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The tumor-infiltrating lymphocyte therapy LN-145 induced promising response rates with acceptable safety in patients with recurrent, metastatic, or persistent cervical cancer—a patient population of great unmet need.
Amir A. Jazaeri, MD
The tumor-infiltrating lymphocyte (TIL) therapy LN-145 induced promising response rates with acceptable safety in patients with recurrent, metastatic, or persistent cervical cancer—a patient population of great unmet need, said Amir A. Jazaeri, MD, according to results from the phase II Study C-145-04.
In the ongoing, open-label, multicenter trial, investigators set out to determine the safety and effectiveness of the TIL therapy in patients with advanced disease who have received at least one prior line of chemotherapy. Objective response rate (ORR) per RECIST 1.1 is the primary endpoint of the trial, while secondary endpoints include duration of response (DOR), disease control rate (DCR), and safety.
Results presented at the 2019 ASCO Annual Meeting for 27 patients who received LN-145 infusion showed an ORR of 44% (n = 12), with 3 complete responses (CRs; 11.1%) and 9 partial responses (PRs; 33.3%). Eleven (40.7%) patients achieved stable disease. Furthermore, disease control was achieved in 85.2% of patients (n = 23). At a median follow-up of 7.4 months, the median DOR had not been reached.
“I would like to point out that with the caveat that the follow-up is short, a response rate of 44% is truly significant in this patient population,” said Jazaeri. “As a comparison, we can look to pembrolizumab (Keytruda), which received preliminary FDA approval with a response rate of 14%. That gives you an indication of the need in this population.”
In an interview with OncLive, Jazaeri, vice chair for clinical research and the director of the Gynecologic Cancer Immunotherapy Program in the Department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center, provided insight into LN-145 in cervical cancer, the next steps for research with this treatment approach, and the promise of TIL therapy in oncology across tumor types.
OncLive: What does current treatment look like for patients with recurrent, metastatic, or persistent cervical cancer?
Jazaeri: Patients with recurrent, metastatic [or persistent] cervical cancer are frequently deemed as patients whose cancer is treatable but not curable. Usually, the initial line of therapy is a combination of a platinum drug, taxane, and bevacizumab (Avastin) and that usually provides benefit in about 60% or 70% of patients to varying degrees. Some patients may have a CR and all evidence of cancer may disappear, while others may have shrinkage of their tumor or PR. But even in the best-case scenarios, in almost everyone, recurrence is basically inevitable. In those patients who recur or progress after a combination of platinum, taxane, and bevacizumab, the second-line agents have poor response rates in the single digits and very short DOR. This patient population is definitely one of unmet need. As a result, there’s a lot of interest in novel therapies in clinical trials [to address this need].
What is the role of adoptive cell transfer using TILs? How is this approach being used in this space?
Adoptive cell transfer essentially refers to methods in which immune cells are removed from the body, expanded in the lab, and then returned to the patient. They can be divided into genetically-modified T-cell therapies and [therapies] where T cells are not genetically modified. Within the latter group, TIL therapy is one type of adoptive cell therapy in which the source of the immune cells is from the tumor tissue. The rationale for that is the lymphocytes or T cells that are present in the tumor tissue must recognize some aspect of the tumor, and therefore, maybe the most relevant immune cells in the body for fighting the cancer. Again, it's felt that in the tumor where they reside, there is too few of them and too many immunosuppressive mechanisms that prevent these lymphocytes from eradicating the tumor.
As such, TIL immunotherapy, or TIL adoptive cell therapy, involves a process whereby the tumor is harvested and the lymphocytes out of the tumor are grown over some number of weeks and expanded many-fold to several billions of cells. Those cells are then returned to the patient. However, there is also an important preconditioning or lymphodepletion aspect where a week before the T cells are infused, patients start high doses of chemotherapy to eradicate the nonspecific immune cells and "make room" for the T cells. Following T cell infusion, there's usually administration of high-dose interleukin-2 (IL-2). IL-2 is a growth-promoting cytokine for T cells and its used in the lab stages of T cell expansion and then administered to patients to help promote T cell growth inside the body after the TIL have been infused.
LN-145 is just a name that Iovance Biotherapeutics has used for TIL that are grown through their manufacturing process. It’s not qualitatively different [from other TIL therapies]. It's a living treatment, a living drug so-to-speak.
Could you discuss Study C-145-04 with LN-145? What were the key takeaways from this research?
In terms of patient population, this investigation was largely in those who had already progressed on or recurred after treatment with platinum, taxane, and bevacizumab. Initially, patients who had prior immune checkpoint inhibitor treatment were included in the trial, but through an early amendment of the protocol, these patients were excluded. Only 4 of the subjects in the data that were presented at the 2019 ASCO Annual Meeting had prior immune checkpoint inhibitor exposure.
The other aspect of this treatment was that essentially the treatment as a whole, as I mentioned, consisted of lymphodepletion with cyclophosphamide and fludarabine chemotherapies, TIL infusion, and then up to 6 doses of high-dose IL-2. It was a one-time treatment after which patients were followed and underwent scans at 6 weeks and then 12 weeks.
All patients [included in the trial] had prior exposure to a platinum drug, 96% to taxane, and then about 82% of patients also had bevacizumab or anti-VEGF therapy. About three-quarters had prior radiation.
In terms of safety, the definition of treatment-emergent adverse events (AEs) are those that started after T cell infusion. The majority of high-grade AEs happened shortly after T cell infusion and were related mostly to the effects of the lymphodepleting chemotherapy and the IL-2. Once patients were out of that initial 10- to 14-day window, there were very few AEs.
We reported an objective response rate of 44% [with this approach]. Of those who responded, 11% were complete responders and 33% were partial responders. Another 40% of patients had stable disease as their best response. It’s worth mentioning that the follow-up for this study was very short; median follow-up was 7.4 months, and the median DOR had not reached. Those are the results in a nutshell.
Would you say overall that the treatment was well tolerated overall? Were there any surprising safety signals?
The treatment was well tolerated. Most of the AEs were consistent with what is to be expected with high doses of chemotherapy and IL-2. The protocol was written with a little bit of flexibility in that patients who had prior pelvic radiation were expected to have lower bone marrow reserve, and so they were allowed to receive reduced doses of cyclophosphamide so that they would not develop profound and prolonged neutropenia.
The other flexible aspect of the trial was the fact that if there were any significant AEs to high-dose IL-2 administration, the number of treatments could be stopped; the IL-2 was prescribed to tolerance. What we saw was the median number of treatments was 6, so that means that at least 50% of patients were able to receive at least 6 treatments.
I will say that there are definitely patient selection considerations. These patients had to have a performance status of 0 to 1 and they had to be deemed able to tolerate the high doses of chemotherapy and high-dose IL-2. As such, this is not necessarily a treatment that would be applicable to all patients with recurrent or metastatic [or persistent] cervical cancer. However, within the study population, I would describe it as very well tolerated with expected toxicities, nothing surprising.
Does this treatment have the potential to be used in the community setting?
Administering this treatment safely requires a multidisciplinary approach. As such, I believe it's probably best suited for academic medical centers, at least initially.
Following this trial, what are the next steps for this research?
After discussions with the FDA, the study has been amended to include up to 75 patients. We will continue to accrue more patients and obtain additional longer-term follow-up on the patients who have already been treated. I believe that will be very important in order to ensure consistency of the findings that were reported in our abstract.
I believe that the company is also considering other cohorts. For example, this study did not include previously checkpoint-exposed patients, and the possibility of testing efficacy of this approach in patients who may have been previously exposed to pembrolizumab, for example, is a consideration. Getting more data, longer-term follow-up, and possibly exploring this approach in other patient populations probably summarizes the future direction of this work.
What is your take-home message to your colleagues regarding TIL therapy?
TIL therapy has a long history of efficacy in melanoma. Like many immunotherapies, it started in that disease and so it may be instructive to look at outcomes in melanoma that tend to be durable. I'm hoping that's what we will find in cervical cancer. However, of course, that remains to be seen.
What is the potential of TIL therapy in oncology overall going forward?
That's a great question. We have ongoing clinical trials that are testing TIL therapy among different solid tumor types; those studies are currently ongoing. These studies are being done by our group, but I know there are other TIL therapy groups that are also asking similar questions and looking at solid tumors. As such, I believe that within the next year or 2, we're going to have a better picture, a better sense, of whether TIL therapy is going to be limited to melanoma and cervical cancer or if it may have broader application in other solid tumors.
Jazaeri AA, Zsiros E, Amaria RZ, et al. Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical cancer. J Clin Oncol. 2019;37(suppl 15, abstr 2538). doi: 10.1200/JCO.2019.37.15_suppl.2538.