Lisa Astor

After more than 28 months of follow-up, the tumor-infiltrating lymphocyte (TIL) therapy lifileucel (LN-144) showed a positive objective response rate (ORR) with the median duration of response (DOR) not yet reached in pretreated patients with advanced melanoma who had received immune checkpoint inhibition, according to findings from a cohort of the phase 2 C-144-01 trial (NCT02360579) presented at the 2021 American Association for Cancer Research (AACR) Annual Meeting.

“It is clear based on these data that lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma represents a viable therapeutic option warranting further investigation,” said Jason A. Chesney, MD, PhD, who presented the findings during the AACR meeting. Chesney is the chief of the Division of Medical Oncology and Hematology and director of the James Graham Bron Cancer Center, University of Louisville in Kentucky.

Currently, few treatment options exist for patients with advanced melanoma who are refractory to or develop resistance to an immune checkpoint inhibitor, including retreatment with immunotherapy or chemotherapy, and neither has a significant impact on response or survival.

Previously, autologous TIL therapy has had the most efficacy in melanomas and has demonstrated antitumor efficacy and durable complete responses (CRs) in patients with heavily pretreated metastatic melanoma.

The C-144-01 trial was a global, open-label, multicohort, multicenter study of the centrally manufactured and cryopreserved autologous TIL therapy lifileucel in patients with unresectable or metastatic melanoma who have progressed on immune checkpoint inhibitors and BRAF/MEK inhibitors if the patient is 

Patients were eligible if they had 1 tumor lesion (about 1.5 cm in diameter) resectable for TIL generation, at least 1 tumor lesion for assessment of response, aged 18 years old or older, and had an ECOG performance status of 0 or 1.

The study consisted of 4 cohorts, 3 of which are now closed to enrollment. Cohort 1 included treatment of 30 patients with a first-generation non-cryopreserved TIL therapy, cohort 2 included 66 patients who were treated with a second-generation cryopreserved TIL therapy, and 75 patients were included in the pivotal cohort and received treatment with a cryopreserved second-generation TIL product. The ongoing third cohort includes 10 patients who will receive re-treatment with a TIL therapy. During the AACR meeting, Chesney focused on findings from the second cohort.

Primary end point for the second cohort was investigator-assessed ORR by RECIST 1.1; the secondary end points included safety and other efficacy assessments.

At baseline, the 66 patients had a median age of 55 (range, 20-79) 59% were male, 56% had an ECOG performance status of 0, 68% had 

wild-type disease, and 35% were PD-L1 positive (tumor proportion score ≥5). The median number of prior therapies was 3.3 (range, 1-9), which included anti–PD-1/PD-L1 therapy in all patients, anti–CTLA-4 therapy in 80%, and BRAF/MEK inhibition in 23%.

Patients in the cohort also had a high tumor burden at baseline, Chesney pointed out, with a mean target lesion size of 10.6 cm in diameter (range, 1.1-34.3), 77% had more than 3 target and non-target lesions, and 42% had liver and/or brain lesions.

The process of manufacturing lifileucel consisted of tumor tissue procurement across various resection sites, and the tissue was then sent to the central manufacturing facility where the tissue was fragmented and the TILs were isolated and cultured ex vivo before being expanded, reinvigorated, harvested, and cryopreserved—a process which took 22 days to complete. The cryopreserved products were then shipped back to the treatment center where the patients received a nonmyeloablative lymphodepletion regimen of cyclophosphamide 60 mg/kg for 2 days followed by fludarabine 25 mg/m

 for 5 days. Then, lifileucel was infused followed by administration of up to 6 doses of a interleukin-2 (IL-2) at 600,000 U/kg every 8 to 12 hours for 2 to 4 days.

Lifileucel was successfully manufactured regardless of the organ site of the resected tumor, Chesney noted.

The median study follow-up was 28.1 months, at which point the ORR was 36.4%, which consisted of CRs in 4.5% and partial responses in 31.8%. Additionally, 43.9% had stable disease for a disease control rate of 80.3%. The median DOR was not reached (range, 2.2-35.2+ months).

Responses were observed in patients regardless of 

mutational status or tumor PD-L1 expression and were also seen in patients with various lactate dehydrogenase levels, baseline tumor burdens, the presence of liver and/or brain metastases, and in patients who previously received anti–CTLA-4 therapy or BRAF/MEK inhibition.

The response and disease control rates were consistent with that of prior reports from the cohort presented at the 2020 American Society of Clinical Oncology Annual Meeting.3 However, with extended follow-up, 17.7% of patients had further reduction in target lesion size since the prior data cutoff period. A total of 81% of evaluable patients had a reduction in their tumor burden.

Of the 24 responders, 79% had previously received ipilimumab (Yervoy) and 4% had a partial response converted to a CR after 2 years following infusion with lifileucel; 49% of responders were still on the study at data cutoff.

Chesney noted that the target lesion sum diameter reduction was seen across the range of total TIL doses and that the investigators believed that the target lesion sum diameter reductions were seen across the range of TIL CD4-positive and CD8-positive cell doses.

At least 1 treatment-emergent adverse event (TEAE) was observed in all 66 patients and were of grade 3/4 in severity in 97%. Two patients experienced a grade 5 event due to intra-abdominal hemorrhage that was possibly due to TIL therapy in one patient and acute respiratory failure not related to TIL therapy in the second patient.

“The adverse event profile is manageable and consistent with the underlying advanced disease and known profiles of the nonmyeloablative lymphodepletion regimen and high-dose IL-2,” Chesney commented.

The most common any-grade TEAEs were thrombocytopenia (89.4%), chills (80.3%), anemia (68.2%), pyrexia (59.1%), neutropenia (56.1%), and febrile neutropenia (54.5%). The most common grade 3/4 TEAEs were thrombocytopenia (81.8%), anemia (56.1%), febrile neutropenia (54.5%), and neutropenia (39.4%).

No new safety risks were identified with the longer follow-up. Additionally, the number of TEAEs reduced over time.

“The decreasing frequency of adverse events over time supports the risk/benefit proposition of one-time therapy of lifileucel for these patients,” Chesney said.

1. Chesney JA, Larkin JMG, Kirkwood JM, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up. Presented at: 2021 American Association for Cancer Research Annual Meeting; April 10-15, 2021; Virtual. Abstract CT008.

2. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. 

2011;17(13):4550-4557. doi:10.1158/1078-0432.CCR-11-0116

3. Sarnaik A, Khushalani NI, Chesney JA, et al. Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies. 

2020;38(suppl 15):10006. doi:10.1200/JCO.2020.38.15_suppl.10006

Articles

In the phase 2 C-144-01 trial, patients had durable responses to treatment with the tumor-infiltrating lymphocyte lifileucel after more than 28 months of follow-up.

Lifileucel TIL Therapy Demonstrates Durable Responses in Pretreated Advanced Melanoma

The FDA has accepted a biologics license application (BLA) and granted it a priority review for tisotumab vedotin for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

A target action date of October 10, 2021, has been set by the FDA under the Prescription Drug User Fee Act.

“The FDA’s filing of the tisotumab vedotin BLA with Priority Review marks an important step forward for this ADC as a potential treatment for patients with recurrent or metastatic cervical cancer,” said Roger Dansey, MD, chief medical officer at Seagen, in a press release. “We are collaborating closely with the FDA throughout the review process to make this important therapy available to patients.”

Tisotumab vedotin is an investigational antibody-drug conjugate directed at tissue factor, which is highly prevalent in cervical cancer, and covalently linked to the microtubule-disrupting agent MMAE via a protease-cleavable linker.

“We are pleased that the tisotumab vedotin BLA has been accepted with Priority Review by the FDA as there is an unmet need for effective therapies for women with recurrent or metastatic cervical cancer, who have disease progression on or after chemotherapy,” said Jan van de Winkel, PhD, chief executive officer of Genmab, in a statement.

Approval for tisotumab vedotin is based on findings from the pivotal phase 2 innovaTV 204 clinical trial (NCT03438396), data from which were presented during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.

The ongoing innovaTV 204 trial is a single-arm, global, multicenter study of tisotumab vedotin in patients with recurrent or cervical cancer who had progressed during or following doublet chemotherapy with bevacizumab (Avastin). A total of 101 patients were enrolled who had received up to 2 prior systemic regimens and had an ECOG performance of 0 or 1.

Objective response rate (ORR) by independent review committee per RECIST criteria was the primary end point and secondary end points included investigator-assessed ORR, overall survival (OS), duration of response (DOR), time to response (TTR), progression-free survival (PFS), and safety.

Patients had a median age of 50 years (range, 31-78). Ninety-five percent of patients were White, 2% were Asian, 1% were Black/African American, and 2% were classified as “other.” Fifty-eight percent of patients had an ECOG performance status of 0, 94% of patients had extrapelvic metastatic disease, and 68% had squamous cell carcinoma histology.

Fifty-four percent of patients had received prior cisplatin plus radiation therapy, 70% had received 1 previous line of systemic therapy for recurrent/metastatic disease. Sixty-three percent of patients had prior bevacizumab plus doublet chemotherapy as frontline therapy, and 56% of patients did not respond to their last systemic treatment.

The ORR was 24% (95% CI, 15.9%-33.3%) by independent review, which included a complete response rate of 7% and a partial response rate of 17%. Forty-nine percent of patients had stable disease and 24% had progressive disease. Target lesions were reduced in 79% of patients with at least 1 post-baseline scan.

The median DOR was 8.3 months (95% CI, 4.2–not reached). Most responses were rapid, with a median TTR of 1.4 months (range, 1.1-5.1), and activity was observed within the first 2 treatment cycles.

Median PFS was 4.2 months and median OS was 12.1 months. The 6-month PFS rate was 30% and the 6-month OS rate was 79%.

Tisotumab vedotin demonstrated a manageable and tolerable safety profile. The most common treatment-related adverse events (TRAEs) with a 10% or higher incidence rate included alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (24%), dry eye (23%), myalgia (15%), anemia (12%), asthenia (12%), arthralgia (12%), decreased appetite (11%), keratitis (11%), and pruritis (10%). Most of these were grade 1/2, but grade 3/4 TRAEs occurred in 28% of patients. Of the 4 patients who died, 1 was due to septic shock that was considered to be treatment related.

1. Seagen and Genmab Announce U.S. FDA Filing Acceptance for Priority Review of Tisotumab Vedotin Biologics License Application for Patients with Recurrent or Metastatic Cervical Cancer. News release. Seagen Inc and Genmab A/S. April 9, 2021. Accessed April 9, 2021. 

2. Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA32.

The FDA has accepted a biologics license application and granted it a priority review for tisotumab vedotin for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

FDA Has Granted Priority Review to Tisotumab Vedotin for Advanced Cervical Cancer

Half of all patients with hepatocellular carcinoma (HCC) treated with the combination of regorafenib (Stivarga) and nivolumab (Opdivo) following progression on 2 lines of chemotherapy achieved disease control, according to initial results from a phase 2 proof-of-concept trial.

Study authors, led by Yasmina Ben Merabet, MD, of the Hepato-Biliary Center at the Paul-Brousse Hospital in Villejuif, France, suggested in a poster presented at the Digital Liver Cancer Summit 2021 that this disease control rate (DCR) was unexpected in these patients with advanced, pretreated HCC.

Patients with HCC who progress after more than 2 lines of chemotherapy have a very poor prognosis, but preclinical data are emerging to suggest that an angiogenic agent may enhance the activity of anti–PD-1 antibodies in HCC.

This was especially seen in the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin), which recently gained an FDA approval in the frontline treatment of patients with unresectable or metastatic HCC.

 The approval was granted based on findings from the phase 3 IMbrave150 trial (NCT03434379), which demonstrated a significant benefit for overall survival (OS) compared with sorafenib (Nexavar).

The risk of death was reduced by 42% with the combination regimen compared with sorafenib, and at 12 months, the OS rate was 67.2% with atezolizumab/bevacizumab compared with 54.6% with sorafenib.

However, this approach had not yet been investigated in a later-line setting for patients previously treated with 2 or more lines of chemotherapy.

The proof-of-concept phase 2 study sought to explore the potential for the combination of nivolumab and regorafenib in patients with HCC in the third-line setting or beyond.

The study included 10 patients with advanced or metastatic HCC who had progressed beyond a second line of oral chemotherapy, had good hepatic function (Child-Pugh score < 7), and an ECOG performance status of 0 or 1. Patients were also considered ineligible for atezolizumab and bevacizumab.

Patients were treated with 80 mg daily regorafenib for 3 out of 4 weeks of the first cycle followed by regorafenib in combination with 3 mg/kg intravenous nivolumab every 14 days until disease progression or unacceptable toxicity.

The primary end point of the study was safety and secondary end points were objective response rate (ORR), DCR, and time to response (TTR).

The included patients had a median age of 69.5 years (range, 62-72.5) and 80% were male. Most patients had an ECOG performance status of 0 (60%), although 1 patient had a score of 2 (10%). One-third of patients had liver cirrhosis, 20% had macrovascular invasion, and 80% had extrahepatic metastasis. Two-thirds of patients had Child-Pugh A5 disease and 80% had Barcelona Clinic Liver Cancer stage C disease. Alpha-fetoprotein (AFP) levels were below 400 ng/mL for 70% of patients.

Only 3 patients had received at least 3 prior lines of systemic therapy before inclusion in the study. Patients had a median time of 6 months (range, 4-7) to progression with first-line therapy and 8 months (range, 6-11) to progression with second-line therapy.

Patients received regorafenib/nivolumab for a median of 5 months (range, 4.5-8.5). The ORR was 30%, which consisted of all partial responses, and 2 other patients had disease control. The median time to response was 2.5 months (range, 2.1-3.3) and the median duration of disease control was 6 months (range, 5-7). AFP level decreases were observed in all responders after only 2 cycles of nivolumab.

Adverse events (AEs) were observed in all patients, but were mostly grade 1 or 2 and related to regorafenib treatment. However, 20% of patients experienced grade 3/4 events. Three patients interrupted treatment with regorafenib and/or nivolumab because of an AE, which included 2 who interrupted treatment with both agents and 1 who interrupted regorafenib treatment only. Two patients discontinued treatment with nivolumab because of AEs, 1 from a grade 3 cytolysis and 1 from a grade 2 rhizomelic pseudopolyarthritis requiring corticosteroids. Another patient discontinued regorafenib because of a grade 2 heart failure that was reversible.

The study serves as rationale for further clinical study of the combination of regorafenib and nivolumab in the treatment of patients with refractory HCC who have progressed on or after oral chemotherapy, the investigators concluded.

1. Merabet YB, Pascale A, Guettier C, et al. Safety and benefit of the combination of regorafenib and nivolumab in patients with hepatocellular carcinoma (HCC) in progression beyond two lines of oral chemotherapy. Presented at: EASL Digital Liver Cancer Summit 2021; February 5-6, 2021; Virtual. Abstract P-123. 

2. FDA approves atezolizumab plus bevacizumab for unresectable hepa-tocellular carcinoma. FDA. June 1, 2020. Accessed February 23, 2021. https://bit.ly/37GCqC6

3. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

Half of all patients with hepatocellular carcinoma treated with the combination of regorafenib and nivolumab following progression on 2 lines of chemotherapy achieved disease control, according to initial results from a phase 2 proof-of-concept trial.

Regorafenib/Nivolumab Proof of Concept Suggested in Third-Line, Refractory HCC

The FDA has approved idecabtagene vicleucel (ide-cel; formerly bb2121; Abecma) for the treatment of adult patients with relapsed or refractory multiple myeloma after 4 or more prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.

Ide-cel represents the first B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapy approved.

Approval for ide-cel is supported by findings from the pivotal phase 2 KarMMa trial (NCT03361748), for which data from 100 study patients who were doses with 300 to 460 x 106 CAR-positive T cells were announced in a press release from Bristol Myers Squibb. showed that ide-cel led to deep and durable responses in patients with heavily pretreated multiple myeloma. Of the population treated, 88% had received 4 or more prior lines of therapy and 85% were triple-class refractory.

Patients were first treated with lymphodepleting chemotherapy of fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day) followed by 1 of 3 dose levels of ide-cel: 150 x 10

 (n = 54) CAR-positive T cells. Those who remained on the trial for 2 years were asked to continue on to a follow-up study (GC-LTFU-001; NCT03435796).

The primary outcome measure was overall response rate (ORR) by International Myeloma Working Group (IMWG) criteria as assessed by independent review committee, and secondary end points were complete response (CR) or better rate, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD), safety, pharmacokinetics, and immunogenicity.

“In the KarMMa study, ide-cel elicited rapid responses in the majority of patients, and these deep and durable responses were observed in patients with triple-class exposed and refractory multiple myeloma. As a treating physician, I often work with patients with relapsed or refractory multiple myeloma who are in critical need of new therapies. Now, with the approval of ide-cel as the first anti-BCMA CAR T cell therapy, we are excited to finally be able to offer patients a new, effective personalized treatment option that is delivered through a single infusion,” said Nikhil C. Munshi, MD, associate director, The Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston, Massachusetts, in a statement.

Among the patients evaluable for efficacy, the objective response rate achieved with ide-cel was 72% (95% CI, 62%-81%) with stringent CRs (sCR) in 28% (95% CI, 19%-38%). The median time to response was 30 days (range 15-88) and response were durable. In the all-responder population, median DOR was 11 months (95% CI: 10.3-11.4), and in the group of patients that achieved a sCR, the median DOR was 19 months (95% CI: 11.4-NE). Notably, of the patients in the sCR population, remission lasted for 12 months or more in 65% (95% CI: 42%-81%).

, a total of 140 patients who had received at least 3 prior treatment regimens for multiple myeloma including an IMiD, a PI, and an anti-CD38 antibody and were refractory to their last treatment regimen, were enrolled in the study. However, only 128 patients received infusion with ide-cel.

At baseline, the median patient age was 61 years (range, 33-78) and patients had a median of 6 years (range, 1-18) since their diagnosis. A majority of the patients were male (59%), had high tumor burden (51%), BCMA expression ≥50% at screening (85%), ECOG performance status of 1 (53%), and Revised International Staging System disease stage of II (70%). Thirty-five percent of patients had high-risk features.

The median number of prior therapies was 6 (range, 3-16) and 94% had previously undergone at least 1 autologous hematopoietic stem cell transplant (94%). Eighty-eight percent of patients required bridging therapy. Eighty-nine percent of patients had double-refractory disease, 84% were triple-refractory, and 26% were penta-refractory.

Sixty-two patients were still on study treatment as of the data cutoff; overall, patients were followed for a median of 13.3 months (range, 0.2-21.2).

Twenty-six percent of patients achieved MRD-negative status and 79% of the patients who achieved a CR or better were MRD negative.

Median PFS was 8.8 months (95% CI, 5.6-11.6) overall; among patients with a CR or better, the median PFS was 20.2 months (95% CI, 12.3-NE). The median OS was 19.4 months (95% CI, 18.2-NE) and at 12 months, the OS rate was 78%, although OS data are still immature.

Updated safety data from the study show a low incidence of cytokine release syndrome (CRS) in patients. According to the Lee grading system, any-grade CRS was observed in 85% of patients, grade >3 CRS occurred in 9%, and grade 5 CRS occurred in 0.8%. the median time to CRS onset was 1 day (range, 1-23 days), and it lasted for a media duration of 7 days (range, 1-63 days). Cases of CRS most commonly manifested as pyrexia (98%), hypotension (41%), tachycardia (35%), chills (31%), hypoxia (20%), fatigue (12%), and headache (10%).

Treatment with ide-cel also showed a low occurrence of neurotoxicity (28%) in the study. Grade 3 events of neurotoxicity were seen in 4% of patients.

Nonlaboratory adverse events (AEs) were observed in more than 20% of patients in the study and included CRS, infections, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite. Sixty-seven percent of patient experienced serious nonlaboratory AEs of predominantly CRS (18%), general physical health deterioration (10%), pneumonia (12%), infections (19%), viral infections (9%), sepsis (7%), and febrile neutropenia (6%). Febrile neutropenia which occurred in 16%, and infections in 14% were the most common grade 3 or 4 nonlaboratory AEs. Finally, AEs were fatal for 6% of the patients.

“CAR T cell therapies have shown transformational potential for the treatment of hematologic malignancies, and we, with our partners at bluebird bio, are proud to bring the first CAR T-cell therapy to appropriate triple-class exposed patients with relapsed or refractory multiple myeloma, offering the chance for durable response,” said Samit Hirawat, MD, chief medical officer, Bristol Myers Squibb, in a statement. “Bristol Myers Squibb is now the only company with 2 approved CAR T-cell therapies with distinct targets of CD19 and BCMA. As our second FDA-approved CAR T-cell therapy, Abecma underscores our commitment to deliver on the promise of cell therapies for patients who are battling aggressive and advanced blood cancers with limited effective treatment options.”

The recommended dose of ide-cel is a one-time infusion at a range of 300 to 460 x 106 CAR-positive T cells.

The label for ide-cel includes boxed warnings for CRS, neurologic toxicities hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia.

1. U.S. Food and Drug Administration Approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagene vicleucel), the First Anti-BCMA CAR T Cell Therapy for Relapsed or Refractory Multiple Myeloma. News release. Bristol Myers Squibb. March 26, 2021. Accessed March 27, 2021. https://bit.ly/3m0V915

2. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. 

. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850

The FDA has approved idecabtagene vicleucel for the treatment of adult patients with relapsed or refractory multiple myeloma after 4 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody.

Lisa Astor | Authors

Articles

Lifileucel TIL Therapy Demonstrates Durable Responses in Pretreated Advanced Melanoma

FDA Has Granted Priority Review to Tisotumab Vedotin for Advanced Cervical Cancer

Regorafenib/Nivolumab Proof of Concept Suggested in Third-Line, Refractory HCC

FDA Approves Ide-Cel for Relapsed/Refractory Multiple Myeloma