Infinity Reports Clinical and Translational Data from Expansion Cohorts of MARIO‑1 Phase 1b Study of IPI-549 in Combination with Opdivo® (nivolumab) at SITC's 33rd Annual Meeting

CAMBRIDGE, Mass., Nov. 10, 2018 /PRNewswire/ -- Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) announced that data to be presented today at the 33^rd Annual Meeting of the Society for Immunotherapy of Cancer (SITC) demonstrated preliminary evidence that IPI-549 in combination with Opdivo® (nivolumab) is clinically active in indications not expected to respond to Opdivo alone. In particular, evidence of reversal of resistance to Opdivo included a partial response in a patient with metastatic melanoma who progressed on immediate prior Opdivo therapy. IPI-549 plus Opdivo also resulted in a 26% reduction of tumor target lesions in a patient with chemotherapy-resistant triple negative breast cancer (TNBC), a tumor type intrinsically resistant to checkpoint inhibition. The data also included long-term follow up on sustained partial responses in two patients from combination dose escalation: one with microsatellite stable (MSS) gallbladder cancer and one with adrenocortical carcinoma. The observed early clinical activity from the combination expansion, in addition to findings from the monotherapy cohorts, including associated translational data, support on-mechanism proof of concept for IPI-549. The late-breaking abstract describing these findings will be presented today in a poster presentation at the SITC's 33^rd Annual Meeting taking place in Washington, D.C., November 7 – 11, 2018.

"There continues to be a significant need for improvement in the treatment of patients with advanced solid tumors who do not respond to checkpoint inhibitors alone. IPI-549's potential to improve upon the existing CPIs makes it an important first-in-class drug in development," said David Hong, M.D. Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. "The reversal of resistance to checkpoint inhibition is particularly encouraging for the further development of IPI-549, and I look forward to my continued participation in the development of IPI-549."

Infinity is evaluating IPI-549 in MARIO-1, a Phase 1b study in approximately 200 patients with advanced solid tumors. Additionally, Infinity is planning to initiate MARIO-275, a global, randomized Phase 2 study to evaluate the effect of adding IPI-549 to Opdivo in approximately 150 checkpoint-inhibitor naïve advanced urothelial cancer patients who have progressed or recurred following treatment with platinum-based chemotherapy.

"The rigorous design of our Phase 1b study sets a high bar for the determination of proof of concept, given that the goals of our study are to see clinical activity both in settings where patients are not expected to respond to Opdivo alone, and in indications where there are high levels of immunosuppressive macrophages," said Dr. Sam Agresta, Chief Medical Officer of Infinity Pharmaceuticals. "We do this with the intention of re-sensitizing patients to Opdivo to overcome the limiting effects of macrophages to checkpoint inhibitor therapy, and we are excited that the data we shared today demonstrate clinical activity in this patient population. We look forward to the maturation of MARIO-1 and the advancement of the IPI-549 clinical development program in the checkpoint-inhibitor naïve setting with MARIO-275."

"Today's data validate our scientific rationale for the development of IPI-549 as a potentially first-in-class therapeutic alternative for patients lacking better treatment options," said Adelene Perkins, Chief Executive Officer of Infinity Pharmaceuticals. "We will be expanding our melanoma cohort, with patients refractory to immediate prior anti-PD1 therapy, to 40 patients based on promising early signals and have triggered expansion of the TNBC cohort. We will also be initiating our Phase 2 MARIO‑275 trial in urothelial cancer with an emphasis on patients with high myeloid derived suppressor cell levels, given that MDSCs further promote immunosuppression. We look forward to providing an update on these efforts."

Details of Today's Late-Breaking Presentation

Infinity will present a poster entitled "The first clinical/translational data from the expansion cohorts of a Ph1/1b Study of IPI-549, a tumor macrophage-reprogramming small molecule, in combination with nivolumab in advanced solid tumors" (Poster P716). The data reported today from an October 14, 2018 data cutoff included 82 patients treated with IPI-549 at 40 mg QD and Opdivo at 240mg IV once every two weeks.

Summary of Data

Combination expansion data demonstrated that IPI-549 in combination with Opdivo is well tolerated and is associated with a favorable safety profile. Among 82 patients evaluable for safety, the majority of side effects reported were Grade 1 or Grade 2, with 3 (4%) patients discontinuing the study due to treatment-related toxicities. There were no treatment-related deaths. These 82 patients have been treated in seven distinct cohorts: non-small cell lung cancer (n=8), melanoma (n=15), head and neck cancer (n=12), triple negative breast cancer (n=17), adrenocortical cancer (n=5), mesothelioma (n=11), and a biomarker defined baseline MDSC high cohort (n=14). The majority of the study population is 4^th line and resistant to anti-PD1/PDL1 therapy. Among the 44 patients evaluable for activity (approximately one-third of the planned 129 patients in the combination expansion cohorts), 15 patients showed a best response of stable disease or better, including one partial response in an advanced melanoma patient who progressed on immediate prior Opdivo therapy. In addition, a patient with chemotherapy-resistant triple negative breast cancer showed 26% reduction in tumor target lesions at the first assessment. Reductions in elevated baseline levels of MDSCs as well as corresponding increases in the proliferative fraction of previously exhausted memory cytotoxic T-cells were seen in these patients. Another partial response was observed in a patient with advanced mesothelioma. Twenty-five patients remain on study and were not evaluable for activity as of the data cutoff. The data included long-term follow up on additional partial responses in two patients from the combination dose escalation: one with microsatellite stable gallbladder cancer and one with adrenocortical carcinoma and these two partial responses were maintained for over 12 and 17 months, respectively. These patients also demonstrated sustained inhibition of MDSCs during the period in which the partial response was maintained. Enrollment is ongoing.

Infinity Investor/Analyst Reception and Webcast
In conjunction with SITC's 33^rd Annual Meeting, Infinity will host a reception and webcast for investors and analysts today, November 10, 2018, beginning at 6:30 a.m. ET to discuss the clinical development of IPI-549, including a review of data from the Phase 1b clinical study.

The event will feature David Hong, M.D., Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.

The webcast and accompanying slides can be accessed in the "investors/media" section of the company's website, www.infi.com. A replay of the event will also be available.

About IPI-549 and the Ongoing MARIO-1 Phase 1/1b Study
IPI-549 is an investigational first-in-class, oral, immuno-oncology product candidate targeting tumor-associated myeloid cells through selective phosphoinositide-3-kinase-gamma (PI3K-gamma) inhibition, thereby reducing pro-tumor macrophage function and increasing anti-tumor macrophage function. In preclinical studies, IPI-549 demonstrated the ability to reprogram macrophages from a pro-tumor (M2), immune suppressive function, to an anti-tumor (M1) immune activating function and enhance the activity of, and overcome resistance to, checkpoint inhibitors.^{i ii} As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially additive or synergistic approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

The ongoing Phase 1/1b study being conducted by Infinity is designed to evaluate the safety, tolerability, activity, pharmacokinetics and pharmacodynamics of IPI-549 as a monotherapy and in combination with nivolumab (Opdivo^®) in approximately 200 patients with advanced solid tumors.ⁱⁱⁱ The study includes monotherapy and combination dose-escalation components, in addition to monotherapy expansion and combination expansion components. The monotherapy dose-escalation and expansion components are complete. The combination dose-escalation component is also complete, and combination expansion cohorts are enrolling.

The combination expansion component of the study includes multiple cohorts designed to evaluate IPI-549 in patients with specific types of cancer, including patients with non-small cell lung cancer, melanoma and head and neck cancer whose tumors show initial resistance or initially respond to but subsequently develop resistance to immune checkpoint blockade therapy. The combination expansion component also includes a cohort of patients with triple negative breast cancer who have not been previously treated with immune checkpoint blockade therapy, a cohort of patients with mesothelioma, a cohort of patients with adrenocortical carcinoma and a cohort of patients with high baseline blood levels of MDSCs.

About the Planned MARIO-275 Phase 2 Study
Infinity is planning to conduct MARIO-275: MAcrophage Reprogramming in Immuno-Oncology, a global, randomized Phase 2 study to evaluate the effect of adding IPI-549 to Opdivo in checkpoint-naïve advanced urothelial cancer patients who have progressed or recurred following treatment with platinum-based chemotherapy. Approximately 150 patients will be randomized between combination therapy and Opdivo monotherapy. The primary endpoint of the trial will be overall response rate, which will be assessed in the overall population as well as in subsets of patients with different baseline levels of myeloid derived suppressor cells (MDSCs). Opdivo is approved for use by the FDA as a single agent in patients with locally advanced or metastatic urothelial cancer who have progressed or recurred following treatment with platinum-based chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. In exploratory analyses of the CheckMate-275 data, high levels of MDSCs were associated with shorter overall survival in patients treated with Opdivo². In Infinity's MARIO-1study, MDSCs were reduced in the majority of patients treated with IPI-549 monotherapy.³ IPI-549 in combination with Opdivo has been administered to over 80 patients and demonstrated early evidence of clinical activity with translational studies demonstrating evidence of on-mechanism IPI-549-mediated effects.⁴

IPI-549 is an investigational compound, and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.

About Infinity
Infinity is an innovative biopharmaceutical company dedicated to advancing novel medicines for people with cancer. Infinity is advancing IPI-549, an oral immuno-oncology development candidate that selectively inhibits PI3K-gamma. A Phase 1/1b study in approximately 200 patients with advanced solid tumors is ongoing. For more information on Infinity, please refer to Infinity's website at www.infi.com.

Cautionary Note Regarding Forward-Looking Statements 
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding: the therapeutic potential of PI3K-gamma selective inhibition and IPI-549, alone and in combination with Opdivo; clinical trial plans regarding IPI-549; and the company's ability to execute on its strategic plans. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the company's current expectations. For example, there can be no guarantee that IPI-549 will successfully complete necessary preclinical and clinical development phases. Further, there can be no guarantee that any positive developments in Infinity's product portfolio will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: Infinity's results of clinical trials and preclinical studies; the content and timing of decisions made by the U.S. FDA and other regulatory authorities; Infinity's ability to obtain and maintain requisite regulatory approvals and to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development of agents by Infinity's competitors for diseases in which Infinity is currently developing or intends to develop IPI-549; and Infinity's ability to obtain, maintain and enforce patent and other intellectual property protection for IPI-549. These and other risks which may impact management's expectations are described in greater detail under the caption "Risk Factors" included in Infinity's quarterly report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 5, 2018, and other filings filed by Infinity with the SEC. Any forward-looking statements contained in this press release speak only as of the date hereof, and Infinity expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Any forward-looking statements contained in this press release speak only as of the date hereof, and Infinity expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

OPDIVO^® (nivolumab) is a registered trademark of Bristol-Myers Squibb.

Infinity Pharmaceuticals
Stephanie Ascher, Stern Investor Relations, Inc.
212-362-1200 or stephanie@sternir.com

¹ Henau, O., Merghoub, T., Winkler, D. et al. Checkpoint blockade therapy is improved by altering the immune suppressive microenvironment with IPI-549, a potent and selective inhibitor of PI3K-gamma, in preclinical models. American Association for Cancer Research Annual Meeting 2016, Abstract #554.
² Rausch, M., Tchaicha, Tibbitts, T. et al. The PI3K-gamma inhibitor, IPI-549, increases antitumor immunity by targeting tumor-associated myeloid cells and remodeling the immune-suppressive tumor microenvironment. Presented at Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (Poster B032), 2016.
³ Kaneda, M.M., Messer, K.S., Ralainirina N. et al. PI3K-gamma is a molecular switch that controls immune suppression. Nature, 2016; DOI: 10.1038/nature19834.
ⁱ Kaneda, M., Messer, K., Ralainirina, N., Li, H., et al. PI3Kγ is a molecular switch that controls immune suppression. Nature, 2016 Nov;539:437–442.
ⁱⁱ De Henau, O., Rausch, M., Winkler, D., Campesato, L., et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature, 2016 Nov;539:443-447.
ⁱⁱⁱ www.clinicaltrials.gov, NCT02637531.

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