Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/ 2 Study Examining G100 Alone and in Combination with Pembrolizumab

Background: Despite numerous treatment (Tx)options, follicular lymphoma (FL) remains incurable. G100 is a TLR-4 (toll-like receptor-4) agonist that activates both the innate and adaptive arms of the immune system. When given intratumorally (IT), G100 triggers an anti-tumor immune response that has led to systemic tumor shrinkage and long-lasting disease control in animal models and cancer patients (pts) and the combination of G100/anti-PD-1 antibodies has increased animal survival (Barfi ASH 2015, Bhatia ASCO 2016). We previously reported results of Part 1 dose escalation of IT G100 up to 20µg in FL pts demonstrating that G100 was well tolerated and induced tumor responses in both the locally treated and untreated distal (abscopal) sites (Flowers ASCO 2017). We now present updated results of Part 1 and results of Part 2 which evaluated safety and efficacy of G100 alone and in combination with pembrolizumab (P) in FL pts in a randomized study.

Methods: Previously treated (PTx) or Tx naïve FL pts with ≥2 tumor sites were eligible. Pts received 6-9 doses of IT G100 weekly to a site treated with low dose radiation (RT, 2 Gy x2 doses). A 2^nd course of G100 could be given without RT to an additional site. In Part 2, pts were randomized to IT G100 (10 µg/dose) or IT G100 + P 200mg IV on Day 14 then q3wks for up to 2 years. Responses were evaluated by IrRC criteria based on bidimensional measurements (Wolchok ClCanRes 2009). Untreated sites were followed for abscopal response. Blood samples and tumor biopsies from treated and/or abscopal sites were obtained at baseline and post-G100.

Results: As of 29June2017, 36 FL pts were treated (Part 1, 10 pts; Part 2, 26 pts: 13, G100 vs. 13, G100 + P). Pts included 19 Tx naïve and 17 PTx (median # Tx 3, range 1-7, including 6 with Auto-SCT). G100 was well tolerated; related AEs were all grade (Gr) 1/ 2 with no G100-related DLTs or SAEs. For G100+P, 1 pt each experienced Gr 2 hypothyroidism, Gr 3 colitis/lab abnormalities/adrenal insufficiency (SAE). No deaths were reported.

In Part 2 Randomized (n=26, median follow-up 5.1 mos) overall best responses were: G100 alone, 2 (15%) PRs (50-99% reduction), 4 (31%) MRs (minor response, 25-49% reduction), 5 (39%) SDs (<25% reduction), 2 (15%) PDs (>25% increase); and G100 + P, 4 (31%) PRs, 3 (23%) MRs, 5 (39%) SDs, 1 (7%) PD. Ongoing shrinkage of untreated sites has been observed, indicating that tumor MR may deepen over time. Abscopal tumor reduction occurred in 6 (46%) pts (range 19-52% reduction) on G100 and 8 (62%) pts (range 10-80%) on G100 + P. Abscopal tumor reductions of >10cm² were seen in 1 (8%) pt on G100 and 4 (31%) pts on G100 + P. For PR/MR pts, the median time to progression (TTP) for G100 alone and G100+P has not been reached.

Overall best response to G100 monotherapy in Part 1 and 2 combined (n=23, median follow up 6.8 mos) was 6 (26%) PRs, 6 (26%) MRs, 9 (39%) SDs and 2 (9%) PDs. Abscopal tumor reduction occurred in 11 (48%) pts (range 11-78% reduction). For PR/MR pts, median TTP has not been reached (range: 1.9 to 11.5 mos). Responses were observed in both Tx naïve [11 pts: 2 (18%) PRs, 4 (36%) MRs; 8 (73%) pts with abscopal shrinkage] and PTx pts [12 pts: 4 (33%) PRs, 2 (17%) MRs; 3 (25%) pts with abscopal shrinkage] including 1 PR in a pt with prior Auto-SCT. Tumor biopsies post-G100 exhibited increased CD8 infiltration as well as CD8/CD4 T cells co-expressing PD-L1 in both treated and distal abscopal sites. T cell repertoire studies revealed new and expanded clones of T cells in the tumor (tumor-infiltrating lymphocytes, TILs).

Conclusions: G100 is a well tolerated active agent in FL with 52% pts experiencing clinical benefit (26% PR, 26% MR). The addition of P did not result in unexpected toxicity, and may have an effect on the degree and duration of tumor reduction. Longer follow-up will be required to determine the durability and depth of these responses. IT G100 therapy induced an inflammatory response locally that led to systemic anti-tumor responses with tumor infiltration by activated CD8 T cells and expansion of TIL clones in treated and abscopal sites. Shrinkage of abscopal sites signified the induction or boosting of systemic anti-tumor immunity. With its unique mechanism of action, G100 may be an attractive option for FL pts in need of a low toxicity treatment that would not interfere/reduce the effectiveness of future therapies and could be combined with anti-PD-1 inhibitors or other immunotherapies. This study is ongoing and enrolling pts to examine the activity of 20µg G100/dose.