Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma

Abstract

Background

PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846).

Methods

This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5 mg/kg) and nab-paclitaxel (260 mg/m²) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival.

Results

Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached).

Conclusion

Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.

Introduction

For more than 40 years, platinum-based chemotherapy has been the first-line standard of care for patients with metastatic urothelial carcinoma (mUC) with median survival of 9.3-14 months and the overall response rate (ORR) is 41.249%.^1,2 In recent years, programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) inhibitors have become the new first-line treatment for metastatic urothelial carcinoma for platinum-ineligible patients and salvage treatment for patients with failure of platinum-based chemotherapy.^3,4 Although the duration of response (DOR) has been significantly prolonged, only a small fraction of patients may benefit from PD-1/PD-L1 monotherapy. The 23%-24% ORR is far lower than expected as a first-line therapy,^5,6 and the treatment algorithm has recently been challenged by Enfortumab vedotin (EV) with or without anti-PD-1 antibody.^7,8

There is increasing evidence supporting the combination of immune checkpoint inhibitors (ICIs) with chemotherapy to treat cancer.^9,10 Chemotherapy can induce immunomodulatory effects that can be enhanced by concomitant PD-L1/PD-1 blockade.^11-13 However, in urothelial carcinoma, the results of immune checkpoint inhibitor (ICI) and platinum-based chemotherapy combination is ambiguous. In IMvigor130, the first-line atezolizumab plus gemcitabine/platinum-containing chemotherapy significantly prolonged investigator-assessed progression-free survival (PFS) compared with chemotherapy alone, but that did not bring any significant benefit in overall survival (OS).¹⁴ The same setting in Keynote 361 further confirmed that the addition of pembrolizumab to first-line gemcitabine/platinum-containing chemotherapy failed to improve PFS or OS.¹⁵ In contrast, in CheckMate 901, the addition of nivolumab to the chemotherapy prolonged PFS and OS compared to gemcitabine/platinum-containing chemotherapy alone.¹⁶

Given that albumin-binding paclitaxel (nab-paclitaxel) is used as a single agent for advanced urinary tract carcinoma with ORR of 42% as first-line¹⁷ and of 22%-27.7% as second-line,^18,19 we explored the safety and efficacy of socazolimab²⁰(PD-L1 inhibitor) combined with nab-paclitaxel as first-line treatment for advanced urothelial carcinoma. Socazolimab is an anti-PD-L1 antibody approved by the China’s national medical products administration in December 2023 for recurrent or metastatic cervical cancer.

Material and methods

Study design and patients

The study was a single-armed, multi-center, phase Ib study conducted in 2 medical centers in China—Peking University Cancer Hospital & Institute and The First Affiliated Hospital of University of Science and Technology of China. Eligible patients had to be at least 18 years of age and have a histologically confirmed diagnosis of locally advanced, unresectable or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra, and no previous systemic treatment for advanced disease. Patients who had finished perioperative chemotherapy for resectable urothelial carcinoma more than 6 months before the study entry were also eligible. Patients must have an ECOG score of 0 or 1, measurable lesions with RECIST 1.1 evaluation criteria. Patients who had previously used ICEs, with existing autoimmune disease, active brain metastases, or had received systemic corticosteroid immunosuppressants within 2 weeks were excluded. Finally, patients must have adequate renal function, defined as serum creatinine levels of up to 1.5 times the upper limit of normal status (or calculated creatinine clearance of at least 30 mL/min if serum creatinine levels are more than 1.5 times the upper limit of normal status).

The study was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines defined by the International Council for Harmonization. And the study protocol was reviewed and approved by the institutions of each participating center and an independent ethical review committee. All patients signed informed consent before enrollment, and patients could withdraw from the study for any reason at any time.

Procedures

The study was separated into 2 parts. In part 1, 6 patients were enrolled on socazolimab 5 mg/kg intravenously in combination with nab-paclitaxel 260 mg/m² on day 1 of each 3-week cycle. If chemotherapy-related dose-limiting toxicity (DLT) occurred in 2 or more of these 6 patients, the dose of albumin-binding paclitaxel should be down-regulated. However, the minimum of nab-paclitaxel should not be less than 180 mg/m² in each cycle. If immune-related DLTs occurred in 2 or more of the 6 patients, the trial would be suspended. If no DLTs occurred during part 1, the study would proceed into Part 2 and 14 more patients would be enrolled to evaluate the efficacy and safety of the regimen. After the completion of 6 cycles of combined therapy with no disease progression or intolerable toxicity, socazolimab monotherapy would be continued until disease progression, intolerable toxicity, patient’s decision to withdraw consent, or a maximum of 35 cycles, whichever occurred first. If permanent discontinuation was due to intolerable toxicity with chemotherapy, monotherapy with socazolimab would be provided as aforementioned. Dose adjustment of socazolimab was not permitted. If the intolerable toxicity is due to socazolimab, the regimen would be permanently discontinued.

Imaging assessment was performed every 6 weeks from the date of first dose for the first 48 weeks, and every 9 weeks (window period of ±7 days) thereafter. Responses and disease progression were assessed according to RECIST (version 1.1). During survival follow-up, patients were contacted directly or by phone every 30 days until death, withdrawal of consent, loss of follow-up, or the end of the trial.

Detection of PD-L1-expression status was performed using VENTANA PD-L1 (SP263). Its positive expression satisfies any of the following conditions: (1) the proportion of positive tumor cells (TC+) ≥25%, (2) the proportion of tumor-associated immune cells in the tumor region (ICP) is >1%, and the proportion of PD-L1 positive immune cells in the tumor region (IC+) is ≥25%, (3) ICP = 1% and IC+= 100%.²¹

Adverse events and laboratory abnormalities were collected and assessed regularly by investigators throughout treatment and for 90 days thereafter or before the initiation of a new anticancer therapy, whichever occurred first. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE 5.0).

Outcomes

The primary endpoint was the safety and tolerability of nab-paclitaxel in combination with Socazolimab. Secondary endpoints were the objective response rate (ORR, defined as the proportion of patients with a radiographically confirmed complete response or partial response), disease control rate (DCR, defined as the proportion of patients with a radiographically confirmed complete response, partial response, or stable disease), DOR, defined as the time from first documented complete or partial response to radiographically confirmed disease progression or death from any cause, whichever occurred first, progression-free survival (PFS, defined as the time from randomization to radiographically confirmed disease progression or death from any cause, whichever occurred first), OS, defined as the time from the start of the therapy to the death of the patient due to any reason and exploratory biomarker analyses.

Statistical analysis

In part 1, 6 patients were enrolled to receive the regimen. If the toxicity was controllable, 14 more patients would be enrolled in Part 2 to improve the estimation of security and efficacy.

Safety analysis was based on descriptive statistical summaries. ORR was calculated by the Clopper-Pearson method with the corresponding 95% CI. OS, PFS, and DOR were estimated by the Kaplan-Meier method, providing with the median and 95% CIs. All statistical analysis was performed using SAS version 9.4 or later (SAS Institute). This trial was registered in ClinicalTrials.gov (NCT04603846).

Results

Baseline characteristics of patients

From September 28, 2020 to September 30, 2021, 20 patients were enrolled, including 6 in part 1 and 14 in part 2. Table 1 summarizes the demographic and baseline patient characteristics. The median age was 69years old. Nineteen patients (92.7%) had distant metastases, and common sites of metastasis were lymph node metastases (65%), lung metastases (40%), liver metastases (10%). Twelve patients provided pathological specimens for PD-L1 expression analysis, of which 3 did not meet the testing criteria, 2 were PD-L1 positive, and 7 were PD-L1-negative (Table 1). All patients received one or more doses of study drugs.

Safety and tolerability

As of the cutoff date, May 31, 2023, the median treatment cycle was 12 (range: 2-32) , 17 (85%) of the patients had stopped treatment, 2 (10%) of the patients had completed treatment, and the remaining 1 (5%) patient were still on treatment (Figure 1). Twelve (60%) patients had dose adjustment of nab-paclitaxel, which was mainly due to peripheral neurotoxicity. There were no protocol-defined DLTs reported for the 6 patients in part 1 of the study. No drug-related death was reported during the study period. There were no life-threatening, crippling events that investigators considered to be related to the treatment.

All patients had one or more investigator-assessed treatment-related adverse events (TRAEs), most of which were grade 1 or 2 (Table 2). The common TRAEs (≥ 15%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesia, anorexia, fever, increased thyrotropin, increased LDH, insomnia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (n = 6; 30.0%), increased ALT (n = 2; 10.0%), and increased γGT (n = 1; 5.0%). Two patients (10%) discontinued treatment because of TRAEs as grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4 or5 TRAEs or treatment-related serious AEs were observed.

Among 20 patients, the overall incidence of immune-related adverse events (irAEs) was 45% (9 cases, Table 2). The common irAEs included rash (4/20, 20.0%), increased thyrotropin (3/20, 15.0%), pruritus (2/20, 10.0%), mouth ulcer (1/20, 5%), fever (1/20, 5%), hyperglycemia (1/20, 5%), hyperthyroidism (1/20, 5%), diarrhea(1/20, 5%) and lung fibrosis (1/20, 5%), which were all lower grade irAEs. There was only 1 (5%) reported grade 3 mouth ulcer. There were no grade 4 or above irAEs. All TRAEs or irAEs were relieved or stabilized after symptomatic treatment.

Efficacy assessment

By May 30, 2023, 17 patients had been evaluated at least once and included in the anti-tumor response assessment. The median follow-up time was 17 months (range: 3.35-29.96). In the overall population (N = 17), 10 patients achieved PR and 5 patients achieved SD as assessed by RECIST v1.1, resulting in an ORR of 58.8% (95% CI, 32.9-81.6) and DCR of 88.2% (95% CI, 63.6-98.5, Table 3). Median time to response was 2.02 months (range, 1.18-4.04, Figure 2), and the median DOR was 13.3 months (95% CI, 2.0-20.1). Best percentage change from baseline in target lesion size for the 17 patients who had one or more evaluable post baseline imaging assessment is shown in Figure 3. Reductions in individual tumors from baseline were durable (Figure 4), and there were no case of pseudo-progression.

At the time of data cutoff, 14 patients (82.4%) in the total population had experienced disease progression or death. Median PFS was 8.3 months (95% CI, 5.2 to 19.5), and the estimated PFS rate at 6 months was 64.7% (Figure S1). Median OS was 19.5 months (95% CI, 11.2-NE) (Table 3), and 6-month OS rate was 82.4% in the total population (Figure S2).As exploratory objectives, PD-L1 expression levels was retrospectively evaluated as potential biomarkers for therapy in the 9 (52.9%) of 17 patients for whom data was available. Two patients with tumors expressing PD-L1 were assessed as PR, with PFS of 6.9 months (95% CI, 5.4-8.3). Among the 7 patients with tumors negative for PD-L1 expression, 5 had PR and 2 had SD. In the population with tumors that were PD-L1–negative, the PFS was 13.6 months (95% CI, 6.9-NE, Table 3).

Discussion

Enfortumab vedotin (EV) has brought revolutionary change in the first-line therapy of aUC. The phase I/IIb EV-103 demonstrated that cisplatin-ineligible treatment-naïve UC patients with EV + pembrolizumab achieved an ORR of 73.3% and median PFS of 12.3 months, which led to its accelerated approval by US FDA in 2020(7).The results of a confirmatory phase III EV-302 trial compared the efficacy of this combination vs standard chemotherapy for platinum-eligible patients, with urolthelial cancer, which had met the co-primary endpoints of OS and PFS.²² There is no doubt that for most patients with advanced UC, from the point of view of efficacy, EV + PD-1 antibody will replace traditional chemotherapy of gemcitabine + cisplatin/carboplatin as frontline therapy. However, resistance will eventually emerge, and clinicians may also need to consider other factors instead of efficacy alone.

The first concern is the cost. Qiuji Wu et al assessed the cost-effectiveness of EV for the treatment of aUC from a payer’s perspective in developing countries such as China and developed countries such as the United Kingdom and the United States and found that even in the United States, the probability of EV being cost-effective was >50% only at 10% of the current price.²³ Note that EV has not yet become accessible in most countries outside of Europe and the United States. The second concern is the safety. The results of EV-302 showed that the occurrence of EV treatment-related AEs of peripheral neuropathy and skin reactions was high—up to 66.8% and 63.2%, respectively,²² which means some patients with severe AEs might discontinue the regimen permanently. It is agreed that EV + PD-1 will become the mainstay of first-line therapy for aUC in the next decade, but unmet needs remain. For patients in whom EV + PD-1 failed, the optimal regimen is still needed. Our study results could provide some clues for future explorations.

Anti-PD-1 antibody pembrolizumab plus nab-paclitaxel has been investigated as salvage therapy for platinum-treated advanced urothelial carcinoma in the PEANUT trial and other similar studies, achieving ORR of 25%-38.6% and PFS of 5.8-5.9 months.^24,25 Here, we applied this regimen as first-line therapy in patients with platinum-eligible UC. Although the efficacy of the combined regimen was overshadowed in the era of EV + PD-1, we can foresee that this platinum-naive population may resemble most patients with urothelial carcinoma that failed frontline treatment including EV + PD-1 or EV-ineligible/EV clinically inaccessible.

In our study, anti-PD-L1 plus nab-paclitaxel as frontline achieved an ORR of 58.8%, PFS of 8.3 months and OS of 19.5 months. Three phase III trials, IMvigor130, KEYNOTE-361, and CheckMate 901, tested GC + PD-1 as first-line in aUC, but failed to demonstrate significant improvements in OS over GC alone, with the exception of CheckMate 901^14-16 The data from the 3 trials demonstrated that the combination regimen has a PFS ranging from 7.9 to 8.3 months and OS from 16.0 to 21.7 months, which is similar with our study. Most patients with urothelial carcinoma are >65 years of age and around 50% of them are older than 70 years of age. Many of these patients have comorbidities and thus may not be able to tolerate cisplatin-based chemotherapy. Only about 50% of patients with aUC can tolerate standard platinum-containing chemotherapy due to postoperative renal function failure.²⁶ Especially for patients with upper urothelial carcinoma treated with radical nephrectomy, the application of platinum-containing regimen was further limited due to the solitary kidney.²⁶ We compared our safety results with the data of Keynote 361 and IMvigor 130.^14,15 In those 2 studies, 29%-32% of patients treated with gemcitabine and platinum with anti-PD-1/PD-L1 antibody experienced treatment related SAEs and 31%-34% of patients discontinued the treatment due to adverse events. Notably, in this current study, the occurrence of SAEs and the discontinuation of treatment due to toxicity were much less than that in Keynote 361 and IMvigor 130. For example, there was no treatment-related renal function disorders occurring in the current study, although with 20 patients enrolled there may be insufficient numbers to make this comparison. Therefore, nab-paclitaxel with PD-1 might have more applicable marketing as second-line therapy compared with GC with or without PD-1 who failed with EV with PD-1, or as first-line treatment for patients who are EV intolerable. However, as in metastatic renal cell carcinoma, adding PD-1 to cabozantinib did not improve clinical outcome comparing to cabozantinib monotherapy after progression with previous immune checkpoint inhibitor treatment.²⁷ For aUC patients with disease progression on EV with PD-1, the role of adding PD-1 as second-line should be carefully evaluated. More importantly, it is critical to find predictive biomarkers, which could identify patients with aUC who have long-lasting responses to chemotherapy plus immunotherapy.

There are some design differences of the regimens between PEANUT and the current study. In PEANUT, the participants were treated with 125 mg/m² nab-paclitaxel on days 1 and 8 in each cycle, while in the current study, patients only received 6 cycles of nab-paclitaxel with the dosage of 260 mg/m². The safety results of our study showed that socazolimab in combination with nab-paclitaxel was well tolerated. There were no DLTs observed and no attributable deaths occurred. The most common TRAEs reported in patients were peripheral neurotoxicity (85.0%) and alopecia (80.0%). Nine patients (45%) in the current study developed irAEs and only 1 patient (5.0%) developed grade 3 irAE and there was no grade 4 irAE. No new safety events were identified compared to combination therapy, highlighting the safety of socazolimab combined with nab-paclitaxel as first-line therapy in patients with advanced urothelial carcinoma. Meanwhile, we found that in PEANUT, the occurrence and severity of peripheral neuropathy was much less common than that in the current study (all grade: 34.3% vs 85.0%, grade 3/4: 2.9% vs 34%), which suggested that some modification of the regimen is needed in the future design or application.

Limitations of this study include the single-arm design. The lack of a control group limits the evaluation of efficacy to compare with standard platinum-based chemotherapy; the small sample size and relatively short follow-up period make it impossible to gain further insight into the effect of socazolimab plus nab-paclitaxel on survival. Especially in the era of EV, it is more practical to try this regimen as second-line therapy patients with aUC patients who experienced disease progression on frontline of EV + PD-1 or who were EV-ineligible/EV clinically inaccessible.

Conclusion

Anti-PDL1 inhibitor socazolimab combined with nab-paclitaxel has controllable toxicity and promising efficacy as a new treatment option in selected patients with locally advanced or metastatic urothelial carcinoma, and needs to be further validated.

Acknowledgements

We thank Dr. Michael Wong for English editing. We appreciated the contribution of the patients and their family who were involved in the study.

Author contributions

Bixia Tang: Provision of study material or patients, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript. Jun Xiao: Provision of study material or patients, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript. Zhihong Chi: Provision of study material or patients, Data analysis and interpretation, Final approval of manuscript. Rong Duan: Collection and/or assembly of data, Data analysis and interpretation, Final approval of manuscript. Chuanliang Cui: Provision of study material or patients, Final approval of manuscript. Lu Si: Provision of study material or patients, Final approval of manuscript. Yixun Liu: Provision of study material or patients, Final approval of manuscript. Xuechun Hu: Provision of study material or patients, Final approval of manuscript. Zhi Liu: Provision of study material or patients, Final approval of manuscript. Ping Xiang: Provision of study material or patients, Final approval of manuscript. Siming Li: Collection and/or assembly of data, Final approval of manuscript. Xieqiao Yan: Collection and/or assembly of data, Final approval of manuscript. Li Zhou: Collection and/or assembly of data, Final approval of manuscript. Juan Li: Collection and/or assembly of data, Final approval of manuscript. Yujie Li: Collection and/or assembly of data, Manuscript writing, Final approval of manuscript. Xiaohui Yu: Collection and/or assembly of data, Final approval of manuscript. Xiangrong Dai: Conception/Design, Final approval of manuscript. Xiaoyi Li: Conception/Design, Final approval of manuscript. Jun Guo: Conception/Design, Provision of study material or patients, Data analysis and interpretation, Final approval of manuscript. Xinan Sheng: Conception/Design, Provision of study material or patients, Data analysis and interpretation, Final approval of manuscript.

Funding

The study was funded by Zhaoke (Guangzhou) Oncology Pharmaceutical Limited, Guangzhou, China.

Conflicts of interest

J.G. is the member of the advisory board/consultant of MSD, Roche, Pfizer, Bayer, Novartis, Simcere, Shanghai Junshi Bioscience, Oriengene. X.S. has the following potential conflicts of interest to disclose: Consulting or advisory role: Pfizer, Astellas, RemeGen, and Junshi Biosciences, Speakers fees from Novartis, MSD, and BeiGene. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

References

Author notes