The FDA has delivered a complete response letter to Incyte Corporation stating it is unable to approve the biologics license application (BLA) for retifanlimab (INCMGA 0012). The application sought to treat adult patients with locally advanced or metastatic squamous cell carcinoma of the anal canal who have either progressed on, or cannot tolerate, platinum-based chemotherapy, in its present form. 

The regulatory agency determined that more data are needed to showcase the clinical benefit of the intravenous PD-1 inhibitor for use in this patient population. The global biopharmaceutical company is reviewing the letter and will discuss next steps with the FDA in the future.

“Patients with SCAC who have progressed after first-line chemotherapy currently do not have approved treatment options,” Hervé Hoppenot, chief executive officer of Incyte, stated in a press release. “While we are not surprised with the FDA decision given the Oncologic Drugs Advisory Committee [ODAC] recommendation, we are disappointed. We remain committed to advancing science to find solutions for patients with unmet medical needs, and we will ensure close coordination with the FDA in order to address feedback and determine next steps for the review of retifanlimab.”

Previously, in June 2021, the FDA’s ODAC voted 13 to 4 to hold off on a decision regarding the accelerated approval of the immunotherapy for use in this population.

 The BLA submission was supported by data from the phase 2 P0D1UM-202 trial (NCT03597295), which were presented during the 2020 ESMO Virtual Congress and had demonstrated that the agent had promising activity in patients with platinum-refractory SCAC, including those positive for human immunodeficiency virus (HIV).

In the open-label, single-arm, multicenter trial, investigators enrolled 94 patients with confirmed locally advanced or metastatic SCAC. Patients needed be at least 18 years of age, have progressed on or following platinum-based chemotherapy, and had measurable disease per RECIST v1.1 criteria. Patients also needed to have an ECOG performance status of 0 or 1.

Study participants were administered retifanlimab intravenously at a dose of 500 mg once every 4 weeks as part of a 28-day treatment cycle for up to 2 years. The primary end point of the trial was objective response rate (ORR) by ICR and RECIST v1.1 criteria. Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

The median age of patients on the trial was 64 years, 61% were female, and 77% were White. Fifty-nine percent of patients had an ECOG performance status of 1, 10% of patients had known HIV positivity, and 42% had liver metastases. Moreover, 73% of patients had previously received chemoradiation, 17% had prior radiotherapy, and 97% had prior platinum-based treatment.

The PD-1 inhibitor was found to induce an ORR of 13.8% (95% CI, 7.6%-22.5%) per independent central review assessment, in accordance with RECIST v1.1 criteria; this included a complete response rate of 1.1%, a partial response rate of 12.8%, and a stable disease rate of 35.1%. Moreover, 45.7% of patients had progressive disease.

The median DOR with the immunotherapy was 9.5 months, and responses were reported in patients, irrespective of PD-L1 status, the presence of liver metastases, age, or HIV status. Additionally, the DCR achieved with retifanlimab in this population was 48.9%.

At a median follow-up of 7.1 months, the median PFS with retifanlimab was 2.3 months (95% CI, 1.9-3.6), and the median OS was 10.1 months (95% CI, 7.9–not estimated).

Just under 60% of patients (58.5%) reported a treatment-related toxicity with retifanlimab; 11.7% of these patients experienced an effect that was grade 3 or higher. About 4% of patients experienced an adverse effect that led to treatment discontinuation.

Moreover, 25.5% of patients reported an immune-related toxicity with the agent, 6.4% of which were grade 3 or higher. About 2% of patients reported an immune-related toxicity that led to discontinuation. Of all the patients who received the agent, 4.3% experienced infusion reactions. Notably, no loss of HIV control was observed in the 9 patients who were HIV positive.

Previously, retifanlimab was granted an orphan drug designation from the FDA for the treatment of patients with anal cancer.

The immunotherapy is under investigation in the ongoing phase 3 POD1UM-303/InterAACT 2 trial (NCT04472429), where it is being combined with carboplatin and paclitaxel vs placebo in patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal cancer who have not received prior systemic chemotherapy.

Incyte provides regulatory update on retifanlimab for the treatment of certain patients with squamous cell carcinoma of the anal canal (SCAC). News release. Incyte Corporation. July 23, 2021. Accessed July 26, 2021. 

Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. June 24, 2021. Accessed July 26, 2021. 

https://www.youtube.com/watch?v=zj1lRsDwWB0

Rao S, Capdevila J, Gilbert D, et al. POD1UM-202: phase 2 study of retifanlimab in patients with squamous carcinoma of the anal canal who progressed following platinum-based chemotherapy. 

. 2020;31(suppl 4):S1170-S1171. doi:10.1016/j.annonc.2020.08.2272

Carboplatin-paclitaxel with retifanlimab or placebo in participants with locally advanced or metastatic squamous cell anal carcinoma (POD1UM-303/InterAACT 2). ClinicalTrials.gov. Updated June 11, 2021. Accessed July 26, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04472429

This article was originally published on OncLive as 

“FDA Issues a Complete Response Letter for Retifanlimab for Squamous Cell Carcinoma of the Anal Canal”

Articles

The FDA has determined that more data are necessary to certify the clinical benefit of retifanlimab for the treatment of squamous cell carcinoma of the anal canal. 

FDA Delivers Complete Response Letter for Retifanlimab for SCC Subgroup 

The FDA has approved an extended indication for pembrolizumab (Keytruda) for patients with recurrent or metastatic, or locally advanced cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation, according to Merck, the manufacturer of the immunotherapy agent.

“This approval is great news for these patients and further demonstrates Merck’s commitment to the skin cancer community. Keytruda has shown meaningful efficacy in patients with locally advanced or recurrent or metastatic cutaneous squamous cell carcinoma that cannot be cured by surgery or radiation,” said Vicki Goodman, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “This expanded indication reinforces the role of Keytruda in this cancer type, which is the second most common form of non-melanoma skin cancer.”

The approval was based off findings from the multicenter, multi-cohort, non-randomized, open label, phase 2 KEYNOTE-629 trial (NCT03284424). The study assessed patients with recurrent or metastatic, or locally advanced cSCC, excluding patients with autoimmune disease or medical conditions requiring immunosuppression.

The patients treated with pembrolizumab demonstrated an overall response rate (ORR) of 50%, which included 17% complete and 33% partial response rates. In a range of follow-up times spanning from 1.0 to 17.2 months, (the average follow-up time was 13.4 months), 81% of patients had a duration of response (DOR) greater than 6 months while 37% reported a DOR greater than 12 months.

The median duration of exposure to pembrolizumab was 6.9 months for the 159 patients enrolled in the trial.

Adverse events (AEs) among the patients with recurrent or metastatic, or locally advanced cSCC were comparable to those reported in the 2,799 patients who were administered pembrolizumab as a single agent to treat their melanoma or non-small cell lung cancer.

Potentially fatal or severe immune-mediated AEs included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. For more severe AEs, it may be appropriate to administer corticosteroids in place of pembrolizumab, according to the release. Grade 3 to 4 laboratory abnormalities that appeared at a higher incidence included lymphopenia (10%) and decreased sodium (10%).

FDA Approves Expanded Indication for Merck’s KEYTRUDA® (pembrolizumab) in Locally Advanced Cutaneous Squamous Cell Carcinoma (cSCC). News release. Merck. July 6, 2021. Accessed July 6, 2021. https://www.merck.com/news/fda-approves-expanded-indication-for-mercks-keytruda-pembrolizumab-in-locally-advanced-cutaneous-squamous-cell-carcinoma-cscc/

The Food and Drug Administration has approved pembrolizumab for the treatment of patients with a locally advanced form of skin cancer. 


FDA Approves Expanded Indication for Keytruda in Recurrent or Metastatic cSCC

While merkel cell carcinoma (MCC) tends to have poor prognoses and limited treatment options, promising response rates with checkpoint inhibitors may pave the way for better treatment for the rare skin cancer, according to James A. DeCaprio, MD. 

“Within the medical community there has been awareness raised for MCC because of the success [seen] with checkpoint blockade therapy,” said DeCaprio. “Now, more people know about MCC, and even people who are not involved in skin cancer [treatment] are aware of it. We’re never going to see an ad on TV for MCC treatment because it is rare, but there are certainly opportunities to build on the really spectacular responses to checkpoint blockade [we’ve seen].”

For example, the novel, oral, MDM2 small molecule inhibitor KRT-232 is being evaluated in a phase 2 study (NCT03787602) for patients with 

 wild-type MCC who have failed treatment with a PD-1/PD-L1 inhibitor.

 Initial results of the study demonstrated early efficacy signals and good tolerability with KRT-232 monotherapy in this patient population.

, DeCaprio, a physician at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, discussed the incidence of MCC, risk factors for the disease, established treatment options, and investigational regimens on the horizon.

: MCC is a very interesting cancer. It is among the rarer skin cancers; it is 40 times less common compared with melanoma and many times less common compared with squamous cell carcinoma and basal cell carcinoma. MCC is highly aggressive, so we can’t fool around with [diagnosing] it. It shows up as an innocuous little skin bump but can grow very quickly. Usually, just the speed of growth has a patient coming to their doctor.

Many patients with MCC already have a dermatologist because they have a history of skin cancer, such as squamous cell carcinoma or basal cell carcinoma. A few patients with melanoma have also gone on to develop MCC.

[The incidence of MCC] is about 1 per 100,000 in the United States. The incidence is going up, however. Part of that increase in incidence is because MCC is a rare cancer. It was only first described in 1972 by [the late] Cyril Toker, [MBBCh, FRCS, MS, JD, of the University of Maryland]. MCC is rarely suspected when a patient shows up with a skin bump. Most pathology specimens do not have [the ability to] rule out MCC on the clinical diagnosis. In fact, I’ve only seen one pathology report even suggest that [a patient] could have MCC. Usually, MCC is thought to be a benign cyst that [can be resected]. Then, the pathologist will call back and let [the patient] know it is MCC.

Sunlight exposure, as well as age, are contributing to the rising incidence of MCC. MCC can show up in younger people in their 20s with tanning bed exposure, as well as in people in their 30s and 40s. The incidence starts taking off in [individuals between the ages of] 60 years to 90 years.

What are some of the risk factors for MCC?

One risk factor for MCC is sunlight exposure or intense ultraviolet (UV) exposure. Often sun-exposed areas, such as the face, neck, arms, and legs, are where many MCC [nodules] show up.

Maybe as much as 10% of all patients with MCC are immunocompromised in some way. Solid organ transplantation is another risk factor, as well as the treatments of some autoimmune diseases, such as rheumatoid arthritis, and psoriatic arthritis. Therefore, there is an immune component to this disease, both in its risk factors and treatment. We have had a few patients have some genetic predisposition to immunosuppression as well.

MCC is rare even under all of those circumstances. Most people with psoriatic arthritis do not develop MCC, but it is definitely a risk factor.

How do you categorize some of the unique challenges in MCC?

There are 2 unique challenges with MCC: one is on the biologic side and the other is on the clinical side.

On the biologic side, MCC can be caused by excessive UV damage to the tumor genome [that causes] lots of mutations. The other form of MCC is caused by the Merkel cell polyomavirus. This virus is very common; everyone has it living on the skin. On the wrong day, the virus can get into the wrong place and become integrated into a normal cell to transform it into MCC.

The tumors of [both forms] of MCC look and act identically. They are almost indistinguishable in where they show up on a patient, who is at risk, and how they respond to treatment; it’s quite striking. The similar phenotypes, presentations, histologies, and biologies, but completely unique etiologies are why I study MCC. How does this [polyomavirus] trick a normal cell into becoming this highly aggressive cancer? [The UV-exposure form] helps us to decipher thousands, if not millions, of mutations that UV light [can] introduce into the tumor genome. What driver mutations are really causing the cancer?

On the clinical side, MCC is a solid tumor with the highest response rate to checkpoint inhibitor therapy. PD-1/PD-L1 antibodies have dramatic activity in [patients with] MCC [inducing response rates of] 50% to 60%, often for quite a long time.

It’s great news that MCC responds, but why does it do that? Conversely, why do some patients with MCC not respond to checkpoint blockade? There are a lot of very important questions [being asked] related to that. Of course, we use the biology of this virus to understand this phenotype as well as why [a patient’s disease] would be sensitive [to checkpoint inhibitors] or not.

The other unique thing about MCC is that it shows up commonly on the head and neck area [where] a lot of important and complicated structures [are], but it can also show up in the hands. Because MCC is a rare cancer, there is not much experience in treatment. However, it is very clear that we need skilled teams of physicians that can take care of these patients. These tumors are very sensitive to radiation therapy; radiation can cure MCC without the need for disfiguring surgery to remove the entire tumor. How much of the tumor do we need to remove? How much do we need to radiate? Is there need for additional therapy, such as checkpoint blockade? Often, a lot of morbidity related to surgery or chemotherapy could be spared if the team has experience and knows how to best take care of these patients [with a good] treatment plan.

How have checkpoint inhibitors improved upon historical treatment, such as chemotherapy? How can the field improve upon responses with checkpoint inhibitors?

The world is completely different since 2016 with the first report of checkpoint blockade response in MCC. Up until 2016, we were commonly giving chemotherapy with cisplatin or carboplatin plus etoposide for advanced cases of MCC. This is very toxic chemotherapy but very effective in MCC. Most patients would respond rapidly to that form of therapy.

Chemotherapy itself is immunosuppressive so we were inhibiting the body’s own immune system in trying to protect against MCC by using a cytotoxic therapy. It was also recognized that the responses to chemotherapy did not last that long—maybe 2 to 3 months on average.

When checkpoint inhibitors became available and showed efficacy in MCC, it changed practice dramatically. Pembrolizumab [Keytruda] and avelumab [Bavencio] were both FDA approved rapidly with very small case numbers because responses were so dramatic and there wasn’t an FDA-approved alternative. [The treatment landscape] is completely different now since 2016.

In melanoma, we know that checkpoint inhibitors are also very effective, but [they don’t elicit] response rates as high as 50%. Often in melanoma, the response duration is quite long, [meaning] up to several years. I think of [former president] Jimmy Carter [who has melanoma with brain metastases] and how well he has responded to checkpoint inhibitors for years now.

In MCC, the responses to checkpoint inhibitors may not last as long [as they do in melanoma], so physicians are forced to adapt their checkpoint blockade by changing the dosing schedule, drug, or combining drugs. Because the response durations are not as long, there are significant challenges and opportunities to improve what is already a success story.

Can we extend the responses for patients who do respond? Can we improve the response? Can we find something to help patients who don’t respond at all, either up front or later on? A lot of key challenges [exist].

We study the biology of the virus, which has definitely given us clues about how to go after virus-positive MCC. One of the opportunities [to improve upon responses] is [to use] p53 and MDM2 inhibitors. As it turns out, the polyomavirus goes after 

 susceptible to MDM2 inhibition; it is a unique virus in that sense. It gives us the perfect opportunity to activate 

 by inhibiting MDM2. Papillomavirus, for example, goes after 

 very well, but it eliminates our opportunity to activate it. We haven’t been able to get in the middle of papillomavirus and 

. In MCC, polyomavirus leaves itself exposed to 

 activation. There is a phase 2 clinical trial [NCT03787602] from Kartos using KRT-232, a small molecule inhibitor for MDM2, that is showing very promising activity. We are excited about that and hopefully we will hear more about it in the coming months.

Are there other research efforts ongoing that you would like to highlight?

There is a great [clinical] opportunity with MDM2 [inhibitors] but related to that are MDM4 [inhibitors]. 

 work collaboratively with each other to get rid of 

. Our lab has found that we can independently inhibit MDM2 and MDM4, and that combination will synergistically activate 

. There is a golden opportunity to target 

 together, so with some luck, we will have an [FDA] approval for MDM2 inhibitors [, and potentially MDM4 inhibitors, in the future]. This can also be expanded for drugs that inhibit both [MDM2 and MDM4].

Another pathway we’ve uncovered is LSD1. There is an opportunity for LSD1 inhibitors in MCC and we have talked to a few companies [about trials to that end]. Because MCC is rare, it makes it challenging to put together a study. The MCC that we have studied has been very sensitive to LSD1 inhibitors.

Because the virus is driving a normal cell [to turn into a cancer cell], we’ve found several other targets that could be opportunities for therapy. We are just getting started and there is certainly a really interesting possibility that one of the drug targets could synergize with checkpoint inhibitors. We could have a rational strategy to inhibit checkpoint blockade but then work with the virus to activate the immune response. We will look at some inhibitors in that regard too. Hopefully, we will all be reading about that soon.

How can the community raise awareness for MCC?

In Australia, MCC is a household word and is well understood because of [Australians’] increased risk for all skin cancers. MCC is of a higher incidence [in Australia]—though it is still rare—so it is well understood.

Although melanoma, for example, is a terrible disease, patients can often live a long time with it, particularly when it is caught early before metastasizing. Now, because of certain therapies, even patients with metastatic disease live long to tell their story. MCC is so aggressive that patients don’t often live to tell their story. Patients with stage I or II disease with just a lump and no lymph node [involvement] can mostly be cured.

[Advanced-stage disease] is highly aggressive. Those are the patients we are trying to learn from so that some of them will be able to tell their stories. We are getting some success in this disease. Encouraging patients to tell their stories is one way to get the word out.

This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with (p53WT) Merkel cell carcinoma who have failed anti-PD-1/PD-L1 immunotherapy. ClinicalTrials.gov. Updated December 20, 2019. Accessed June 1, 2021. https://clinicaltrials.gov/ct2/show/NCT03787602.

Wong MKK, Kelly CM, Burgess MA, et al. KRT-232, a first-in-class, murine double minute 2 inhibitor (MDM2i), for TP53 wild-type (p53WT) Merkel cell carcinoma (MCC) after anti–PD-1/L1 immunotherapy. 

. 2020;38(suppl 15):10072. doi:10.1200/JCO.2020.38.15_suppl.10072


This article was originally published on OncLive as, "

Novel Targets Set to Add to Checkpoint Blockade Success in Merkel Cell Carcinoma

While merkel cell carcinoma (MCC) tends to have poor prognoses and limited treatment options, promising response rates with checkpoint inhibitors may pave the way for better treatment for the rare skin cancer. 

New Targets May Improve the Treatment of Rare Skin Cancer

Durable improvements were seen with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) compared to treatment with single-agent ipilimumab in patients with previously untreated advanced melanoma, according to a 6.5-year follow-up of the CheckMate-067 trial presented at the 2021 ASCO Annual Meeting.

The long-term data showed that the median OS with the combination was 72.1 months (95% CI, 38.2–not reached) and 36.9 months with nivolumab alone (95% CI, 28.2-58.7), compared with 19.9 months with ipilimumab alone (95% CI, 16.8-24.6). This is reportedly the longest median OS in a phase 3 clinical trial of advanced melanoma.

Additionally, the 6.5-year progression-free survival (PFS) rate was 34% with nivolumab and ipilimumab and the median PFS was 11.5 months. The rates were 29% and 7% with nivolumab and ipilimumab as single agents, respectively; the median PFS was 6.9 months and 2.9 months, respectively.

“The sustained OS and PFS benefit shown with nivolumab-based treatment, particularly the nivolumab plus ipilimumab combination, has changed the way we look at long-term efficacy outcomes for patients with advanced melanoma,” Jedd D. Wolchok, MD, PhD, FASCO, lead author and chief of the Immuno-Oncology Service, Human Oncology and Pathogenesis Program, at Memorial Sloan Kettering Cancer Center, stated in a press release.2 “These new results from the CheckMate-067 trial, with nearly half of patients treated with the nivolumab and ipilimumab combination surviving to 6.5 years, confirm the durable, sustained benefit of the combination in patients with advanced melanoma.”

In 2015, the FDA approved the combination of nivolumab and ipilimumab for the treatment of patients with metastatic melanoma, based on earlier findings from CheckMate-067. Nivolumab is also approved for use as a single agent in this patient population.

In the double-blind, phase 3 CheckMate-067 study, investigators randomized patients with previously untreated unresectable advanced (stage III or IV) melanoma 1:1:1 to receive the combination of nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks (n = 314), nivolumab alone at 3 mg/kg every 2 weeks plus placebo (n = 316), or ipilimumab alone at 3 mg/kg every 3 weeks for 4 doses plus placebo (n = 315). Treatment was administered until disease progression or unacceptable toxicity.

Patients were stratified by PD-L1 status, 

 mutational status, and metastasis stage.

The co-primary end points of the trial were PFS and OS; secondary end points included objective response rate, descriptive efficacy assessments, and safety.

At the 6.5-year analysis, 49% of patients were alive and in follow-up. Of this percentage, 77% of patients who were treated with nivolumab plus ipilimumab were reported to be off of therapy and did not receive subsequent systemic treatment. Sixty-nine percent of those on nivolumab alone, and 43% of those on single-agent ipilimumab also have been off of treatment and did not require subsequent systemic therapy.

The clinical benefit was sustained and observed with both nivolumab/ipilimumab and nivolumab alone across relevant key subgroups, which included those with 

 wild-type tumors, and patients with baseline liver metastases.

 wild-type melanoma, the OS rate was 46% in those who received the combination, 42% for nivolumab alone, and 22% for ipilimumab alone. In those with liver metastases, the OS rates were 38%, 31%, and 22% for the combination, nivolumab monotherapy, and ipilimumab monotherapy, respectively.

In the combination arm, as well as in the single-agent nivolumab arm, the median duration of response (DOR) has still not yet been reached; the median DOR was 19.2 months for those on the ipilimumab arm.

Regarding safety, the profile of nivolumab and ipilimumab combined was found to be consistent with prior data of the regimen and no new safety signals were observed. No additional treatment-related deaths had occurred since the 5-year analysis of CheckMate-067.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 59% of patients on the nivolumab/ipilimumab arm, in 24% on the nivolumab-alone arm, and in 28% of patients on the ipilimumab arm.

“These results build upon our decade-long legacy in treating melanoma, which began when the average life expectancy following a diagnosis of metastatic melanoma was roughly six months and less than 10% of patients survived beyond five years,” stated Gina Fusaro, development lead, melanoma, Bristol Myers Squibb.

 “With some of the longest follow-up with immunotherapies to date, Opdivo and Yervoy have consistently demonstrated durable, long-term survival benefits for patients diagnosed with advanced melanoma.”

Previously, 5-year follow-up findings from CheckMate-067, which were published in the 

, showed that the median OS with nivolumab/ipilimumab was not reached and was 36.9 months with nivolumab alone, compared with 19.9 months with ipilimumab alone (HR, 0.52 for nivolumab/ipilimumab vs ipilimumab; HR, 0.63 for nivolumab vs ipilimumab). The median follow-up was 60 months.

At 5 years, the OS rate was 52% with nivolumab plus ipilimumab, 44% with nivolumab alone, and 26% with ipilimumab alone.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. J Clin Oncol. 2021;39(suppl 15):9506. doi:10.1200/JCO.2021.39.15_suppl.9506

Six-and-a-half-year outcomes for Opdivo (nivolumab) in combination with Yervoy (ipilimumab) continue to demonstrate durable long-term survival benefits in patients with advanced melanoma. News release. Bristol Myers Squibb. May 19, 2021. Accessed June 6, 2021. https://bit.ly/3pnRufC

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. 

. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836

Nivolumab with or without ipilimumab improved survival over ipilimumab alone in patients with previously untreated advanced melanoma. 

Melanoma Outcomes Are Improved With Nivolumab Alone or With Ipilimumab

Tumor-infiltrating lymphocytes (TIL), a neoantigen-targeting therapy, has been shown to be a potentially curative treatment for patients with metastatic melanoma, and has led to clinical responses in this population even after failure with checkpoint inhibitors, according to Inge Marie Svane, MD, PhD.

However, several questions remain with this therapeutic approach, Svane, a professor in Clinical Cancer Immune Therapy at the University of Copenhagen, and director of National Center for Cancer Immune Therapy at Herlev and Gentofte Hospital, said in a presentation during the AACR Annual Meeting 2021.

“We don’t really know the whole truth about antigen specificity driving TIL efficacy. We know that some of the tumor-reactive TILs represent neoantigen-specific T cells, [while] some represent more shared or tumor-associated antigens, and some may be viral antigens; however, there is also a population of these tumor-reactive T cells that are still unknown to us,” Svane explained. “We need to improve on how we can define TIL potency to document the efficacy of this therapy, and we need to clarify the role of CD4 T cells in the product. [Another] broad area of [interest is] to figure out how to increase the efficacy of TIL therapy in non-melanoma cancers.”

TILs represent the most developed strategy for neoantigen-targeting immunotherapy, and it is well known that this therapy has shown efficacy in infiltrating tumors, Svane said. Additionally, efforts to expand, isolate, and stimulate TILs have been examined, according to Svane.

“We can show that a certain fraction of these expanded cells react toward the tumor, Svane said. “In this subpopulation of tumor-reactive T cells, we find neoantigen-specific T cells, as well as tumor-associated antigen-specific T cells, and T cells reactive toward viral antigens like human papillomavirus [HPV]. Then, the last fraction of these tumor-reactive T cells are of unknown specificity.”

Adoptive T-cell therapy is established by taking tumor tissue from the patient and driving out the T cells from the tumor lesion, which is followed by initial TIL expansion. In the last 2 weeks, TIL is rapidly expanded through the stimulation of anti-CD3 feeder cells and high doses of interleukin (IL)-2 to achieve 50 to 200 x 109 TILs for infusion, according to Svane. Patients are preconditioned with high-dose chemotherapy for 1 week prior to infusion with the TILs. Then, the TILs are infused and thereafter they are supported with high doses of IL-2.

This method for TIL infusion was established over a decade ago and published data showed response rates ranging from 50% to 70% in patients with metastatic melanoma. Additionally, more than 20% of patients experienced long-term survival with this therapy. Twenty patients achieved a complete response (CR); among these complete responders, the 3-year survival rate was 100%, and the 5-year survival rate was 93%.

“With a long-term follow-up of more than 8 years, the National Cancer Institute has recently shown that this is an extremely durable response if the patients achieved CR, and it is highly likely that they will be cured of their metastatic melanoma,” Svane said.

In another phase 1/2 study (NCT00937625), adoptive cell therapy with TILs was examined in patients with metastatic melanoma who had progressed on prior treatment with high-dose IL-2 and ipilimumab (Yervoy). Overall, 25 patients were enrolled to the study and underwent a 3-step treatment comprised of high-dose chemotherapy, TIL infusion, and IL-2.

 The overall response rate (ORR) achieved with this regimen was 42%, and once again, patients who achieved a CR demonstrated a long duration of response (DOR) to treatment, according to Svane.

Additionally, results from a meta-analysis that examined studies that administered adoptive cell therapy with TILs at treatment centers worldwide showed that durability of response can be experienced with this treatment if a CR is achieved.

Responses in PD-1–Resistant Melanoma With TILs

Anti–PD-1 therapy is one of the main treatment strategies for patients with metastatic melanoma, according to Svane, and as such, it was important for investigators to examine whether adoptive cell therapy with TILs can be utilized in patients who had progressed on this therapy.

“We showed in a small cohort of patients that we were, indeed, able to induce remission of metastatic lesions in patients progressing on anti-PD-1 [agents],” Svane said. “We also found tumor-reactive T cells in the product as well as in the peripheral blood after treatment. [However,] the durability of the treatment seems to be shorter lasting.”

This was also demonstrated in a study that examined clinical responses to TIL therapy in patients who were PD-1 naïve (n = 32) vs those who had progressed on previous PD-1 treatment (n = 23). Results showed a response rate of 42% in PD-1–naïve patients vs 32% in those who had progressed on PD-1 treatment.6 The median overall survival (OS) in these 2 cohorts was 19.6 months and 14.0 months, respectively, while the median progression-free survival (PFS) was 3.9 months and 2.8 months, respectively. Additionally, the DOR for patients who achieved a CR and partial response (PR) was 32.2 months for PD-1–naïve patients vs 7.6 months for those who had progressed on PD-1 treatment.

“The number of patients who had a response were lower when they had previously progressed on a checkpoint inhibitor and the durability of responses was far shorter [in those who were] refractory to PD-1 therapy,” Svane noted.

Additionally, data from a study presented during the 2020 ASCO Virtual Scientific Program demonstrated that when the cryopreserved TIL product lifileucel (LN-144) was used in patients with PD-1–resistant melanoma, the ORR achieved was 36.4%.

 Moreover, 81% of patients treated in this study (n = 50/62) experienced a reduction in tumor burden with the treatment.

Only a small number of studies examining TIL therapy in patients with other cancers beyond melanoma have been published, and very few trial results have been finalized, according to Svane.

However, one of the published studies examined treatment with HPV-targeted TILs in 9 patients with metastatic cervical cancer. Results showed durable complete regression with the approach, with 3 patients experiencing objective tumor responses to treatment.

 Additionally, a phase 1 study (NCT03215810) examined adoptive cell transfer with TILs in 13 patients with non–small cell lung cancer (NSCLC) and durable CRs were reported in some of these patients.

Notably, TIL therapy also led to a durable CR in a patient with metastatic breast cancer, according to a patient report published in 

 “The treatment that they offered this patient was very complex, as they aimed to increase the number of new antigens between T cells in the TIL product,” Svane explained.

To do this, the investigators sequenced the tumor from the patient and predicted different neoepitopes. Based on that prediction, investigators prepared minigenes, which were transduced into dendritic cells established from the patients; this was so the dendritic cell could then present the neoantigen epitopes to the TILs during the outgrowth, and increase the fraction of neoantigen-specific T cells in the infusion product.

“Indeed, they saw very impressive responses, with multiple lesions disappearing after therapy,” Svane noted.

Additionally, an ongoing phase 1/2 trial (NCT03296137) is examining TIL therapy in 25 patients with advanced cancer who have been heavily pretreated, including with anti–PD-1 therapy. Of the patients treated on this study, 7 have GI cancers (28%), 6 have melanoma (24%), 3 have cholangiocarcinoma (12%), 2 have squamous cell carcinoma (8%), 2 have sarcoma (8%), and 5 have other carcinomas (20%).

On this study, investigators sought to take advantage of treatment with checkpoint inhibitors at different points throughout treatment, according to Svane. Patients were pretreated with 1 dose of ipilimumab to recruit more TILs into the tumor lesion, as well as to expand the repertoire of the TILs prior to tumor resection. After conditioning with chemotherapy, patients were then infused with the TILs, and received treatment with 4 doses of nivolumab (Opdivo). Additionally, patients received treatment with low-dose IL-2 for 14 days.

Results from this study showed that some patients did achieve regressive disease with this therapy, and 5 out of 25 patients demonstrated substantial tumor regression, according to Svane. However, the durability of these responses was short.

Treatment with TIL therapy has also been examined in several pilot studies in patients with ovarian cancer. In one study that examined TIL therapy without the addition of checkpoint inhibitors, results showed that patients only achieved disease stabilization, according to Svane.

 However, in another study, that utilized ipilimumab and nivolumab to increase TIL efficacy, responses deepened, Svane explained.

Future Directions Toward Standard of Care

Currently, an ongoing, randomized phase 3 trial is comparing TIL-based adoptive cell therapy vs standard ipilimumab treatment in patients with PD-1–resistant melanoma, according to Svane. The goal is to enroll 168 patients with metastatic melanoma who have progressed on prior anti–PD-1 therapy.

Patients will be randomized 1:1 to receive ipilimumab at a daily dose of 3 mg/kg every 3 weeks for 4 cycles (arm A) or nonmyeloablative chemotherapy comprised of cyclophosphamide plus fludarabine followed by intravenous (IV) adoptive transfer of at least 5 x 109 TIL followed by high-dose IL-2 (arm B). Patients will be stratified by 

 V600 mutational status (yes vs no), line of treatment (first vs second), and treatment center.

The primary end point of the study is 6-month PFS, while secondary end points include PFS per immune-related response criteria (irRC), ORR per RECIST v1.1 criteria and irRC, as well as CR, OS, and safety.

“Accrual has been moving along and has been successful for the past couple of years. We aim to have the full recruitment of the trial within the next year,” Svane said.

In terms of which patients could be the best candidates to receive TIL therapy as a potential standard of care, a lot of information has been gathered from past studies, according to Svane. Ideal patients are younger than 70 years, have at least 1 resectable metastatic lesion of sufficient size, and have a good clinical performance status. Additionally, patients with metastatic melanoma, who have progressed after standard therapy, with no brain metastases and sufficient organ function, have demonstrated the best responses with this approach.

However, questions regarding predictive factors and markers of response remain, Svane noted. It has been suggested that mutational load and inflammation may be potential biomarkers.

“Indeed, mutational load correlates with clinical benefit, and it also correlates with PFS, as well as OS for patients treated with T-cell therapy,” Svane said. Moreover, immune system activation profile has been shown to be a hallmark of responding tumors.

Moreover, immunology has been found to correlate with tumor regression, with the number of T cells in the infusion product reacting toward the tumor playing a key role in efficacy, according to Svane. As such, the patients with the best reduction of tumor lesions had the highest number of tumor-reactive TILs in the infusion product.

 This was also seen in blood samples collected months after treatment.

Additionally, a qualitative analysis of expanded TILs across multiple tumor types, significantly more tumor-reactive T cells were found in the products for patients with melanoma compared to those with other types of cancer, according to Svane.

“This is, indeed, [the case] for both the CD8 cells, as well as the CD4 cells,” Svane said. “If you look at the total percentage of tumor-reactive T cells, we have generally more CD8 tumor-reactive T cells than CD4s, but these 2 fractions do correlate.”

Moreover, stem-cell–like CD8 T cells in TIL infusion products were also found to be associated with clinical responses, as well as survival. These T cells, CD39-negative and CD69-negative, correlated with complete cancer regression, according to Svane. Additionally, while most antitumor neoantigen-reactive TILs were found in a differentiated CD39-positive state, those who responded to treatment also maintained CD39-negative neoantigen-specific TILs.

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This article was originally published on OncLive as, "

TIL-Based Therapies Possess Potential for Cure in Metastatic Melanoma, But Questions Remain.

Tumor-infiltrating lymphocytes show great promise in the metastatic melanoma space, but questions remain. 

TIL Therapy May Be the Curative Answer for Metastatic Melanoma

Chronic immune-related adverse effects (irAE) arising from adjuvant anti–PD-1 therapy in patients with high-risk melanoma are more common than previously recognized, and often persisted with longer follow-up, according to findings from a multicenter cohort study published in 

Chronic irAEs, which are defined as those that persist after 12 weeks of anti–PD-1 discontinuation, occurred in 43.2% of patients enrolled to the trial (n = 167/387). Although the majority of these chronic irAEs were grades 1 or 2 (96.4%; n = 161/167), most of the effects persisted until last available follow-up (85.6%; n = 143/167).

“It is certainly important to recognize that anti–PD-1 therapy, regardless of this study and others, certainly does improve outcomes for patients with melanoma and is something that I will certainly still be offering my patients” lead study author Douglas Johnson, MD, MSCI, an associate professor of Medicine at Vanderbilt University Medical Center, and clinical director of Melanoma at Vanderbilt-Ingram Cancer Center, told 

. “There is a subset of patients with stage III melanoma who have a very low risk of recurrence, and for those patients, [these data] may make us reevaluate how to [treat] them, and perhaps [revisit] how [we] make risk/benefit determinations in those settings.”

Moreover, irAEs such as endocrinopathies (83.0%; n = 73/88), arthritis (48.9%; n = 22/45), xerostomia (52.9%; n = 9/17), neurotoxicities (73.3%; n = 11/15) and ocular effects (62.5%; n = 5/8), were the most likely to become chronic, while effects impacting visceral organs like the liver, colon, lungs, and kidneys, had much lower rates of becoming chronic.

“We tend to think of specific organs that are being affected by these toxicities,” Johnson said. “The big ones that come to mind are the colon, the lungs, and the liver, but the toxicities in those organs seem to really get better; it was toxicities in the smaller organs that seemed to more commonly develop into chronic [effects].”

Chronic immune-related adverse effects arising from adjuvant anti–PD-1 therapy in patients with high-risk melanoma are more common than previously recognized, and often persisted with longer follow-up.

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