapy as treatments for patients with melanoma.

A few years ago, the only two immune therapies that were approved for melanoma were interleukin-2 and interferon, Kluger says. Interferon has never been proven to prolong survival and interleukin-2 only prolongs survival in a small subset of patients.

About two years ago, Kluger says, ipilimumab was approved and is active in a majority of patients. Currently, there is a trial looking at the efficacy of adding a PD-1 inhibitor to ipilimumab. Kluger thinks that these two immune therapies may even be able to be used sequentially.

Kluger predicts that in the future, the first-, second-, and third-line therapy for patients with metastatic melanoma will be an immune-targeted therapy.

Harriet Kluger, MD, associate professor of medicine (medical oncology), associate director, Hematology/Oncology Fellowship Program, Yale Cancer Center, discusses the future for immune therapies in melanoma.

Harriet Kluger, MD

Articles

Dr Kluger on the FDA Approval of Lifileucel in Advanced Melanoma

Dr. Kluger on Systemic Management of Melanoma With Brain Metastases

Dr. Kluger on Toxicity of Nivolumab/ Ipilimumab for Advanced Melanoma

Dr. Kluger on a Phase I Trial of Concurrent Nivolumab and Ipilimumab

Dr. Kluger on the Challenges of Treating Melanoma

Dr. Kluger on Immunotherapy in Melanoma