SRK-181 Alone or With Anti–PD-(L)1 Therapy Elicits Early Efficacy in Select Solid Tumors

When the fully human IgG4 monoclonal antibody SRK-181 was given as a monotherapy or in combination with anti–PD-1 or PD-L1 agents in patients with locally advanced or metastatic solid tumors, it was found to be generally well tolerated and to demonstrate early indications of efficacy, according to data from the phase 1 DRAGON trial (NCT04291079).¹

Updated data from part B the trial were presented at the 2023 ESMO Targeted Anticancer Therapies Congress. As of the data cutoff date of December 2, 2022, 20 patients had been dosed spanning the following cohorts: clear cell renal cell carcinoma (ccRCC; n = 9), non–small cell lung cancer (NSCLC; n = 3), urothelial carcinoma (n = 4), melanoma (n = 1), and other (n = 3; enrollment closed).

When paired with pembrolizumab (Keytruda), SRK-181 at doses of 1500 mg every 3 weeks or 1000 mg every 2 weeks was found to be well tolerated. Two patients with ccRCC that was resistant to anti–PD-1 treatment experienced confirmed partial responses (PRs) to treatment.

As of the cutoff date, 11 patients with ccRCC were enrolled to part A2 and part B of the trial; 2 of these patients were in part A2 and 9 were in part B. A total of 3 patients with ccRCC that was resistant to anti–PD-1 treatment experienced confirmed PRs to study treatment, equating to an objective response rate (ORR) of 27%.

“SRK-181 was generally well tolerated in combination with anti–PD-(L)1 at all doses,” lead study author Timothy Yap, MBBS, PhD, FRCP, of The University of Texas MD Anderson Cancer Center, Houston, Texas, said in a presentation of the data. “No dose-limiting toxicities [DLTs] were observed up to 3000 mg every 3 weeks (q3w) or 2000 mg every 2 weeks (q2w) as a monotherapy and up to 2400 mg every 3 weeks as combination treatment.”

Because SRK-181 targets TGFβ1 it is thought to possess the potential to overcome resistance to checkpoint inhibitors (CPIs). The agent also targets the latent form of TGFβ1 which shuts off the growth factor prior to activation. The agent is also noted to be context independent in that it inhibits all sources of TGFβ1.

Moreover, preclinical data have suggested that SRK-181 is highly selective to β1 isoform compared with 2 and 3; this increases the therapeutic window and offers potential avoidance of dose-limiting challenges and AEs that are typically linked with non-selective TGFβ1 inhibition.

The first-in-human trial enrolled patients who were at least 18 years of age and who had measurable disease per RECIST v1.1 criteria at the time of screening.2 Part A1 enrolled patients with advanced solid tumors for whom available standard options have failed. Parts A2 and B enrolled those who did not respond to previous anti–PD-1 treatment, who had stable disease (SD) or progressive disease (PD) following 3 cycles of treatment. To be eligible for part B only, patients were required to have received their most recent dose of anti–PD-1 agent within 6 months of trail enrollment; for the urothelial cohort, this was 9 months.

If patients had an ECOG performance status of 2 or higher, received concurrent anticancer treatment, had a history of active metastatic central nervous system disease, active or a prior history of autoimmune disease, were hypersensitive to anti–PD-1 treatment, or had a concurrent second malignancy, they were excluded.

The dose-escalation portion of the research was comprised of part A1 and part A2 and utilized a 3+3 design. In part A1, SRK-181 was examined as a single agent at doses of 80 mg q3w (n = 1), 240 mg q3w (n = 1), 800 mg q3w (n = 3), 1600 mg q3w (n = 4), 2400 mg q3w (n = 3), 3000 mg q3w (n = 3), and 2000 mg q2w (n = 4). Part A2 began after 800 mg q3w was examined. In part A2, the agent was examined in combination with an anti–PD-1 agent at doses of 240 mg q3w (n = 3), 800 mg q3w (n = 3), 1600 mg q3w (n = 6), and 2400 mg q3w (n = 3).

The primary end points for part A were to examine the safety and tolerability of SRK-181 and to identify the maximum tolerated dose as well as the recommended dose for part B. Secondary end points comprised pharmacokinetics (PK) and antidrug antibodies (ADA). Exploratory end points included antitumor activity in the form of ORR and duration of response and biomarker analyses.

Parts A1 and A2 have been completed and some data have been previously reported at the 2022 SITC Annual Meeting.³

The median age of those enrolled to parts A1 and A2 of the trial were 66 years (range, 41-79) and 65 years (range, 32-75), respectively.1 Most patients were male, not Hispanic or Latino, and all were White. In part A1, the median number of prior lines of therapy received was 4 (range, 1-10); in part A2, this was 3 lines (range, 2-7).

At the time of data cutoff, no patients in either part were still on study. The most common reasons for discontinuation on parts A1 and A2, respectively, were toxicity (n = 2; n = 4), clinical progression (n = 3; n = 5), investigator decision (n = 2; n = 0), disease progression by RECIST v1.1 criteria (n = 11; n = 4), and withdrawn consent (n = 1; n = 2).

Of the 19 patients enrolled to part A1, 8 experienced a best response of SD and all 3 patients with ovarian cancer had stability that lasted for 6 to 10 months. Moreover, no DLTs were observed. Only 1 patient experienced a grade 3 treatment-related adverse effect (AE) in the form of increased alanine aminotransferase.

Of the 15 patients who were enrolled to part A2, 9 had a best response of SD and 6 were stable beyond the 16-week cutoff. One patient with head and neck cancer experienced a tumor reduction of 29.4%. In part A2 cohort, no DLTs were observed. Grade 3 treatment-related pruritus (n = 2), blister (n = 1), immune-mediated lung disease (n = 1), pemphigoid (n = 1), rash (n = 1), rash maculopapular (n = 1), and rash vesicular (n = 1) were reported. Serious treatment-related AEs were experienced by 2 patients: blister, pruritus, and rash (all in 1 patient) and immune-mediated lung disease (n = 1). No grade 4 or 5 treatment-related AEs occurred.

The dose-expansion portion of the research (part B) is still enrolling patients. Here, SRK-181 is under exploration at a dose of 1500 mg q3w in combination with an anti–PD-(L)1 agent in those with NSCLC who are not responders to prior anti–PD-(L)1, those with urothelial cancer who are not responders to prior anti–PD-(L)1, those with melanoma who are not responders to anti–PD-(L)1, those with ccRCC who progressed on their most recent prior anti–PD-(L)1 therapy, and those with head and neck squamous cell carcinoma who had progressed on their most recent previous anti–PD-(L)1 therapy.

The primary end point for this portion of the research is to further examine the safety and tolerability of SRK-181 in these cohorts, and key secondary end points included antitumor activity, PK, and ADA. Exploratory end points comprise survival outcomes and biomarker analyses.

Additional data were reported on the 3 patients with ccRCC who achieved a PR with combination treatment in parts A2 and B of the trial.

One male patient had been enrolled to part A2 of the trial and received SRK-181 at a dose of 800 mg q3w. This patient was aged 56 years and previously received sunitinib (Sutent), nivolumab (Opdivo) plus ipilimumab (Yervoy), cabozantinib (Cabometyx), lenvatinib (Lenvima) plus everolimus (Afinitor), and pembrolizumab plus axitinib (Inlyta).

At the time of screening, he was determined to have poor-risk disease by International Metastatic RCC Database Consortium (IMDC) criteria. He had metastatic disease in the following sites: the lung, lymph nodes, pleural, pancreas, and bone. This patient is now off study; he received treatment for a duration of 30 weeks and experienced a best percentage change in sum of diameters (SOD) in target lesions from baseline of 57%.

The male patient, aged 58 years, was enrolled to part B of the trial and received SRK-181 at a dose of 1500 mg q3w. This patient received prior nivolumab plus ipilimumab, as well as cabozantinib.He also was noted to have a IMDC score of poor risk at the time of screening. Metastatic disease sites included the lung, lymph nodes, and liver. This patient is still on study and received at treatment for a duration of at least 32 weeks. He experienced a best percentage change in SOD from baseline of 67%.

The last patient was also male, aged 63 years, and had been enrolled to part B of the trial where he was given SRK-181 at a dose of 1500 mg q3w. This patient previously received nivolumab plus ipilimumab, nivolumab alone, and cabozantinib. He had a IMDC score of intermediate risk, and metastatic disease in the lung and lymph nodes. He is still receiving treatment, which he has received for a duration of at least 16 weeks. The best percentage change in SOD from baseline in this patient is 50%.

Enrollment of part B is still ongoing.

References

1. Yap TA, Gainor J, McKean M, et al. Safety, pharmacokinetics, efficacy, and biomarker results of SRK-181 (a latent TGFβ1 inhibitor) from a phase I trial (DRAGON trial). Presented at: 2023 ESMO Targeted Anticancer Therapies Congress; March 6-8, 2023; Paris, France. Abstract 10. Accessed March 15, 2023.
2. Yap TA, Barve MA, Gainor JF, et al. First-in-human phase 1 trial (DRAGON) of SRK-181, a potential first-in-class selective latent TGFβ1 inhibitor, alone or in combination with anti-PD-(L)1 treatment in patients with advanced solid tumors. J Clin Oncol. 2021;39(suppl 15):TPS3146. doi:10.1200/JCO.2021.39.15_suppl.TPS3146
3. Recent phase 1 DRAGON data show SRK-181 continues to be well tolerated with early indications of efficacy. News release. Scholar Rock. November 10, 2022. Accessed March 15, 2023. https://www.businesswire.com/news/home/