INDUCE-1 – Toward a New Therapeutic Target in Urothelial Carcinoma or Just a Detour?

Presentation of: Arjun V Balar, MD, medical director of Clinical Trials Office, and director of the genitourinary medical oncology program at Perlmutter Cancer Center, NYU Langone Health, New York.

FELADILIMAB (GSK3359609) is a humanized immunoglobulin G4 (IgG4) monoclonal antibody with potent, binding agonist activity through the human inducible T cell costimulator (ICOS) receptor and low/no T cell depleting effects via antibody-dependent cellular toxicity.1 In nonclinical models feladilimab showed antitumor activity in combination with cytotoxic T-lymphocyte lymphocyte-associated protein 4 (CTLA-4) and PD -1 blockade. The Phase 1 INDUCE-1 (NCT02723955) study has been evaluating the safety, pharmacology, and preliminary antitumor activity of feladilimab in patients with selected advanced or recurrent tumors, firstly as monotherapy (Part 1) and in combination with pembrolizumab, chemotherapy, or other immune therapies (Part 2). Each part of the study consists of a dose escalation phase and a cohort expansion phase. First results from INDUCE-1 supported ICOS as a therapeutic target, showing single-agent activity in PD-(L)1-experienced head and neck squamous cell carcinoma (HNSCC)3 and relapsed/refractory melanoma.4

INDUCE-1: urothelial carcinoma

At ASCO 2021, preliminary results for urothelial carcinoma (UC) expansion cohorts of INDUCE-1 were presented by Arjun V Balar, MD, medical director of Clinical Trials Office, and director of the genitourinary medical oncology program at Perlmutter Cancer Center, NYU Langone Health, New York.2 These data also provided evidence of clinical activity with feladilimab, as monotherapy in heavily pretreated PD-(L)1-experienced patients with advanced UC and in combination with pembrolizumab in patients with anti-PD-(L)1-naïve UC. Early and durable responses were seen in both cohorts. Feladilimab is the first ICOS agonist to show single-agent activity in UC patients who have progressed on PD-(L)1 based therapy.

Patients enrolled in the INDUCE-1 UC cohorts had histological or cytological documentation of an invasive malignancy diagnosed as recurrent or metastatic UC of the upper or lower urinary tract, with ≤5 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Feladilimab was dosed at 0.3 or 1 mg/kg (monotherapy) or 0.3 mg/kg plus 200 mg pembrolizumab (combination) every 3 weeks, up to 35 cycles until disease progression or unacceptable toxicity. “You have to get the dose just right; there are consequences to overdosing because you can develop T-cell exhaustion by overdosing the agonistic molecule, Dr. Balar stressed, discussing his presentation after the meeting.5

Feladilimab efficacy and safety

At the time of the ASCO meeting, data for the monotherapy expansion cohort were available for 14 patients (median duration of follow-up 12.6 months [range: 1.1–29.2]). The overall response rate (ORR) in this cohort was 7% (95% CI: 0.2, 33.9), consisting of 1 immune-related partial response (PR). Disease control rate (DCR, response or stable disease for ≥9 weeks) in this cohort was 23% (95% CI: 5.0, 53.8).

Median duration of response (DoR) in this cohort was 6.1 months. Median overall survival (OS) was 14.5 months (95% CI: 3.0, NR), with 77% of patients alive at 6 months. “The activity is modest, but we did see clear activity at least in the patient with a PR,” Dr. Balar noted. “This was an 81-year-old gentleman with visceral disease involving a fairly sizable lung metastasis that responded quite well with a durable response of up to 36 weeks, then ultimately progressed.”

“I think most of us want to see at least some evidence of monotherapy activity before we get too excited, because, at the end of the day, you want to see that you’re engaged in the immune system and that the immune system is leading to an antitumor immune response. To me, to show this activity is proof of concept,” Dr. Balar commented. “The fact that there was only one response among 14 patients on monotherapy suggests that maybe this activity is not going to be earth shattering, although to see a visceral response in a patient like this is noteworthy.”

In 32 evaluable patients in the combination expansion cohort (median duration of follow-up 9.6 months [range 0.8-31.1]). ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–NR). DCR was 63% (95% CI: 43.7, 78.9), and median OS 10.7 months (95% CI: 5.2, 18.4), with 64% of patients alive at 6 months.

Measurement of tumor PD-L1 and ICOS expression status at baseline, although “essentially small retrospective data sets, which are always problematic,” showed that the subcohort of so-called double-positive patients, i.e. those who were both PD-L1- and ICOS- positive, had improved survival compared to those who were double-negative. “That’s not surprising. When you see higher expression levels of the target protein of interest, that’s generally associated with a higher likelihood of response and maybe that translates to better survival,” Dr Balar noted, while cautioning “We know that these immune-based biomarkers are highly inconsistent and poorly replicable.”

Overall, feladilimab was well tolerated, with a manageable profile as monotherapy and combination therapy. Most treatment-related adverse events (AEs) were Grade 1 or 2, Dr Balar reported. “Combination therapy did not add much on top of what we would expect with pembrolizumab alone,” he added.

Future development

Clinical development of feladilimab was already on hiatus by the time the latest INDUCE-1 data were presented at ASCO. On April 14, 2021, GlaxoSmithKline (GSK, London, UK), announced that it had halted two mid-stage phase 2 studies of feladilimab in recurrent or metastatic HNSCC, INDUCE-3 (NCT04128696) and INDUCE-4 (NCT04428333), following a recommendation from the Independent Data Monitoring Committee.6 GSK did not reveal the reasons for stopping the studies and said that it is evaluating “the totality of the data” to determine the impact on future clinical development of feladilimab. This announcement followed only a few months after a phase 2 trial with another ICOS agonist was halted after indications that it was unlikely to meet the study endpoints in non-small cell lung cancer patients. The EMERGE (NCT03989362) trial was evaluating the combination of vopratelimab plus ipilimumab and had planned to enroll patients with urothelial carcinoma.7

Addressing the challenges that have recently emerged in trials of immune combination therapy, Dr. Balar suggested that “too much weight is placed on single-arm trials of combination therapies that appear to produce better results than would be expected with anti-PD-1 monotherapy,” adding, “I think most of us look at those data with a lot of skepticism.” He expressed “cautious optimism” about CheckMate 901 (NCT03036098), a trial currently studying nivolumab plus ipilimumab or standard of care (SOC) versus SOC alone in patients with previously untreated unresectable or metastatic UC.8 He predicted that in 3 or 4 years’ time “…it’s going to be very similar to what we do in kidney cancer right now, which is VEGF plus PD-1 for some patients and CTLA-4 plus PD-1 for other patients.”

References

  1. Brett S, Yadavilli S, Seestaller-Wehr L, et al. 1840P – Preclinical evaluation of a non-deplet- ing, first-in-class humanized IgG4 agonist anti-ICOS antibody. Ann Oncol. 2018;29(suppl 8):viii652-viii653.
  2. Balar AV, Moreno V, Angevin E, et al. Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs). J Clin Oncol. 2021; 39(suppl 15):Abstract 4519.
  3. Rischin D, Groenland S, Lim AML, et al. 1119PD: Inducible T cell costimulatory (ICOS) receptor agonist, GSK3359609 (GSK609) alone and in combination with pembrolizumab (pembro): Preliminary results from INDUCE-1 expansion cohorts (EC) in head and neck squamous cell carcinoma (HNSCC). Ann Oncol. 2019;30(Suppl 5):v454-v455.
  4. Maio M, Weber JS, Villar MVV, et al. Inducible T cell costimulatory (ICOS) receptor agonist, feladilimab (FE), alone and in combination (combo) with pembrolizumab (PE): Results from INDUCE-1 relapsed/refractory (R/R) melanoma expansion cohorts (EC)
  5. Cancer Res. 2021;81(13 Suppl):Abstract CT033.Balar A. The Uromigos. Episode 105: A Phase 2 study of novel immune combinations (ICOS) in bladder cancer. June 7, 2021. Available at https://anchor.fm/the-uromigos/episodes/Episode-105-A-Phase-2-study-of- novel-immune-combinations-ICOS-in-bladder-cancer-e12as3t Accessed July 27, 2021.
  6. GSK provides update on feladilimab, an investigational inducible T cell co-stimulatory (ICOS) agonist. News release. GlaxoSmithKline; April 14, 2021.
  7. Jounce Therapeutics announces update on vopratelimab program. News release. Jounce Therapeutics; November 2, 2020.
  8. Galsky MD, Powles T, Li S, Hennicken D, Sonpavde G. A phase 3, open-label, random- ized study of nivolumab plus ipilimumab or standard of care (SOC) versus SOC alone in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC; CheckMate 901). J Clin Oncol. 2018;36(6 suppl). Abstract TPS539