Long Term Follow-up of a Phase 2 Study Examining Intratumoral G100 Alone and in Combination with Pembrolizumab in Patients with Follicular Lymphoma
Authors: Flowers Christopher R , Panizo Carlos , Isufi Iris , Herrera Alex F. , Okada Craig , Cull Elizabeth H. , Kis Bela , Chaves Jorge M. , Bartlett Nancy L. , Ai Weiyun , de la Cruz-Merino Luis , Bryan Locke J. , Houot Roch , Linton Kim , Briones Javier , Chau Ian , von Keudell Gottfried R. , Lu Hailing , Hsu Frank J , Halwani Ahmad S 
Published: October 2019

Abstract
Background: Despite numerous treatment (Tx) options, follicular lymphoma (FL) remains incurable, and established common treatments such as chemoimmunotherapy combinations and kinase inhibitors can have significant morbidity, especially in older patients or in those with comorbidities. G100 is a TLR4 (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 leads to systemic tumor shrinkage (Flowers ASCO 2017). Initial data from a randomized study of the combination of G100 and pembrolizumab (P) demonstrated that the addition of P resulted in more PRs, abscopal tumor shrinkage, and a trend to a better PFS than G100 alone. In addition, an association between baseline tumor TLR4 expression by immunohistochemistry (IHC) and clinical response was observed (Flowers ASH 2017). We now present updated response data and long-term follow-up of this randomized study.
Methods: Previously treated or Tx naïve FL pts with ≥2 tumor sites were eligible. Pts received 6-9 doses of IT G100 (G) weekly to a site treated with low dose radiation (RT, 2 Gy x2 doses). A 2nd course of G could be given without additional RT to an additional site. Pts were randomized to IT G (10 µg/dose) or IT G + 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.
Results: As of 3July2018, 26 FL pts were treated (13, G vs. 13, G + P). 7 and 5 pts were Relapsed/Refractory (R/R) in G and G+P, respectively. Median number of prior therapies were 3 for G and 4 for G+P and included 5pts previously Tx with auto-SCT. Median duration of observation was 14.3 and 16.6 mos for the G and G+P, respectively. G was well tolerated; related AEs were all grade (Gr) 1/ 2 with no G-related DLTs or SAEs. For G+P, 1 pt experienced Gr 2 hypothyroidism and 1pt, Gr 3 colitis/lab abnormalities/adrenal insufficiency (SAE). No deaths were reported.
Overall best responses (PRs) were: 23% in pts on G and 54% in pts on G+P. In the R/R population, PRs occurred in 29% of pts on G and in 80% of pts on G+P. Median time to response was 2.3 mos (range 1.7-18.1) for G and 3.7 mos (range 2.2-17.1) for G+P, and included delayed responses at ≥18mos. Among pts with baseline TLR4high (≥50%) tumor expression, ORR was 17% for G (n=6) vs 75% for G+P (n=8). Within the GELF high tumor burden pts, PRs occurred in 0% of pts in G and in 33% of pts in G+P. Likewise, in pts failing R-Chemo <2 y, PRs occurred in 20% of pts in G and 67% of pts in G+P. Abscopal tumor reduction occurred in 53% pts on G and in 77% pts on G+P, respectively. The median PFS for pts on G is 7.4 mos (95% CI 1.9-NA) and 11.7 mos (95% CI 6.0-NA) for pts on G+P. The median time to progression (TTP) for PR pts has not been reached for either arm.
Conclusions: Longer term follow-up of this Phase 2 study demonstrates that additional responses related to G100 continue to develop over time and they are durable. The combination with pembrolizumab is well tolerated and yields an increased clinical benefit both in the percentage of patients responding and its durability, including in patients at high risk with R/R FL. G100 may be an attractive option for R/R FL pts in combination with anti-PD-1 inhibitors or other therapies.

Disclosures
Flowers: Pharmacyclics: Research Funding; Pharmacyclics/ Janssen: Consultancy; Burroughs Wellcome Fund: Research Funding; Bayer: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; BeiGene: Research Funding; Denovo Biopharma: Consultancy; OptumRx: Consultancy; Gilead: Consultancy; Spectrum: Consultancy; V Foundation: Research Funding; Millennium/Takeda: Research Funding; Janssen Pharmaceutical: Research Funding; National Cancer Institute: Research Funding; Acerta: Research Funding; Abbvie: Consultancy, Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Consultancy; Karyopharm: Consultancy. Panizo:Roche: Consultancy, Speakers Bureau; Acerta Pharma: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees. Isufi:Genentech: Consultancy; Novartis: Consultancy. Herrera:Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Research Funding; Immune Design: Research Funding; Merck, Inc.: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding. Cull:Celgene: Speakers Bureau. Bartlett:Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Janssen: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Millennium: Research Funding. de la Cruz-Merino:Roche: Consultancy, Other: travel, Speakers Bureau; Novartis: Consultancy, Other: travel, Speakers Bureau; BMS: Consultancy, Other: travel, Speakers Bureau; Merck: Consultancy, Other: travel, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: travel, Research Funding, Speakers Bureau. Houot:Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Chau:Five Prime Therapeutics: Other: Advisory Board; Bristol Meyers Squibb: Other: Advisory Board; Janssen-Cilag: Research Funding; Eli-Lilly: Honoraria, Other: Advisory Board, Research Funding; Roche: Other: Advisory Board; Merck Serono: Other: Advisory Board, Research Funding; MSD: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Sanofi Oncology: Research Funding; Bayer: Other: Advisory Board. von Keudell:Genentech: Consultancy; Bayer: Consultancy. Lu:Immune Design: Employment. Hsu:Immune Design: Employment. Halwani:Abbvie: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Research Funding; Genentech, Inc.: Research Funding; Immune Design: Research Funding; Kyowa Hakko Kirin: Research Funding; Miragen: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding.