Wayne Kuznar

Immune-checkpoint inhibitor (ICI) therapy, involving anti–CTLA-4 and anti–PD-1/ PD-L1 agents, has transformed the treatment of melanoma. Nonetheless, even with combination anti–PD-1 and anti–CTLA-4 therapy, nearly 50% of patients die of their disease at 5 years.

In patients with advanced, ICI-refractory melanoma (either primary or acquired resistance), the rate of response to retreatment with ICIs or chemotherapy is poor. For example, the overall response rate (ORR) with chemotherapy in this setting is 4% to 10%,1 with a median overall survival (OS) of only 7 to 8 months.

Several abstracts from the recent 2021 American Society of Clinical Oncology Annual Meeting were devoted to the search for better second- and later-line treatment options in patients with advanced melanoma that has progressed on or is refractory to ICIs.

One promising approach in the refractory population is adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) derived from a patient’s own tumor and expanded ex vivo. Lifileucel (Contego), a cryopreserved autologous TIL therapy, has demonstrated efficacy and durable long-term responses in patients with advanced melanoma who progress on or after anti–PD-1 therapy. Results of a global, phase 2, open-label, multicohort, multicenter study (C-14401; NCT02360579) examining the impact of prior anti–PD-1/PD-L1 use on duration of response (DOR) with lifileucel showed that median DOR had not yet been reached,

 as presented by James Larkin, PhD, consultant medical oncologist, The Royal Marsden, NHS Foundation Trust, London, United Kingdom.

Patients in C-144-01 had unresectable or metastatic melanoma treated with at least 1 prior systemic therapy including a PD-1–blocking antibody and, if positive for a BRAF V600 mutation, a BRAF inhibitor with or without a MEK inhibitor.

Sixty-six patients in the trial were treated with lifileucel, which was infused as a 1-time treatment after nonmyeloablative lymphodepletion. Lifileucel administration was followed by up to 6 doses of IL-2. At enrollment, all 66 patients had received antiPD-1/PD-L1 therapy, 80% had been treated with an anti–CTLA-4 agent, and 52% had received a combination of an anti–PD-1 and anti–CTLA-4 agent.

The ORR was 36.4%; 3 patients had a complete response (CR), and 21 had a partial response (PR). Some 81% of patients had a reduction in tumor burden, and 17.7% had further tumor burden reduction since the April 2020 data cutoff (TABLE 1

“Responses have continued to deepen over time,” said Larkin during his presentation of the data. “Most of the responses were seen at the time of the first scan.” One PR converted to a CR 24 months after treatment with lifileucel.

The ORR was not predicted by any patient or clinical characteristics assessed, including baseline level of lactate dehydrogenase (LDH), baseline ECOG performance status, and the presence of brain or liver metastases at baseline.

“Early intervention with lifileucel at the time of initial progression on anti–PD-1 agents may maximize benefit,” Larkin said.

Jason J. Luke, MD, director of the Cancer Immunotherapeutics Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pennsylvania, commented after the presentation that “this is clearly an active regimen in the post–PD-1/CTLA-4 setting. It differentiates mechanistically from other systemic therapies. I would note that the response rate for lifileucel appears to be approximately similar to what we have described previously for pembrolizumab [Keytruda] and low-dose ipilimumab [Yervoy] in the post–PD-1 setting.”

Luke continued, “The duration of response that is reported by these investigators is quite impressive, given that the median has not been reached over a long period of time. Also interesting, it appears that this therapy is predominantly active in those patients who progressed initially on anti–PD-1, and many of those patients had PD-L1–low tumors.”

Percutaneous image-guided cryoablation modulates the immune microenvironment and may also enhance responses in patients with unresectable melanoma who progress on ICIs. As reported in a poster session by Meghan Mooradian, MD, of Massachusetts General Hospital, Boston, and colleagues, a single-center phase 2 study (NCT03290677) examined this approach in 17 patients who had previously received anti–PD-1/ PD-L1 therapy, 12 of whom had primary resistance. Patients underwent cryoablation of an enlarging lesion and continued ICI therapy for at least 2 additional cycles.

At a median follow-up of 8.5 months, 3 patients had experienced a PR, for an ORR of 18% and a disease control rate (DCR) of 47%. Three patients experienced periprocedural events: 1 grade 2 pneumothorax, 1 grade 2 diaphragm puncture, and 1 grade 3 infection.

“Efficacy of this potentially synergistic approach in patients with PD-1–refractory metastatic melanoma is encouraging,” the investigators concluded. Correlative analyses are in process to identify potential biomarkers of response.

A less successful strategy for recurrence appears to be ICI rechallenge. Alexander M. Eggermont, MD, PhD, chief scientific officer at Princess Máxima Center, Utrecht, the Netherlands, presented data from the EORTC 1325-MG/KEYNOTE-054 study of pembrolizumab in patients with completely resected high-risk stage III melanoma (NCT02362594). Among 20 patients who experienced disease recurrence and were rechallenged with pembrolizumab, the median progression-free survival (PFS) was 4.1 months.

 In a more select group of 9 patients who had stage IV disease and had recurrence more than 6 months after the completion of 1 year of pembrolizumab, the activity of pembrolizumab was low, with only 1 CR (11%).

Several combinations involving immunotherapy are under investigation in the second- line setting.

The combination of domatinostat and pembrolizumab induced an ORR of 7.5% and a DCR of 30% in the SENSITIZE study (NCT03278665) of patients with advanced (unresectable or metastatic) melanoma refractory or unresponsive to prior ICI therapy,

 according to preliminary phase 1b data presented by Jessica C. Hassel, MD, of Heidelberg University Hospital, Germany, and colleagues.

Domatinostat is a class I–selective histone deacetylase inhibitor that influences the tumor microenvironment by increasing the expression, processing, and presentation of tumor-associated antigens, as well as promoting infiltration of cytotoxic T cells into tumors. Patients were enrolled in 5 different domatinostat dose cohorts, ranging from 100 mg/day to 200 mg twice daily, combined with pembrolizumab at 2 mg/kg every 3 weeks.

All patients had stage III or IV melanoma, and approximately one-third had elevated LDH levels.

At baseline, most patients had had an inflammatory tumor phenotype and T-cell exhaustion. Increases in inflammation scores, major histocompatibility complex molecules, and antigen-processing machinery components were observed. “The translational research results support the immune-modulating mode of action to synergize with checkpoint inhibition,” said Hassel.

In a phase 2 study (NCT03780608), the investigational ATR kinase inhibitor ceralasertib exhibited activity when combined with durvalumab (Imfinzi) in patients with metastatic melanoma who had confirmed progression on anti–PD-1 therapy,

 reported Minsuk Kwon, MD, PhD, of Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea.

“ATR kinase is one of the central regulators in the DNA damage response [DDR] pathway. Alterations in DDR are associated with increased somatic tumor mutational burden,” said Kwon.

The melanoma study enrolled 30 patients with confirmed progression on an anti–PD-1 agent. Patients with active brain metastases were excluded. Ceralasertib 240 mg was administered twice daily on days 15 to 28, and durvalumab 1500 mg was given on day 1 of a 28-day cycle. Treatment continued until disease progression.

Median PFS was 7.1 months, and median OS was 14.2 months. Best response to the ceralasertib/durvalumab combination was PR in 9 patients and stable disease in 10, for an ORR of 30% and a DCR of 63.3%.

Siwen Hu-Lieskovan, MD, PhD, a discussant during the presentation and director of solid tumor immunotherapy at Huntsman Cancer Institute, University of Utah, Salt Lake City, was impressed with this combination.

Interestingly, a phase 1 trial (NCT02630199) by the same group of investigators showed a similar response rate to ceralasertib combined with chemotherapy,

 she noted. The ORR in the trial was 33%, calling into question the benefit of adding durvalumab, which gave an ORR of 30% (TABLE 2

). However, the median PFS and OS were almost doubled with the combination of ceralasertib with durvalumab compared with ceralasertib and chemotherapy, “which seems to suggest that adding durvalumab might increase the survival benefit, even though this is an antiPD-1–resistant population, [perhaps due to] the potential synergistic effect of ceralasertib with durvalumab,” Hu-Lieskovan said during presentation of the data.

Ceralasertib, which is considered a targeted therapy, is usually highly effective at suppressing tumor growth but is limited by a high rate of relapsed disease over time. ICIs such as durvalumab are associated with a lower response rate but prolonged patient survival.

“When we combine a targeted therapy with immunotherapy, the goal is not an additive effect but synergy to achieve a high response rate with prolonged survival in the majority of patients,” said Hu-Lieskovan. The longer median PFS and OS suggest that ceralasertib and durvalumab are synergistic, she said, given that these patients had already progressed on anti–PD-1 agents in the past.

The potential synergy could be due to increased tumor mutational burden from the DNA damage repair defect, an influence on the tumor immune microenvironment, or a direct effect on immune cells, she said.

The triplet combination of nivolumab (Opdivo) with the mechanisms of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) induced an impressive 88% ORR in the anti–PD-1–refractory setting in patients with BRAF-mutated metastatic melanoma in the phase 2 TRIDeNT study (NCT02910700),

 said Elizabeth M. Burton, MBA, of The University of Texas MD Anderson Cancer Center in Houston.

“Clinical trials evaluating BRAF-MEK inhibitors in combination with PD-1 [inhibitors] have reported mixed results. Notably, all trials excluded patients previously treated with PD-1 [inhibitors] and also patients with active brain metastases,” said Burton during the presentation. “Additionally, retrospective studies have reported short median PFS of around 5 months for patients treated with targeted therapy after PD-1 [inhibitor] failure,” pointing to the unmet need to identify effective therapies for patients who have active brain metastases and have progressed on immunotherapy.

The single-center TRIDeNT study enrolled 27 patients with PD-1–naive or –refractory BRAF-mutated metastatic melanoma, with or without active brain metastases.

At a median follow-up of 18.4 months, the median PFS was 8.2 months in the 16 evaluable patients who were refractory to anti–PD-1 therapy. The ORR was 92% in the overall study population: 100% in the anti–PD-1 therapy–naive patients (n = 10), with 1 CR, and 88% in the anti–PD-1– refractory cohort, with 2 CRs. Median PFS was not different between those with and without brain metastases. “What is striking with our cohort, albeit with small numbers, is the median PFS of 8 months [in patients with brain metastases],” Burton said.

The LEAP-004 study (NCT03776136) assessed the combination of lenvatinib (Lenvima) and pembrolizumab in patients with confirmed progression on an ICI. Updated findings after 3 months of additional follow-up (median follow-up, 15.3 months) revealed 1 additional CR, a disease control rate of 66.0%, and an improvement in the median DOR from 6.3 to 8.2 months,12 reported Ana Maria Arance Fernandez, MD, PhD, of Hospital Clinic Barcelona in Spain.

LEAP-004 enrolled 103 patients with progressive disease confirmed per iRECIST within 12 weeks of their last dose of a PD-1/ PD-L1 inhibitor given alone or with antiCTLA-4 or other therapies. Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity.

The ORR was 33.3% in the 30 patients with progression on prior anti–PD-1 plus antiCTLA-4 therapy, 18.2% in the 11 patients who received prior anti–PD-1/PD-L1 treatment in the adjuvant setting only, 22.6% in the 62 patients with primary resistance to prior anti–PD-1/PD-L1 therapy in the advanced setting, and 22.7% in the 22 patients with secondary resistance in the advanced setting.

Lenvatinib plus pembrolizumab “is an active regimen in the [post–]PD-1/CTLA-4 setting,” commented Luke. “It’s unclear to me whether or not this efficacy really differentiates from what we’ve seen from previous combinations.”

The ORR for the entire patient cohort remained 21.4%, which “appears on first pass to be useful in a PD-1–refractory setting, but I’ll note that the duration of response is less than one might expect for checkpoint blockade,” he added. “[The DOR] has improved from 6 months at their initial report to 8.3 months now, but I think, again, this calls into question the mechanism whereby we’re pursuing this anticancer effect.”

 Another strategy that combined an MDM2 inhibitor with an ICI, was studied in a phase 2 trial (NCT03611868).13 The investigators assessed the combination of pembrolizumab and alrizomadlin, an orally bioavailable MDM2 antagonist.

“MDM2 blocks normal p53 function by binding to the p53 protein, leading to ubiquitination and protein degradation,” said Anthony W. Tolcher, MD, FRCPC, of Texas Oncology-San Antonio Babcock and lead investigator of the study. “Retrospective clinical data indicate that MDM2 amplification in tumors is associated with tumor hyperprogression to checkpoint inhibitors.”

Alrizomadlin (APG-115) restores p53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 (gene encoding p53) and/or MDM2 amplification. Preclinical studies demonstrate synergy between alrizomadlin and PD-1 blockade in both wild-type and TP53-mutant tumors in syngeneic murine tumor models.

The phase 2 study included a cohort of 26 patients with melanoma that was resistant to immuno-oncology agents. Other cohorts enrolled patients with resistant non–small cell lung cancer and solid tumors with ATM mutations.

The ORR in the melanoma cohort, of which 29 patients were evaluable for efficacy, was 24.1% and the DCR was 55.2%. Among the responders, there was 1 CR and 6 PRs, with 2 of the PRs being unconfirmed. Results remain preliminary in the other expansion cohorts. In the immuno-oncology–resistant melanoma cohort, the combination appeared to perform best in patients with cutaneous melanoma, with an ORR of 26.7% and a DCR of 46.7%.

An optimal approach might be frontline treatment with an anti–PD-1 therapy, perhaps combined with an anti-LAG3 antibody, said Luke. “[Patients could] then could be treated with PD-1 and low-dose CTLA-4, and then have those TILs available so that they could be reinfused should they progress on that regimen,” he said.

Mario Sznol, MD, of Yale University School of Medicine, New Haven, Connecticut, agrees that that the choice of second-line therapy would depend on the frontline treatment. “It becomes a little complex,” he said in an interview with Targeted Therapies in Oncology. If a LAG3 antibody with an anti–PD-1 agent is used up front, the choice upon progression would depend on whether an anti–CTLA-4 therapy would have activity in a patient already treated with a LAG3 antibody.

Interpreting activity in the resistant/ refractory setting may be difficult because of the potential for late responses to anti–PD-1 therapy and/or anti–CTLA-4 agents, said Sznol. TILs have shown activity in patients with progression on combined anti–PD-1 and anti–CTLA-4 treatment. “If and when TIL [therapy is] approved, and many of us think it will be approved, it would be a reasonable second-line option for patients with melanoma,” he said. “The durability of some of those responses is very encouraging.”

A number of experimental agents being investigated in the second-line setting (some of which are summarized above) appear promising, he said, but “the problem is we don’t have biomarkers, and it’s possible that all those agents would address a small subset of patients. For example, anti-CD40 is one. Anti–IL-8 is another. But it’s possible that when the patient has already had anti–PD-1 and a LAG3 antibody, those other agents may not have a lot of activity. TILs still seem to be active in patients who have had the combination of ipilimumab and nivolumab. It could be that TILs won’t be active in patients who receive an anti–PD-1 therapy and nivolumab and then a LAG3 antibody and nivolumab.”

The use of newer agents empirically in the clinic, perhaps sequentially, could improve 5-year OS rates, said Sznol. “The exciting part is that these are not overlapping subsets of patients, and some way or another, we’re going to figure out who to use them in,” he said. “And at the end of the day, instead of 50% 5-year survival, it will be at 65% or 70%.”

1. Larkin J, Minor D, D’Angelo S, et al. Overall survival in patients with advanced melanoma who received nivolumab versus investigator’s choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018;36(4):383-390. doi:10.1200/JCO.2016.71.8023

 2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/ NEJMoa1910836 

3. Goldinger SM, Lo S, Hassel JC, et al. The utility of chemotherapy after immunotherapy failure in metastatic melanoma: a multicenter case series. J Clin Oncol. 2018;36(suppl 15):e21588. doi:10.1200/JCO.2018.36.15_suppl.e21588 

4. Kirchberger MC, Hauschild A, Schuler G, Heinzerling L. Combined low-dose ipilimumab and pembrolizumab after sequential ipilimumab and pembrolizumab failure in advanced melanoma. Eur J Cancer. 2016;65:182-184. doi:10.1016/j. ejca.2016.07.003 

5. Larkin J, Sarnaik A, Chesney JA, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced melanoma: evaluation of impact of prior anti–PD-1 therapy. J Clin Oncol. 2021;39(suppl 15):9505. doi:10.1200/JCO.2021.39.15_suppl.9505 

6. Mooradian M, Fintelmann FJ, Kaufman HE, et al. The use of cryoablation to overcome resistance to PD-1 blockade in unresectable melanoma. J Clin Oncol. 2021;39(suppl 15):9538. doi:10.1200/JCO.2021.39.15_suppl.9538 

7. Eggermont AM, Meshcheryakov A, Atkinson V, et al. Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of highrisk stage III melanoma. J Clin Oncol. 2021;39(suppl 15):9500. doi:10.1200/JCO.2021.39.15_suppl.9500

8. Hassel JC, Berking C, Schlaak M, et al. Results from the phase Ib of the SENSITIZE trial combining domatinostat with pembrolizumab in advanced melanoma patients refractory to prior checkpoint inhibitor therapy. J Clin Oncol. 2021;39(suppl 15):9545. doi:10.1200/JCO.2021.39.15_suppl.9545 

9. Kwon M, Kim ST, Smith S, et al. Phase II study of ceralasertib (AZD6738), in combination with durvalumab in patients with metastatic melanoma who have failed prior anti–PD-1 therapy. J Clin Oncol. 2021;39(suppl 15):9514. doi:10.1200/ JCO.2021.39.15_suppl.9514

10. Kim ST, Smith SA, Mortimer P, et al. Phase I study of ceralasertib (AZD6738), a novel DNA damage repair agent, in combination with weekly paclitaxel in refractory cancer. Clin Cancer Res. Published online May 11, 2021. doi:10.1158/1078-0432.CCR-21-0251 

11. Burton EM, Amaria RN, Glitza IC, et al. Phase II Study of TRIplet combination nivolumab (N) with dabrafenib (D) and trametinib (T) (TRIDeNT) in patients (pts) with PD-1 naïve or refractory BRAF-mutated metastatic melanoma (MM) with or without active brain metastases. J Clin Oncol. 2021;39(suppl 15):9520. doi:10.1200/JCO.2021.39.15_suppl.9520

 12. Arance AM, de la Cruz-Merino L, Petrella TM, et al. Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: updated findings of LEAP-004. J Clin Oncol. 2021;39(suppl 15):9504. doi: 10.1200/JCO.2021.39.15_suppl.9504 

13. Tolcher AW, Reeves JA, McKean M, et al. Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs. J Clin Oncol. 2021;39(suppl 15):2506. doi: 10.1200/ JCO.2021.39.15_suppl.2506

Articles

Immune-checkpoint inhibitor therapy, involving anti–CTLA-4 and anti–PD-1/ PD-L1 agents, has transformed the treatment of melanoma. Nonetheless, even with combination anti–PD-1 and anti–CTLA-4 therapy, nearly 50% of patients die of their disease at 5 years.

Unique Immunotherapy Combos Evaluated in Advanced Melanoma

For the treatment of patients with newly diagnosed acute graft-versus-host disease (GVHD, itolizumab, a humanized IgG1 monoclonal antibody that modulates the activated leukocyte cell adhesion molecule (ALCAM) pathway, has demonstrated promise in part A of the multicenter dose-ascending phase 1b/2 EQUATE study, according to results presented during the virtual 2021 Transplantation & Cellular Therapy Meetings.

Data showed that administration of itolizumab resulted in a dose-dependent reduction of CD6 expression on T-effector cells and a 100% overall response rate (ORR) at the 2 highest dose levels at day 29, with almost all responses being complete responses, said lead study author John Koreth, MBBS, PhD.

“The dose-dependent reduction of CD6 expression on CD4+ and CD8+ T cells is consistent with the expected mechanism of action [of itolizumab],” said Koreth, director of translational research, stem cell transplantation, Dana-Farber Cancer Institute, Boston.

The CD6 ALCAM pathway is central to immune infiltration, he explained. “CD6 is a costimulatory receptor that is upregulated and expressed on CD4+ and CD8+ effector T cells. There are multiple CD6 ligands, most prominently ALCAM that is expressed on both antigen-presenting cells and tissues, including the skin and the GI [gastrointestinal] tract,” Koreth said. “ALCAM overexpression leads to the increased infiltration of CD6high cells. The CD6 ALCAM pathway, therefore, potentially can modulate both the activity of T cells and the trafficking of T cells to sites of inflammation.”

CD6high cells adopt a pathogenic phenotype to secrete high amounts of gamma interferon and high amounts of interleukin-17. Itolizumab acts by causing antigenic modulation of cell surface CD6, a pathogenic CD6high cell, resulting in a switch to a CD6 low phenotype in a dose-dependent manner.

Part A of EQUATE is an open-label 3+3 dose escalation design evaluating 4 itolizumab doses ranging from 0.4 mg/kg to 2.4 mg/kg. Patients received intravenous itolizumab administered every 2 weeks for 5 doses, with corticosteroids tapered over the treatment period. At the time of data cutoff, 4 patients were enrolled in cohort 1 (0.4 mg/kg), 3 in cohort 2 (0.8 mg/kg), and 3 in cohort 3 (1.6 mg/kg).

All patients are adult recipients of first allogeneic hematopoietic stem cell transplant with grade III/IV acute GVHD at screening or baseline. Primary disease was acute myeloid leukemia in 4 patients, acute lymphoblastic leukemia in 2, myelofibrosis in 2, and other in 2. The graft source was peripheral blood in 8 of the 10 patients.

Nine patients had lower gastrointestinal (GI) involvement and 2 had upper GI involvement. Eight of the 10 were high risk based on the MacMillan risk score and all patients had Ann Arbor scores of 2 (30%) or 3 (70%). All patients received either methotrexate (70%), tacrolimus (70%), or sirolimus (60%) prophylaxis.

As early as day 15, an ORR of 100% was observed for the 0.8 and 1.6-mg/kg dose level cohorts, all but 1 being a complete response. These responses were sustained through day 57 in the 2 highest dose cohorts. One patient in cohort 1 experienced acute GVHD progression and required rescue therapy at day 7.

The overall CR rate was 100% in cohort 2. In cohort 3, 1 patient who had a partial response at day 15 improved to a CR by day 85 but then experienced grade 2 acute GVHD on steroid taper and drug discontinuation beyond day 57, indicating durability on treatment and the need for potentially longer-term treatment in some patients, said Koreth.

Itolizumab was associated with a reduction in the dose of systemic steroids by 93%, 87%, and 91% at day 85 for cohorts 1, 2, and 3, respectively. A dose-dependent reduction in cell surface CD6 levels, on both CD4 and CD8 T cells, as early as 24 hours after the initiation of therapy was also observed. At the 0.8- and 1.6-mg/kg dose levels, the suppression of CD6 levels was sustained though day 15.

The adverse event (AE) rate was 100%, which was “consistent with this high-risk acutely sick patient population,” he said. Five patients experienced serious AEs; only 2 were considered treatment related. Four patients had serious infections, 1 was grade 4 sepsis deemed to be a dose-limiting toxicity. Three patients, 2 in cohort 2 and 1 in cohort 3, had AEs that led to discontinuation of itolizumab. One patient in cohort 3 had an AE leading to death, unrelated to the study intervention.

Patients experienced a transient decline in absolute lymphocyte count, most commonly with the first dose of itolizumab. “Importantly, there were no infectious or clinical sequelae during this period of transient lymphopenia,” he said.

Koreth J, Loren AW, Nakamura R, et al. Preliminary safety and efficacy of itolizumab, a novel targeted anti-CD6 therapy, in newly diagnosed severe acute graft-versus-host disease: interim results from Equate study. Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract LBA4.

For the treatment of patients with newly diagnosed acute graft-versus-host disease, itolizumab has demonstrated promise in part A of the multicenter dose-ascending phase 1b/2 EQUATE study.

Itolizumab Induces Durable Clinical Responses in Newly Diagnosed aGVHD

Treatment with axicabtagene ciloleucel (axi-cel; Yescarta) is less likely to induce response in patients with refractory large B-cell lymphoma (LBCL) who have never achieved a complete response (CR) to any line of prior therapy, according to findings from a single-center retrospective analysis.

The analysis comprised 171 patients with LBCL treated with axi-cel at the academic center between January 2018 and April 2020. At a median follow-up of 9 months, the median progression-free survival (PFS) was 6 months (95% CI, 4-8) in patients who never attained a CR to prior therapy. There was a trend toward shorter PFS in the group that never attained a CR compared with patients who achieved a CR with any prior line of therapy (5 vs 26 months, respectively; 

The data were presented virtually by Sairah Ahmed, MD, and Paolo Strati, MD, at The University of Texas MD Anderson Cancer Center during the 2021 Transplantation & Cellular Therapy Meetings.

“In our large cohort, we identified lack of prior complete response to any line of therapy to predict for inferior outcomes with axi-cel CAR T-cell therapy,” the investigators noted in their poster. “Despite CAR T-cell therapy having a non-overlapping mechanisms with standard cytotoxic chemotherapy, it appears that disease refractoriness may be therapy agnostic.”

Additional data showed that the median overall survival (OS) showed a similar trend to median PFS. Median OS was not reached in the cohort without a prior CR. However, the 1-year OS rate was shorter at 60% in this group versus those who attain a CR to a prior treatment, at 75%, although the difference missed statistical significance (

Axi-cel is currently approved for the treatment of patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and high-grade B-cell lymphoma after at least 2 lines of systemic therapy. In the phase 2 portion of the ZUMA-1 trial,

 which was the basis for the approval in this setting, there was no significant difference in outcomes in patients with refractory LBCL based on prior lines of treatment, noted the researchers.

“Beyond tumor volume, there is a lack of data in predicting response outcomes,” they wrote.

Of the 171 patients who received axi-cel as standard of care as part of the analysis, 134 did not attain a CR to any prior line of therapy and 37 did achieve a CR.

There was no statistically significant difference in age, gender, histology, ECOG performance status, stage, or International Prognostic Index (IPI) between the 2 groups at baseline. The median age of the overall cohort was 59 years (range, 18-85), 70% were male, 82% had Ann Arbor stage III or IV LBCL, 64% had more than 1 extra-nodal site, 56% had an IPI score of 3 to 5. The median level of lactate dehydrogenase at baseline was 323 U/L. The median number of prior therapies was 4 (range, 2-15). About one-fourth (n = 45; 26%) had received previous autologous stem cell transplant (SCT) and 3 (2%) received prior allogeneic SCT. Fifty percent had bridging therapy, including 30% with chemotherapy as a bridge, 12% with radiation therapy, and 8% with biologic therapy.

The need for bridging therapy, which was 54% in those never attaining a CR versus 35% in those who attained a CR to prior therapy (

 = .04), and lack of prior autologous SCT (22% vs 43%, respectively; 

 = .01) were identified as significant factors associated with lack of a CR to prior therapy.

The findings from this analysis should be explored in larger registry studies and targeted in future clinical trials, the authors concluded.

In September 2020, a supplemental biologics license application was filed with the FDA for axi-cel for the treatment of patients with relapsed/refractory follicular lymphoma and marginal zone lymphoma following 2 or more previous lines of systemic treatment.

1. Ahmed S, Strati P, Fayad LE, et al. Efficacy of chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma (LBCL). Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract 493.

2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-Cell lymphoma. 

Treatment with axicabtagene ciloleucel is less likely to induce responses in patients with refractory large B-cell lymphoma who have never achieved a complete response to any line of prior therapy, according to findings from a single-center retrospective analysis. 

Axi-Cel Treatment Outcomes Correlate With Response to Prior Therapy in Refractory Large B-Cell Lymphoma

Most patients with metastatic renal cell carcinoma (RCC) whose disease progresses after immunotherapy given either alone or in combination with other agents receive subsequent treatment with VEGF tyrosine kinase inhibitors (TKIs) or mTOR inhibitors. When administered post-immunotherapy, cabozantinib (Cabometyx) is associated with superior median progression free survival (PFS), according to retrospective data from a real-world study of patients treated at 16 Italian referral centers.

Of 162 patients with metastatic RCC who were referred to centers that were part of the Meet-Uro group, 111 (68.5%) were treated after progression on immuno-oncology drugs. Of the 79 patients (71.2%) who received subsequent cabozantinib, median PFS was 7.6 months (95% CI, 5.2-10.1 months), compared with a median of 3.2 months (95% CI, 1.8-4.5 months) in the 11 patients (9.9%) who received everolimus as subsequent therapy (

= .001 for cabozantinib vs. everolimus) and a median of 4.3 months (95% CI, 1.3-7.4 months) in the 21 who received other drugs as subsequent therapy.

Median overall survival from first-line therapy was 41.1 months (95% CI, 30.4-51.8 months).

The data were reported at the 2020 Genitourinary Cancer Symposium by investigators led by Daniele Santini, MD, co-chief and professor in the Department of Medical Oncology, Campus Bio-Medico University of Rome, Italy.

They undertook this project because little real-world data exist on safety and outcomes of metastatic RCC patients after progression on immuno-oncology drugs.

Previously, using data from 8 international cancer centers, Graham et al assessed outcomes of patients with metastatic RCC who were treated with targeted therapy after prior immuno-oncology therapy. Their study found an advantage of VEGF-TKIs over mTOR inhibitors on the end points of time to treatment discontinuation (adjusted HR, 0.46; 95% CI, 0.30-0.71;

<.01), 1-year probability of survival (65% vs 47%;

<.01), and objective response rate (29.8% vs 3.6%;

The study presented here included 104 men and 58 women. A total of 136 (83.9%) had prior nephrectomy. About two thirds (65.4%) had received sunitinib (Sutent) as first-line therapy, 29.6% received pazopanib (Votrient), and 5% other agents as first line. Metastatic sites were lymph nodes in 70.3%, visceral in 25.3%, and bone in 76.5%. At baseline, Sixty-six percent of patients had an ECOG performance status of 0-1 and 44% had an ECOG performance status of 2. Histology was clear cell in 87.6% and non-clear cell in 12.4%. Sarcomatoid histology was present in 15.5%.

The median PFS was 4 months in patients pretreated with pazopanib (95% CI, 2.4-5.5 months) versus 3.9 months in those pretreated with sunitinib (95% CI, 2.9-4.9 months).

= .004) in patients reporting adverse events of any grade (5.03 months; 95% CI, 3.8-6.1 months) compared with those not reporting adverse events (2.99 months; 95% CI, 2.4-3.5 months). Median PFS also trended longer among patients without nephrectomy (4.1 months vs. 2.9 months among those with prior nephrectomy;

Physician-assessed best response was stable disease (SD) or partial response (PR) in 55 patients (49.5%) and progressive disease in 26 (23.4%). A total of 42 patients (53.1%) who received cabozantinib as subsequent therapy had SD/PR as best response compared with 2 (18.1%) who received everolimus as treatment subsequent to immune-oncologic therapy and 6 patients (5.4%) who received other agents as subsequent treatment.

Patients with an ECOG performance status of 0 after immuno-oncologic therapy compared with ECOG performance status of 1 or 2.

All-grade adverse events were reported in 83 patients (74%), with grade 3-4 adverse events reported by 39 (35%).

Santini D, Stellato M, De Giorgi U, et al. Clinical outcomes of metastatic renal carcinoma following disease progression to programmed death (PD)-1 or PD-L1 inhibitors (I-O): a Meet-URO group real-world study (Meet-Uro 7). Presented at: GU Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 69

Graham J, Shah AY, Wells JC, et al. Outcomes of patients with metastatic renal cell carcinoma treated with targeted therapy after immuno-oncology checkpoint inhibitors.[published online ahead of print, 2019 Nov 27].

. 2019;S2588-9311(19)30160-9. doi:10.1016/j.euo.2019.1001

Most patients with metastatic renal cell carcinoma whose disease progresses after immunotherapy given either alone or in combination with other agents receive subsequent treatment with VEGF tyrosine kinase inhibitors or mTOR inhibitors. When administered post-immunotherapy, cabozantinib is associated with superior median progression free survival, according to retrospective data from a real-world study of patients treated at 16 Italian referral centers.

Wayne Kuznar | Authors

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