UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Form 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): October 20, 2018
Dynavax Technologies Corporation
(Exact name of registrant as specified in its charter)
Commission File Number: 001-34207
| Delaware | 33-0728374 | |
| (State or other jurisdiction of incorporation) |
(IRS Employer Identification No.) |
2929 Seventh Street, Suite 100
Berkeley, CA 94710-2753
(Address of principal executive offices, including zip code)
(510) 848-5100
(Registrant’s telephone number, including area code)
(Former name or former address, if changed since last report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
| ☐ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ☐ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ☐ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ☐ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Indicate by check mark whether the Registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the Registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
| Item 8.01. | Other Events |
On October 20, 2018, Dynavax Technologies Corporation (“Dynavax”), issued a press release and presented a corresponding poster announcing data from its ongoing Phase 1b/2 SYNERGY-001 study investigating SD-101, Dynavax’s intratumoral TLR9 agonist, in combination with KEYTRUDA® (pembrolizumab), an anti-PD-1 therapy developed by Merck & Co., Inc. (known as MSD outside the United States and Canada) in patients with advanced melanoma naïve to anti-PD-1/L1 therapy, at the 2018 European Society for Medical Oncology Congress, in Munich, Germany (“ESMO”). Dynavax presented two additional posters at ESMO, one was presented October 20, 2018, and the other October 21, 2018. On October 21, 2018, Dynavax held a conference call and webcast to review all data the company presented at ESMO. A copy of the press release, posters and the conference call presentation are filed as Exhibits 99.1, 99.2 and 99.3 to this Current Report on Form 8-K and are incorporated herein by reference.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Dynavax Technologies Corporation | ||||||
| Date: October 22, 2018 | By: | /s/ DAVID JOHNSON | ||||
| David Johnson | ||||||
| Vice President | ||||||
Exhibit 99.1
Dynavax’s SD-101 in Combination with KEYTRUDA® (pembrolizumab) Continues to Show a 70% Overall Response Rate in Advanced Melanoma Patients According to Data Presented Today at the ESMO 2018 Congress
- 70% overall response rate (33/47 patients) at 2 mg dose of SD-101 includes 17 additional patients -
-Progression free survival, response rate in patients with PDL-1 negative tumors and biomarker activity supports clinical impact of SD-101’s activity-
- Conference call and webcast to review all Dynavax data presented at the ESMO 2018 Congress on Sunday October 21st at 1:00 PM EDT
BERKELEY, Calif., October 20, 2018 (GLOBE NEWSWIRE) — Dynavax Technologies Corporation (NASDAQ:DVAX) today presented interim data from its ongoing Phase 1b/2 SYNERGY-001 study investigating SD-101, Dynavax’s intratumoral TLR9 agonist, in combination with KEYTRUDA® (pembrolizumab), an anti-PD-1 therapy developed by Merck (known as MSD outside the United States and Canada) in patients with advanced melanoma naïve to anti-PD-1/L1 therapy. These data were presented in a late breaking poster and discussion session today at the ESMO 2018 Congress, in Munich Germany.
The company reported results on a total of 87 patients (Intention to Treat population) comparing two different doses of SD-101. In the study, 47 patients received £2mg of SD-101 in 1-4 lesions and 40 patients received 8 mg in a single lesion. The primary endpoints of this dose-expansion/dose-finding study are safety and preliminary efficacy. The results showed a 70% overall response rate (ORR) in advanced melanoma patients naïve to anti-PD-1/L1 therapy who received the £ 2 mg dose of SD-101 and a 48% ORR in the group receiving the 8 mg dose of SD-101. The combination of SD-101 and KEYTRUDA remains well tolerated with adverse events related to SD-101 being transient, mild to moderate flu-like symptoms.
“These results are encouraging because the overall response rate in the 2 mg group has remained consistent with the data presented at the 2018 American Society for Clinical Oncology annual meeting, even though the number of patients increased by more than 50 percent. In addition, median progression-free survival has not yet been reached, but statistically is expected to be at least 15.2 months, providing further validation of the potential benefit of the combination therapy,” said Rob Janssen, M.D., Chief Medical Officer. “These data underscore the value of stimulating the innate immune response through TLR9 and build on clinical evidence around the proposed mechanism of action for SD-101.”
Highlights from the poster presentation (LBA45)
| • | ORR of 70% (33 of 47), for advanced melanoma patients who received the £ 2 mg dose of SD-101 per lesion |
| • | Durable response in patients who received £ 2 mg dose of SD-101 with 85% 6-month progression-free survival (PFS) rate |
| • | Median PFS not reached in patients who received £ 2 mg dose of SD-101 with a lower bound of the 95% confidence interval suggesting a minimum ongoing PFS of 15.2 months |
| • | Observed responses in injected lesion(s) and non-injected distant lesions, including visceral metastases in the liver and lung |
| • | Response rates appeared similar regardless of PD-L-1 status |
| • | AEs related to SD-101 treatment were transient, mild to moderate flu-like symptoms at both the £ 2mg and the 8 mg dosing levels |
| • | No increase in the frequency of immune-related adverse events over individual monotherapies reported in other studies1,2 nor evidence of any new safety signals |
Dynavax Conference Call and Webcast
Dynavax will host a conference call and webcast on Sunday at 1:00pm EDT (7:00 PM CEST). The live webcast can be accessed in the “Investors and Media” section of the company’s website at www.dynavax.com. The conference call can be accessed by dialing (866) 420-4066 in the U.S. or (409) 217-8237 internationally, using the conference ID 2036717. A replay of the webcast will be available following the live event.
About SYNERGY-001 (KEYNOTE-184)
SYNERGY-001, previously referred to as MEL-01, is the dose-escalation and expansion study of SD-101 in combination with KEYTRUDA which includes patients with histologically or cytologically confirmed unresectable Stage IIIC/IV melanoma. The primary endpoints of the trial are safety and preliminary efficacy of intratumoral SD-101 in combination with KEYTRUDA.
About SD-101
SD-101, the Company’s lead clinical candidate, is a proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. Dynavax is evaluating this intratumoral TLR9 agonist in several clinical studies to assess its safety and activity, including a Phase 2 study in combination with KEYTRUDA® (pembrolizumab), an anti-PD-1 therapy, in patients with advanced melanoma and in patients with head and neck squamous cell cancer, in a clinical collaboration with Merck. Dynavax maintains all commercial rights to SD-101.
About Dynavax
Dynavax is a fully-integrated biopharmaceutical company focused on leveraging the power of the body’s innate and adaptive immune responses through toll-like receptor (TLR) stimulation. Dynavax discovers and develops novel vaccines and immuno-oncology therapeutics. The Company’s first commercial product, HEPLISAV-B® [Hepatitis B Vaccine (Recombinant), Adjuvanted], was approved by the United States Food and Drug Administration in November 2017 for prevention of infection caused by all known subtypes of hepatitis B virus in adults age 18 years and older. Dynavax’s lead immunotherapy product, SD-101, is an investigational cancer immunotherapeutic currently being evaluated in Phase 1/2 studies and its second cancer immunotherapeutic, DV281, is in Phase 1 development. For more information, visit www.dynavax.com.
Forward Looking Statement
This press release contains “forward-looking” statements, including statements regarding the conduct of clinical trials of SD-101, including results from the Phase 1b/2 trial, and potential value of SD-101 across multiple tumor types. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including whether we can timely provide adequate clinical supplies; initiation, enrollment and completion of clinical trials of SD-101; whether interim and final results of current and future clinical trials will support the initiation or continuation of subsequent trials; issues arising in the regulatory process; the ability to successfully develop and commercialize SD-101; and whether or not Dynavax and parties with whom we are collaborating may reach any future agreement on further studies or a more extensive collaboration beyond the clinical trials contemplated under the existing agreements, as well as other risks detailed in the “Risk Factors” section of our Annual Report on Form 10-K for the fiscal year ended December 31, 2017 and in Quarterly
Report on Form 10-Q for the quarter ended June 30, 2018, as well as discussions of potential risks, uncertainties and other important factors in our other filings with the U.S. Securities and Exchange Commission. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available. Information on Dynavax’s website at www.dynavax.com is not incorporated by reference in our current periodic reports with the SEC.
KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
1. Ribas A, et al. JAMA. 2016;315(15):1600-1609.
2. Specenier P. Expert Opin Biol Ther. 2017;17(6):765-780.
| Contact: Ryan Spencer VP Corporate Strategy and Communications 510.665.4608 |
Media Contact: Rachel St. Martin W2O 646.894.5757 rstmartin@w2ogroup.com |
LBA45: Phase 1b/2, Open Label, Multicenter, Study of the Combination of SD-101 and Pembrolizumab in Patients with Advanced Melanoma Who Are Naïve to Anti-PD-1/L1 Therapy (SYNERGY-001/KEYNOTE-184, NCT02521870) G. Long1, M. Milhem2, A. Amin3, C. J. Hoimes4, T. Medina5, R. Conry6, C. Lao7, G. Daniels8, S. Reddy9, I. Mehmi10, R. Andtbacka11, M. Barve12, M. Shaheen13, T. Tueting14, M. Chisamore15, B. Xing16, A. Candia16, E. Gamelin16, R. Janssen16, A. Ribas17 1Melanoma Institute Australia, The University of Sydney and Royal North Shore and Mater Hospitals, Sydney, Australia; 2University of Iowa, Iowa City, USA; 3Levine Cancer Institute, Charlotte, USA; 4Case Western Reserve University, Cleveland, USA; 5University of Colorado Cancer Center, Aurora, USA; 6University of Alabama School of Medicine, Birmingham, USA; 7University of Michigan Health System, Ann Arbor, USA; 8University of California, San Diego, USA; 9Stanford University, Stanford, USA; 10Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, USA; 11University of Utah, Salt Lake City, USA; 12Mary Crowley Cancer Research, Dallas, USA; 13University of Arizona Cancer Center North, Tucson, USA; 14University Hospital Magdeburg, Magdeburg, Germany; 15Merck & Co., Inc., Kenilworth, NJ, USA; 16Dynavax Technologies Corporation, Berkeley, USA; 17Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, USA BACKGROUND PD-1 blockade has significantly improved outcomes in advanced melanoma, yet durable responses are elicited in less than half of the patients, therefore this remains an area of unmet need.1 KEYTRUDA® (pembrolizumab) is an anti-PD-1 monoclonal antibody (mAb) that is approved by the FDA to treat patients with unresectable or metastatic melanoma.1 SD-101 is a synthetic class-C CpG-oligodeoxynucleotide, agonist of toll-like receptor 9 (TLR9). SD-101 stimulates human plasmacytoid dendritic cells to release interferon-alpha and mature into efficient antigen-presenting cells, enhancing both innate and adaptive immune responses.2 Preclinical studies in multiple mouse tumor models demonstrated that intratumoral injection of SD-101, in combination with PD-1 blockade, suppressed the growth of tumors not only at the injected site, but also at distant non-injected sites.3 In a previous phase 1b/2 study of patients with indolent non-Hodgkin’s lymphoma, treatment of a single lesion with low dose radiation and intratumoral SD-101 induced abscopal tumor shrinkage in 83% of patients.4 Here, we report the latest results from the phase 1b dose escalation and phase 2 expansion cohort of patients with advanced melanoma naïve to anti-PD-1/L1 therapy who were treated with the combination of SD-101 and pembrolizumab. (Updates data presented at ASCO 2018 (Abstract 9513)5. Results of the phase 1b portion of this study were published in Ribas, A., et al., Cancer Discovery (2018).6 Characteristics 2 mg/lesion n = 47 8 mg/lesion n = 40 Median age, years (Min, Max) 66 (36, 85) 66 (33, 89) > 65 years, n (%) 30 (64) 23 (58) Male, n (%) 33 (70) 26 (65) ECOG PS 0, n (%) 30 (64) 30 (75) Baseline LDH, median (Q1, Q3) > ULN, n (%) 193 (162, 234) 8 (17) 195 (177, 238) 10 (25) Stage at Screening, n (%) IIIC 10 (21) 8 (20) IV 37 (79) 32 (80) M1a 16 (34) 11 (28) M1b 9 (19) 9 (23) M1c 12 (26) 12 (30) PD-L1 Expression, n (%)* Positive (≥1%) 19 (40) 13 (33) Negative (<1%) 15 (32) 15 (38) Pending 13 (28) 12 (30) Prior lines of therapy, 0 / 1 / 2 / ≥3. n (%) 34 / 11 / 2 / 0 (72 / 23 / 4 / 0) 28 / 11 / 0 / 1 (70 / 28 / 0 / 3) Table 1. Demographics and Baseline Characteristics (Phase 1b/2) ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; Q1 = first quartile; Q3 = third quartile; ULN = upper limit of normal; * Expression determined by tumor proportion score using Dako 22C3 antibody Safety Table 2. Safety Summary Event, N (%) 2 mg/lesion n = 47 8 mg/lesion n = 40 Total N = 87 Any Treatment-related AE 43 (91) 37 (93) 80 (92) Grade 3-4 12 (26) 16 (40) 28 (32) Chills 4 (9) 1 (3) 5 (6) Myalgia 5 (11) 0 5 (6) Fatigue 2 (4) 3 (8) 5 (6) Headache 4 (9) 2 (5) 6 (7) Malaise 3 (6) 2 (5) 5 (6) Any irAEs 10 (21) 6 (15) 16 (18) Grade 3-4 3 (6) 1 (3) 4 (5) AEs leading to d/c of either or both drug 7 (15) 13 (33) 20 (23) SAEs 14 (30) 15 (38) 29 (33) Death 0 1 (3) 1 (1) irAE = immune-related adverse event; d/c = discontinuation; SAE = serious adverse event. Note: death was considered not related to drug Table 3. Immune-Related Adverse Events 2 mg/lesion n = 47 8 mg/lesion n = 40 Objective response rate, n (%) [95% CI] 33 (70) [56, 81] 19 (48) [33, 63] Complete response 5 (11) 2 (5) Partial response 28 (60) 17 (43) Time to response, median (months) 2.1 2.3 Duration of response, median (months) (95% CI) Not reached (9.0, NE) Not reached (8.2, NE) Stable disease, n (%) 4 (9) 8 (20) Disease Control Rate, n (%) 37 (79) 27 (68) Progressive disease, n (%) 6 (13) 9 (23) Non-evaluable*, n (%) 4 (9) 4 (10) CONCLUSIONS ACKNOWLEDGEMENTS The addition of 2 mg/lesion of SD-101 to pembrolizumab appears to increase immune activity in the tumor microenvironment and efficacy compared with 8 mg/lesion in similar patient populations The ORR in the 2 mg/lesion SD-101 group (70%) was higher than in the 8 mg/lesion SD-101 group (48%) The median PFS in the 2 mg/lesion group (15.2+ months) was significantly longer than in the 8 mg/lesion group (10.4 months) The median DOR in both groups has not been reached Responses occurred in patients with PD-L1 negative tumors and PD-L1 positive tumors Tumor shrinkage occurred in injected lesions, and non-injected visceral lesions including in the liver and lung The combination of SD-101 and pembrolizumab was well tolerated, consistent with previous reports AEs associated with SD-101 were transient, mild to moderate flu-like symptoms that were manageable with over-the-counter medications No increase in immune-related AEs over pembrolizumab monotherapy was observed7,8 Clinical responses were supported by immunologic data consistent with the mechanism of SD-101 Increases in CD8+ cells, NK cells, cytotoxic cells and Th1 cells in the tumor microenvironment were observed in both SD-101 dose groups but were higher in the 2 mg group and appeared to correlate with enhanced clinical efficacy SD-101 is also being investigated in patients with anti-PD-1/L1 resistant/refractory advanced melanoma The addition of SD-101 (8 mg/lesion) to pembrolizumab appears to restore tumor sensitivity to a PD-1 inhibitor in a significant percentage of these patients with an ORR of 21.4% (see ESMO Abstract 3781) Keytruda (pembrolizumab) package insert USA. Merck Sharp & Dohme Corp, Whitehouse Station, NJ. 2014 Guiducci C, et al. J Exp Med 2006;203:1999-2008. Wang S, et al., Proc Natl Acad Sci U S A, 2016. 113(46): p. E7240-e7249 Frank, M.J., et al. Cancer Discovery 2018. DOI: 10.1158/2159-8290. Ribas A. et a; J Clin Oncol 36, 2018 (suppl; abstr 9513) Ribas A, et al. Cancer Discovery 2018; DOI: 10.1158/2159-8290.CD-18-0280. Ribas A, et al. JAMA. 2016;315(15):1600-1609. Specenier P. Expert Opin Biol Ther. 2017;17(6):765-780) This study was sponsored by Dynavax Technologies Corporation in collaboration with Merck & Co., Inc., Kenilworth, NJ USA. We thank the patients and their families and caregivers for participating in the study; the participating study teams; and Tripta Dahiya for contributions to the analysis of the data (Dynavax). Copies of this poster obtained through QR (Quick Response) and/or text key codes are for personal use only and may not be reproduced without written permission of the authors. Corresponding Author: Georgina Long (georgina.long@sydney.edu.au) METHODS Figure 1. Study Design Primary Endpoint: Objective response rate assessed by RECIST v1.1 Secondary Endpoints: Safety and tolerability, progression-free survival, duration of response, and immunophenotype of the tumor environment RESULTS Table 4. Best Overall Response by RECIST v1.1 (ITT Population) SD-101 2 mg i.t. + Pembrolizumab 200 mg i.v. SD-101 4 mg i.t. + Pembrolizumab 200 mg i.v. SD-101 8 mg i.t. + Pembrolizumab 200 mg i.v. SD-101 1 mg i.t.† + Pembrolizumab 200 mg i.v. SD-101 2 mg i.t. in up to 4 lesions + Pembrolizumab 200 mg i.v. OR SD-101 8 mg i.t. in one lesion + Pembrolizumab 200 mg i.v. Phase 1b Dose Escalation* Phase 2 Dose Expansion *DLT period 29 days; †3 patients received 1 mg/lesion; i.t.= intratumoral; i.v. = intravenous. Data Cutoff: September 21, 2018 *Patients discontinued prior to first scan: 2 mg—clinical progression (n=2), irAE (n=1), withdrew consent (n=1); 8 mg—clinical progression (n=1), unrelated AE/death (n=1); irAE (n=1), withdrew consent (n=1). CI = confidence interval; ITT= Intention to treat; NE=not estimable NOTE: Two patients in the 2 mg group with recently reported PRs are not reflected in the figures 2 mg/lesion 8 mg/lesion PFS (Kaplan-Meier method) 6-month rate (95% CI) 85% (70, 93) 60% (42, 73) Median (months) (95% CI) not reached (15.2, NE) 10.4 (4.2, NE) Follow-up, median (months) 5.9 6.9 ORR= objective response rate; PD-L1 expression based on tumor proportion score (Dako 22C3 antibody) Figure 5. Progression-free Survival (ITT Population) Figure 7. Percent Change From Baseline Over Time in Non-injected Target Lesions by Organ System (2 mg SD-101 Per Lesion) PD-L1 Expression 2 mg/lesion 8 mg/lesion N ORR (%) N ORR (%) ≥1% 19 79 13 62 <1 % 15 80 15 33 Pending/missing 13 46 12 50 Phase 1b/2 Trial (SYNERGY-001/KEYNOTE-184) No prior anti-PD-1/L1 therapy At least one injectable lesion CT, computed tomography scan SCREENING TREATMENT TREATMENT 0 1 2 3 4 6 9 12 15 18 21 24 0 1 2 3 4 6 9 12 15 18 21 24.... CT CT CT Biopsy Biopsy Biopsy Biopsy Pembrolizumab Weeks SD-101 Weeks 51 Figure 8. Changes in Immune Activity in the Tumor Microenvironment -100 -80 -60 -40 -20 0 20 40 60 80 100 120 Percent Change from Baseline, % Patients 2 mg/lesion 8 mg/lesion 0.0 0.2 0.4 0.6 0.8 1.0 0 5 10 15 20 25 Months Survival Probability Log-rank test p = 0.02 2 mg/lesion 8 mg/lesion + Censored 2 mg 47 24 9 3 2 0 8 mg 40 23 16 2 1 0 Values above the graphs represent the means and 95% confidence intervals. Methods: biopsies of the injected tumor were collected at screening (prior to dosing) and post-dose. Biopsies were analyzed by the nCounter® PanCancer Immune Profiling Panel (NanoString Technologies, Inc., Seattle WA) to evaluate the immunophenotype of the tumor environment. Nanostring data were analyzed using the nSolver™ Analysis Software Natural Killer Cells 2 mg/lesion 8 mg/lesion Pre: 46.2 ± 18.4 Post: 92.3 ± 31.3 Ave Fold change = 7.11 p < 0.0006 N=23 Pre: 61.4 ± 22.5 Post: 104.7 ± 28.9 Ave fold change = 2.36 p = 0.0076 N=16 Cytotoxic Cells 2 mg/lesion 8 mg/lesion Pre: 37.1 ± 20.8 Post: 142.0 ± 49.2 Ave fold change = 9.86 p < 0.0001 N=23 Pre: 57.0 ± 34.5 Post: 129.4 ± 39.5 Ave fold change = 6.40 p = 0.0052 N=16 Th1 Helper T Cells 2 mg/lesion 8 mg/lesion Pre: 20.6 ± 10.4 Post: 75.1 ± 19.4 Ave fold change = 9.54 p < 0.0001 N=23 Pre: 31.5 ± 15.4 Post: 62.2 ± 13.1 Ave fold change = 3.53 p = 0.0021 N=16 CD8 T Cells 2 mg/lesion 8 mg/lesion Pre: 35.1 ± 18.7 Post: 136.7 ± 42.3 Ave fold change = 11.14 p < 0.0001 N=23 Pre: 46.7 ± 25.8 Post: 91.3 ± 31.7 Ave fold change = 4.61 p = 0.0214 N=16 Figure 2. Best Percent Change From Baseline in All Target Lesions Table 6. Progression-free Survival (ITT Population) Table 5. Responses in Both PD-L1 Negative and Positive Tumors Figure 3. Duration of Follow Up and Patient Status Figure 4. Responses in Two Non-injected Liver Lesions in a Patient with PD-L1 Expression of 1% who Received 2 mg of SD-101 in a Single Lesion Baseline 190 Days Baseline 190 Days Figure 6. Percent Change From Baseline Over Time for Target Lesions in Patients Who Received 2 mg or 8 mg SD-101 Per Lesion All Injected Target Lesions All Non-injected Target Lesions Efficacy Event 2 mg/lesion n = 47 8 mg/lesion n = 40 Total N = 87 irAEs all grades, n (%) Hypothyroidism 7 (15) 3 (8) 10 (12) Pneumonitis 2 (4) 1 (3) 3 (3) Myositis 1 (2) 1 (3) 2 (2) Autoimmune retinopathy 0 1 (3) 1 (1) Autoimmune hepatitis 0 1 (3) 1 (1) Myasthenia gravis 0 1 (3) 1 (1) Colitis 1 (2) 0 1 (1) Autoimmune colitis 1 (2) 0 1 (1) Hypophysitis 2 (4) 0 2 (2) Hyperthyroidism 1 (2) 0 1 (1) Autoimmune myocarditis 0 1 (3) 1 (1) Optic neuritis 0 1 (3) 1 (1) REFERENCES 2 mg/lesion Patients 0 100 200 300 400 500 600 700 800 900 1000 Partial Response Complete Response Progressive Disease Stable Disease Ongoing Days 8 mg/lesion 0 100 200 300 400 500 600 700 800 900 1000 Patients Partial Response Complete Response Progressive Disease Stable Disease Ongoing Days Immune-Related Biomarkers Patients: Unresectable Stage IIIC, Stage IV Metastatic Melanoma ECOG performance status of 0 or 1 . CI = confidence interval; ITT = intention to treat; NE=not estimable; PFS = progression-free survival Exhibit 99.2
Abstract 3781: Phase 1b/2, Open-Label, Multicenter Study of Intratumoral SD-101 in Combination With Pembrolizumab in Patients With Advanced Melanoma Resistant/Refractory to Anti-PD-1/PD-L1 Therapy (SYNERGY-001/KEYNOTE-184, NCT02521870) A. Ribas1, I. Mehmi2, T. Medina3, C. Lao4, S. Kummar5, A. Amin6, S. Deva7, A. K. Salama8, T. Tueting9, M. Milhem10, C. J. Hoimes11, G. Daniels12, M. Shaheen13, S. Jang14, M. Barve15, A. Powell16, S. Chandra17, E. V. Schmidt18, R. Janssen19, G. V. Long20 1Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, USA; 2Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, USA; 3University of Colorado Cancer Center, Aurora, USA; 4University of Michigan Health System, Ann Arbor, USA; 5Stanford University School of Medicine, Stanford, USA; 6Levine Cancer Institute, Charlotte, USA; 7Auckland City Hospital, Auckland, NZ; 8Duke University, Durham, USA; 9University Hospital Madgeburg, Madgeburg, DE; 10University of Iowa, Iowa City, USA; 11Case Western Reserve University, Cleveland, USA; 12University of California, San Diego, USA; 13University of Arizona Cancer Center North, Tucson, USA; 14Melanoma and Skin Cancer Center, Inova Char Cancer Institute, Fairfax, USA; 15Mary Crowley Cancer Research, Dallas, USA; 16Affinity Research, Nedlands, AU; 17Northwestern University, Chicago, USA; 18Merck & Co., Inc., Kenilworth, NJ, USA; 19Dynavax Technologies Corporation, Berkeley, USA; 20Melanoma Institute Australia, University of Sydney, AU BACKGROUND PD-1 blockade has significantly improved outcomes in advanced melanoma, yet durable responses are elicited in less than half of the patients, therefore this remains an area of unmet need.1 KEYTRUDA® (pembrolizumab) is an anti-PD-1 monoclonal antibody (mAb) that is approved by the FDA to treat patients with unresectable or metastatic melanoma.1 SD-101 is a synthetic class-C, CpG-oligodeoxynucleotide, toll-like receptor nine (TLR9) agonist, which stimulates human plasmacytoid dendritic cells (PDCs) to release interferon-alpha and mature into efficient antigen-presenting cells, enhancing both innate and adaptive immune responses (Figure 1).2 Preclinical studies of anti-PD-1 non-responder mouse tumor models demonstrated that intratumoral injection of SD-101, in combination with PD-1 blockade, suppressed the growth of tumors not only at the injected site, but also at distant un-injected sites.3 In the phase 1b portion of this study, intratumoral injections of SD-101 in combination with pembrolizumab demonstrated clinical responses in both injected and distant lesions of patients with metastatic melanoma.4 Here, we report the results from a phase 2 expansion cohort of patients with advanced melanoma resistant/refractory (R/R) to anti-PD-1/PD-L1 therapy who were treated with the combination of SD-101 and pembrolizumab. Preliminary results from the phase 1b portion of this study were presented at AACR 2018 (Abstract: CT139) and published in Cancer Discovery (2018): Ribas, A., et al.5,6 Figure 1. Both Innate and Adaptive Immune Responses Are Increased by Intratumoral Injection of SD-101 Characteristics N = 30 Median age, years (Min, Max) 64 (53, 76) Male, n (%) 23 (76.7) ECOG PS 0/1, n (%) 30 (100) Baseline LDH, mean (SD) ≤ULN, n (%) >1 to ≤2 ULN, n (%) >2 ULN, n (%) 223 (3.0, 1886.0) 17 (55%) 9 (29%) 4 (13%) Stage at Screening, n (%) IIIC 10 (33.3) IV 19 (63.3) Missing 1 (3.3) Metastases involving: Skin/Subcutaneous tissue 20 (66.7) Lymph Nodes 15 (50) Liver 9 (30) Lung 6 (20) Bones 3 (10) Other 13 (43.3) PD-L1 expression, n (%)* Positive (≥1%) 4 (13.3) Negative (<1%) 13 (43.3) Pending 13 (43.3) Table 1. Demographics and Baseline Characteristics ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; SD = standard deviation; ULN = upper limit of normal; * Expression determined using Dako 22C3 antibody Table 2. Baseline Disease Characteristics Characteristics, n (%) N = 30 Prior radiotherapy 6 (20) Prior surgery 28 (93.3) Prior lines of therapy, 1/2/≥3 11/8/11 PD1/PD-L1 therapy Resistant* 18 (60) Refractory** 12 (40) Prior CTLA-4 therapy 12 (40) Event, n (%) N = 30 irAEs all grades 4 (13.3) Hypothyroidism 1 (3.3) Pneumonitis 1 (3.3) Autoimmune hepatitis 1 (3.3) Pancreatitis 1 (3.3) Table 5. Safety Summary Event, N (%) N = 30 Any Treatment-related AE 24 (80) Grade 3-4 12 (40) Chills 1 (3.3) Myalgia 2 (6.6) Injection-site pain 1 (3.3) Fatigue 2 (6.6) Headache 0 Malaise 2 (6.6) Vomiting 3 (10) Any irAEs 4 (13.3) Grade 3-4 2 (6.6) AEs leading to d/c of either or both drug 4 (13.3) SAEs 3 (10) Death** 1 (3.3) Table 6. Immune-Related Adverse Events irAE = immune-related adverse event; d/c = discontinuation; SAE = serious adverse event **Death not related to study treatment Efficacy Table 3. Best Overall Response in mITT by RECIST Best ORR, n (%) N = 29 (mITT*) Objective response rate 6 (21.4) Complete response 1 (3.4) Partial response 5 (17.2) Duration of response (months), median (min, max) 2.1 (1.0, 6.1) Stable disease 5 (17.2) Disease Control Rate 11 (38.0) Progressive disease 11 (37.9) Tumor IFN DC T cell SD-101 induces IFN and DC maturation Dendritic cells take up antigens from dying tumor cells and migrate to the lymph nodes Chemokines IFN IFN SD-101 (CXCL9, 10) Tumor antigens Lymph node DC Dying tumor T cell PD-L1 PD1 Anti-PD1 Dying tumor NK cell IFNs stimulate tumor killing by NK cells Tumor Cell Tumor-specific T cells activated by DC and IFN in lymph node Uninjected tumors are destroyed by CTL generated in the SD-101 injected sites Blood vessel CTL CTL CTL Dying tumor CTL Dying tumor CTL CTL = cytotoxic (CD8+) T cell; DC = dendritic cells; IFN = interferon; NK = natural killer CONCLUSIONS REFERENCES Patient Best Response TPS 1 PR 0 2 SD 0 3 SD 0 4 PD 0 5 PD 0 6 PD 0 7 PR <1 8 SD <1 9 PD <1 10 SD 1 11 SD 1 12 PD 1 13 PD 1 14 CR 3 15 PR 10 16 PR 10 17 PD 90 Table 4. PD-L1 Expression Levels and Efficacy Figure 5. Patient Response History and Current Status The combination of SD-101 and pembrolizumab was well tolerated, consistent with previous reports: AEs associated with SD-101 were transient, mild to moderate injection-site reactions and flu-like symptoms that were manageable with over-the-counter medications Low incidence of immune-related AEs Preliminary data showed encouraging efficacy, with an ORR of 21.4% Responses were observed in both SD-101 injected and non-injected lesions; however, it is too early to determine the durability of responses Responses and disease control were observed in PD-L1 positive and negative tumors The addition of SD-101 to pembrolizumab appears to restore tumor sensitivity to PD-1 inhibitor in patients who are R/R to anti-PD1/PD-L1 therapy Based on results from the phase 2 study in PD-1/PD-L1 naive patients demonstrating higher efficacy of multiple 2mg injections (up to 4 injections) compared to 1 injection of 8 mg, a phase 2 study with the new dosing of 2 mg per injection is ongoing Keytruda (pembrolizumab) for injection, for intravenous use [package insert]. Merck Sharp & Dohme Corp, Whitehouse Station, NJ USA. 2014. Guiducci C, et al. J Exp Med 2006;203:1999-2008. Wang S, et al. Proc Natl Acad Sci U S A, 2016. 113(46):E7240-e7249. Leung ACF, et al. Journal of Clinical Oncology 2017;35:15 (suppl):9550. Ribas A, et al. Cancer Res 2018;78 (13 Supplement):CT139. Ribas A, et al. Cancer Discovery 2018; DOI: 10.1158/2159-8290.CD-18-0280. This study was sponsored by Dynavax Technologies Corporation in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. We thank the patients and their families and caregivers for participating in the study; the participating study teams and Albert Candia, Kavya Kazipeta, and Tripta Dahiya for contributions to the analysis of the data (Dynavax Technologies Corporation). Copies of this poster obtained through QR (Quick Response) and/or text key codes are for personal use only and may not be reproduced without written permission of the authors. Corresponding Author: Antoni Ribas (aribas@mednet.ucla.edu) CT, computed tomography scan SCREENING TREATMENT TREATMENT 0 1 2 3 4 6 9 12 15 18 21 24 0 1 2 3 4 6 9 12 15 18 21 24 CT CT CT Pembrolizumab Weeks SD-101 Weeks TPS: tumor proportion score; PD-L1 expression data are pending for 13 patients PD-L1 negative PD-L1 positive METHODS Ongoing Phase 1b/2, Open-label, Multicenter, Expansion Study of Intratumoral SD-101 in Combination With Pembrolizumab (SYNERGY-001, MEL-01, NCT02521870) Patients: Stage IIIC, Stage IV Metastatic Melanoma Resistant or refractory to prior anti-PD-1/PD-L1 therapy ECOG performance status of 0 or 1 At least 2 lesions that qualify as a target lesion per RECIST v1.1, and 1 of the qualifying lesions must be easily accessible and amenable to multiple intratumoral injections. The target lesion should be of sufficient size such that the required tumor biopsies do not significantly affect tumor assessment per RECIST v1.1. Study Treatment: SD-101 was administered intratumorally in one target lesion, 8 mg Weekly x 4 doses then Q3W x 7 doses* Pembrolizumab was administered IV (200 mg Q3W) Figure 2. Study Design Primary Endpoint: Overall response rate assessed by RECIST v1.1 Secondary Endpoints: Safety and tolerability, duration of response, and immunophenotype of the tumor environment RESULTS SD-101 induces PDCs to secrete high levels of interferon-alpha, a potent immunomodulatory cytokine that is able to boost NK cell cytotoxic activity and induce recruitment of T cells. In addition, SD-101 induces DC maturation cross-presentation of tumor associated antigens, inducing CD8+ T cell responses. STUDY OBJECTIVE To confirm the safety profile and assess the efficacy of SD-101 and pembrolizumab combination therapy in patients with advanced melanoma who were R/R to anti-PD-1 therapy. Figure 3. Best Percent Change from Baseline in Target Lesions Figure 4. Percent Change from Baseline Over Time Days Complete Response Partial Response Stable Disease Progressive Disease Ongoing Patients 0 50 100 150 200 250 300 350 400 100 80 60 40 20 0 -20 -40 -60 -80 -100 Percent change from baseline, % Non-Injected Lesions Patients 100 80 60 40 20 0 -20 -40 -60 -80 -100 Percent change from baseline, % All Target Lesions Patients 100 80 60 40 20 0 -20 -40 -60 -80 -100 Percent change from baseline, % Injected Lesions Patients Note: Patients receiving 1 and 2 mg dosing were excluded (1 of 4 patients who received 1 or 2 mg dosing experienced a partial response) *mITT: excluding patients on treatment but did not yet have their first CT scan and tumor assessment *Out of 38 patients, 4 patients treated with 4 mg per injection and 4 patients treated with up to 2 mg per injection in other cohorts were excluded; 30 patients have been treated with 8 mg per injection. SAFETY *Resistant: progressive disease after at least 3 months on treatment and initial objective response or stable disease. A disease with a relapse while on adjuvant treatment or within 6 months after the end of an adjuvant treatment is also considered resistant. **Refractory: tumor initially resistant, best confirmed response is progressive disease while on treatment.
Abstract 3560: Phase 1b/2, Open-Label, Multicenter Study of Intratumoral SD-101 in Combination With Pembrolizumab in Anti-PD-1 Treatment-Naïve Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (SYNERGY-001/KEYNOTE-184, NCT02521870) Ezra Cohen,1 Alain Algazi,2 Douglas Laux,3 Deborah Wong,4 Asim Amin,5 Lisle Nabell,6 Michael Chisamore,7 Erick Gamelin,8 Robert Janssen,8 Sarwan Bishnoi9 1Moores Cancer Center, University of California San Diego, La Jolla, CA USA; 2University of California San Francisco, CA USA; 3University of Iowa, Iowa City, IA USA; 4Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA USA; 5Levine Cancer Institute, Charlotte, NC USA; 6University of Alabama at Birmingham, Birmingham, AL USA; 7Merck & Co., Inc., Kenilworth, NJ USA; 8Dynavax, Berkeley, CA USA; 9Adelaide Cancer Centre, Kurralta Park, Australia BACKGROUND Historically, patients with recurrent unresectable or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have had a poor prognosis, with limited second-line treatment options (including methotrexate, cetuximab, and paclitaxel) providing an estimated overall response rate (ORR) of 4-14%, a median duration of response (DOR) of 4-7 months, an estimated median progression-free survival (mPFS) of 1.7-3.5 months, and an estimated median overall survival (OS) of less than 7 months.1 KEYTRUDA® (pembrolizumab) is a anti-PD-1 monoclonal antibody (mAb) that received accelerated approval by the FDA to treat patients with R/M HNSCC with disease progression on or after platinum-containing chemotherapy based on results of the KEYNOTE-012 study showing that pembrolizumab monotherapy provided an ORR of 18% with 85% of those responses lasting ≥6 months.2,3 SD-101 is a synthetic Class-C CpG-oligodeoxynucleotide toll-like receptor nine (TLR9) agonist, which stimulates human plasmacytoid dendritic cells (PDCs) to release interferon-alpha and mature into efficient antigen-presenting cells, enhancing both innate and adaptive immune responses (Figure 1).4 Preclinical mouse models of head and neck tumors demonstrated that intratumoral injection of SD-101, in combination with PD-1 blockade, suppressed the growth of tumors not only at the injected site, but also at distant un-injected sites.5 In a phase 1b/2 study of patients with metastatic melanoma, intratumoral injections of SD-101 in combination with pembrolizumab demonstrated clinical responses in both injected and distant lesions.6 Here, we report the results from a phase 2 cohort expansion of patients with R/M HNSCC who were treated with the combination of SD-101 and pembrolizumab. Figure 1. Both Innate and Adaptive Immune Responses Are Increased by Intratumoral Injection of SD-101 Characteristics 8 mg (n=23) 2 mg (n=10) Median age, years (Min, Max) 65 (43, 91) 60 (38, 84) Male/female sex, % 91/9 50/50 ECOG PS 0 or 1, % 100 100 Primary tumor location, n (%) Hypopharyngeal 1 (4.3) 1 (10.0) Nasopharyngeal 1 (4.3) 0 Oral 10 (43.4) 4 (40.0) Oropharyngeal 5 (21.7) 2 (20.0) Laryngeal 3 (13.0) 1 (10.0) Unknown 3 (13.0) 2 (20.0) HPV status, n (%) Negative 6 (26.0) 5 (50.0) Positive 3 (13.0) 2 (20.0) Unknown 14 (60.8) 3 (30.0) Table 1. Demographics and Baseline Characteristics ECOG PS = Eastern Cooperative Oncology Group performance status; HPV = human papillomavirus Table 2. Baseline Disease Characteristics: SD-101 8 mg or 2 mg/Injection Characteristics 8 mg (n=23) 2 mg (n=10) Prior radiotherapy, n (%) 18 (78.3) 5 (50.0) Prior surgery, n (%) 21 (91.3) 8 (80.0) 0/1/2/≥3 prior lines of therapy, n 4/11/5/3 4/6/0/0 Prior systemic therapy* 19 (82.6) 6 (60.0) Organ involvement, n (%) Liver Lung Bone Skin/subcutaneous tissue Lymph nodes Other organs 1 (4.3) 6 (26.1) 2 (8.7) 7 (30.4) 11 (47.8) 15 (65.2) 0 3 (30.0) 0 1 (10.0) 2 (20.0) 2 (20.0) Number of Target Lesions: 1 2 3 4 5 6 (26.1) 5 (21.7) 8 (34.8) 1 (4.3) 2 (8.7) 4 (40.0) 3 (30.0) 0 1 (10.0) 0 Safety Event, n (%) 8 mg (n=23) 2 mg (n=7) irAEs All grades 7 (30.4) 0 Hypothyroidism 1 (4.3) 0 Pneumonitis 1 (4.3) 0 Myositis 2 (8.6) 0 Hepatitis 2 (8.6) 0 Colitis 1 (4.3) 0 Table 5. Safety Summary: SD-101 8 mg or 2 mg/Injection* Event, n (%) 8 mg (n=23) 2 mg (n=7) Any Treatment-related AE 19 (82.6) 2 (28.6) Grade 3-4 8 (34.8) 0 Chills 0 0 Myalgia 2 (8.7) 0 Influenza-like synd. 1 (4.3) 0 Injection-site pain 2 (8.7) 0 Fatigue 4 (17.4) 0 Headache 1 (4.3) 0 Malaise 1 (4.3) 0 Cellulitis 1 (4.3) 0 AEs leading to d/c of either or both drugs 5 (21.7) 1 (14.3) SAEs 6 (26.1) 1 (14.3) Treatment-related SAEs 2 (8.7) 0 Death (treatment-related) 0 0 Table 6. Immune-Related Adverse Events: 8 mg and 2 mg/Injection* d/c = discontinuation; SAE = Serious adverse event * Three patients in the 2 mg cohort have insufficient follow-up for safety assessment Efficacy Table 3. Objective Response Rate: SD-101 8 mg or 2 mg/injection 8 mg 2 mg mITT patients, n* 22 2 Objective response rate, n (%) 6 (27.3) 95% confidence interval (16, 56) Best overall response, n (%) Complete response 0 Partial response 6 (27.3) Stable disease 4 (18.2) 2 (100) Progressive disease 10 (45.5) Time to response (months) Median 2.1 Min, max (2.0, 4.2) Duration of response (months) Median 3.6+ Min, Max (0.0, 6.9) Tumor IFN DC T cell SD-101 induces IFN and DC maturation Dendritic cells take up antigens from dying tumor cells and migrate to the lymph nodes Chemokines IFN IFN SD-101 (CXCL9, 10) Tumor antigens Lymph node DC Dying tumor T cell PD-L1 PD1 Anti-PD1 Dying tumor NK cell IFNs stimulate tumor killing by NK cells Tumor Tumor-specific T cells activated by DC and IFN in lymph node Uninjected tumors are destroyed by CTL generated in the SD-101 injected sites Blood vessel CTL CTL CTL Dying tumor CTL Dying tumor CTL CTL = cytotoxic (CD8+) T cell; DC = dendritic cells; IFN = interferon; NK = natural killer CONCLUSIONS REFERENCES Subject Best Response TPS 1 PD 0 2 PD 0 3 PR <1 4 SD 2 5 PD 5 6 PD 10 7 PD 10 8 PD 15 9 PR 30 10 PR 40 11 PD 60 12 PR 90 13 PD 95 Table 4. PD-L1 Expression Data and Efficacy: SD-101 8 mg Figure 3. Percent Change From Baseline for Target Lesions: SD-101 8 mg Figure 4. Current Patient Status with SD-101 8 mg The combination of SD-101 and pembrolizumab was well tolerated, consistent with previous reports No evidence of an increased incidence or severity of AEs over pembrolizumab monotherapy No increase in immune-related AEs over pembrolizumab monotherapy AEs associated with SD-101 were transient, mainly mild to moderate injection-site reactions and flu-like symptoms that were manageable with over-the-counter medications The combination therapy showed promising efficacy in patients with HNSCC, with an ORR of 27.3% Responses were observed in both SD-101 injected and non-injected lesions Responses were observed in both PD-L1 negative and positive tumors Lala M, Chirovsky D, Cheng JD, Mayawala K. Clinical outcomes with therapies for previously treated recurrent/metastatic head-and-neck squamous cell carcinoma (R/M HNSCC): A systematic literature review. Oral Oncol 2018;84:108-20. Keytruda (pembrolizumab) for injection, for intravenous use [package insert]. Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA. 2014. Mehra R, Seiwert TY, Gupta S, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer 2018;119:153-9.Guiducci C, et al. J Exp Med, 2006. 203(8): p. 1999-2008. Guiducci C, Ott G, Chan JH, et al. Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J Exp Med 2006;203:1999-2008. Sato-Kaneko F, Yao S, Ahmadi A, et al. Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer. JCI Insight 2017;2. Ribas A, Milhem MM, Hoimes CJ, et al. Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy. Journal of Clinical Oncology 2018;36 (suppl; abstract 9513). CT, computed tomography scan. SCREENING TREATMENT TREATMENT 0 1 2 3 4 6 9 12 15 18 21 24 0 1 2 3 4 6 9 12 15 18 21 24 CT CT CT Biopsy Biopsy Biopsy Biopsy Pembrolizumab Weeks SD-101 Weeks * mITT = excluding patients on treatment but did not yet have their first CT scan and tumor assessment Patients 0 50 100 150 200 250 300 350 400 Partial Response Stable Disease Progressive Disease Ongoing Days TPS: tumor proportion score; additional PD-L1 expression data pending PD-L1 negative PD-L1 positive METHODS Ongoing Phase 1b/2, Open-label, Multicenter, Expansion Study of Intratumoral SD-101 in Combination With Pembrolizumab (NCT02521870, SYNERGY-001 DV3-MEL-01/Keynote-184) Patients: Advanced/metastatic head and neck squamous cell carcinoma Prior anti-PD-1/PD-L1 naïve ECOG performance status of 0 or 1 At least one injectable lesion Study Treatment: Two dose levels were assessed: 8 mg one lesion and 2 mg per lesion up to 4 lesions Pembrolizumab was administered IV (200 mg Q3W) Figure 2. Study Design Primary Endpoint: Overall response rate assessed by RECIST v1.1 and reported for the modified intent-to-treat (mITT) population that excludes patients on study who have not yet reached the first CT scan. Secondary Endpoints: Safety and tolerability, DOR, time to relapse, pharmacodynamics, immunophenotype of the tumor environment Data cutoff date: August 16, 2018 RESULTS irAE = immune-related adverse event * Three patients in the 2 mg cohort have insufficient follow-up for safety assessment This study was sponsored by Dynavax Technologies Corporation in collaboration with Merck & Co., Inc., Kenilworth, NJ USA. We thank the patients and their families and caregivers for participating in the study; the participating study teams and Albert Candia, Brit Harvey, Kavya Kazipeta and Tripta Dahiya for contributions to the analysis of the data (Dynavax Technologies Corporation). Copies of this poster obtained through QR (Quick Response) and/or text key codes are for personal use only and may not be reproduced without written permission of the authors. Corresponding Author: Ezra Cohen (ecohen@ucsd.edu) SD-101 induces PDCs to secrete high levels of interferon-alpha, a potent immunomodulatory cytokine that is able to boost NK cell cytotoxic activity and induce recruitment of T cells. In addition, SD-101 induces DC maturation cross-presentation of tumor associated antigens, inducing CD8+ T cell responses. * No patients received prior PD-1/PD-L1/CTLA-4 therapy
Intro Slide Exhibit 99.3
BACKGROUND Page PD-1 blockade has significantly improved outcomes in advanced melanoma, yet durable responses are elicited in less than half of the patients. There remains an area of unmet need in patients who are anti-PD-1 naïve or experienced. KEYTRUDA® (pembrolizumab) is an anti-PD-1 monoclonal antibody (mAb) that is approved by the FDA to treat patients with unresectable or metastatic melanoma and recurrent or metastatic HNSCC. SD-101 is a synthetic class-C, CpG-oligodeoxynucleotide, toll-like receptor nine (TLR9) agonist
BACKGROUND CONT. Page In preclinical studies of anti-PD-1 non-responder mouse tumor models, intratumoral injection of SD-101, in combination with PD-1 blockade, suppressed the growth of tumors at the injected and distant non-injected sites. Wang S, et al., PNAS, 2016. 113(46): p. E7240-e7249 In a previous phase 1b/2 study of patients with indolent non-Hodgkin’s lymphoma, treatment of a single lesion with low dose radiation and intratumoral SD-101 induced abscopal tumor shrinkage in 83% of patients. Frank, M.J., et al. Cancer Discovery 2018. DOI: 10.1158/2159-8290 In the phase 1b portion of SYNERGY-001/MEL-01, intratumoral injections of SD-101 in combination with pembrolizumab demonstrated clinical responses in both injected and distant lesions of patients with metastatic melanoma, both those who were naïve to anti-PD-1/L1 therapy or experienced. Ribas A, et al. Cancer Discovery 2018; DOI: 10.1158/2159-8290.CD-18-0280
BACKGROUND CONT. Page Here, we report the results presented at ESMO from the ongoing phase 2 expansion of SYNERGY-001 in patients with: advanced melanoma resistant/refractory (R/R) to anti-PD-1/L1 therapy; advanced melanoma naïve to anti-PD-1/L1 therapy; and advanced head and neck squamous cell carcinoma naïve to anti-PD-1/L1 therapy.
BACKGROUND CONT. Page Figure 1. Both Innate and Adaptive Immune Responses Are Increased by Intratumoral Injection of SD-101
Abstract 3781: Phase 1b/2, Open-Label, Multicenter Study of Intratumoral SD-101 in Combination With Pembrolizumab in Patients With Advanced Melanoma Resistant/Refractory to Anti-PD-1/PD-L1 Therapy (SYNERGY-001/KEYNOTE-184, NCT02521870) A. Ribas1, I. Mehmi2, T. Medina3, C. Lao4, S. Kummar5, A. Amin6, S. Deva7, A. K. Salama8, T. Tueting9, M. Milhem10, C. J. Hoimes11, G. Daniels12, M. Shaheen13, S. Jang14, M. Barve15, A. Powell16, S. Chandra17, E. V. Schmidt18, R. Janssen19, G. V. Long20 1Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, USA; 2Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, USA; 3University of Colorado Cancer Center, Aurora, USA; 4University of Michigan Health System, Ann Arbor, USA; 5Stanford University School of Medicine, Stanford, USA; 6Levine Cancer Institute, Charlotte, USA; 7Auckland City Hospital, Auckland, NZ; 8Duke University, Durham, USA; 9University Hospital Madgeburg, Madgeburg, DE; 10University of Iowa, Iowa City, USA; 11Case Western Reserve University, Cleveland, USA; 12University of California, San Diego, USA; 13University of Arizona Cancer Center North, Tucson, USA; 14Melanoma and Skin Cancer Center, Inova Char Cancer Institute, Fairfax, USA; 15Mary Crowley Cancer Research, Dallas, USA; 16Affinity Research, Nedlands, AU; 17Northwestern University, Chicago, USA; 18Merck & Co., Inc., Kenilworth, NJ, USA; 19Dynavax Technologies Corporation, Berkeley, USA; 20Melanoma Institute Australia, University of Sydney, AU
METHODS CONT. Page
RESULTS Page Characteristics N = 30 Median age, years (Min, Max) 64 (53, 76) Male, n (%) 23 (76.7) ECOG PS 0, n (%) 16 (53.3) Baseline LDH, mean (SD) ≤ULN, n (%) >1 to ≤2 ULN, n (%) >2 ULN, n (%) 223 (3.0, 1886.0) 17 (55%) 9 (29%) 4 (13%) Stage at Screening, n (%) IIIC 10 (33.3) IV 19 (63.3) Missing 1 (3.3) Metastases involving: Skin/Subcutaneous tissue 20 (66.7) Lymph Nodes 15 (50) Liver 9 (30) Lung 6 (20) Bones 3 (10) Other 13 (43.3) Table 1. Demographics and Baseline Characteristics ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; SD = standard deviation; ULN = upper limit of normal; * Expression determined using Dako 22C3 antibody
RESULTS CONT. Page
RESULTS CONT. Page Efficacy Table 3. Best Overall Response in mITT by RECIST Best ORR, n (%) N = 29 (mITT*) Objective response rate 6 (20.7) Complete response 1 (3.4) Partial response 5 (17.2) Duration of response (months), median (min, max) 2.1 (1.0, 6.1) Stable disease 5 (17.2) Disease Control Rate 11 (37.9) Progressive disease 11 (37.9) Note: Patients receiving 1 and 2 mg dosing were excluded (1 of 4 patients who received 1 or 2 mg dosing experienced a partial response) *mITT: excluding patients on treatment but did not yet have their first CT scan and tumor assessment
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CONCLUSIONS Page Preliminary data show encouraging efficacy, with an ORR of 21% Responses were observed in both SD-101 injected and non-injected lesions; however, it is too early to determine the durability of responses The addition of SD-101 to pembrolizumab appears to restore tumor sensitivity to PD-1 inhibitors in patients who are R/R to such therapy Based on data from the anti-PD-1/L1 naïve melanoma population, 25 patients with R/R disease are being enrolled to receive 2 mg per injection
LBA45: Phase 1b/2, Open Label, Multicenter, Study of the Combination of SD-101 and Pembrolizumab in Patients with Advanced Melanoma Who Are Naïve to Anti-PD-1/L1 Therapy (SYNERGY-001/KEYNOTE-184, NCT02521870) G. Long1, M. Milhem2, A. Amin3, C. J. Hoimes4, T. Medina5, R. Conry6, C. Lao7, G. Daniels8, S. Reddy9, I. Mehmi10, R. Andtbacka11, M. Barve12, M. Shaheen13, T. Tueting14, M. Chisamore15, B. Xing16, A. Candia16, E. Gamelin16, R. Janssen16, A. Ribas17 1Melanoma Institute Australia, The University of Sydney and Royal North Shore and Mater Hospitals, Sydney, Australia; 2University of Iowa, Iowa City, USA; 3Levine Cancer Institute, Charlotte, USA; 4Case Western Reserve University, Cleveland, USA; 5University of Colorado Cancer Center, Aurora, USA; 6University of Alabama School of Medicine, Birmingham, USA; 7University of Michigan Health System, Ann Arbor, USA; 8University of California, San Diego, USA; 9Stanford University, Stanford, USA; 10Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, USA; 11University of Utah, Salt Lake City, USA; 12Mary Crowley Cancer Research, Dallas, USA; 13University of Arizona Cancer Center North, Tucson, USA; 14University Hospital Magdeburg, Magdeburg, Germany; 15Merck & Co., Inc., Kenilworth, NJ, USA; 16Dynavax Technologies Corporation, Berkeley, USA; 17Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, USA
METHODS Page
RESULTS Page Characteristics 2 mg/lesion n = 47 8 mg/lesion n = 40 Median age, years (Min, Max) 66 (36, 85) 66 (33, 89) > 65 years, n (%) 30 (64) 23 (58) Male, n (%) 33 (70) 26 (65) ECOG PS 0, n (%) 30 (64) 30 (75) Baseline LDH, median (Q1, Q3) > ULN, n (%) 193 (162, 234) 8 (17) 195 (177, 238) 10 (25) Stage at Screening, n (%) IIIC 10 (21) 8 (20) IV 37 (79) 32 (80) M1a 16 (34) 11 (28) M1b 9 (19) 9 (23) M1c 12 (26) 12 (30) PD-L1 Expression, n (%)* Positive (≥1%) 19 (40) 13 (33) Negative (<1%) 15 (32) 15 (38) Pending 13 (28) 12 (30) Prior lines of therapy, 0 / 1 / 2 / ≥3. n (%) 34 / 11 / 2 / 0 (72 / 23 / 4 / 0) 28 / 11 / 0 / 1 (70 / 28 / 0 / 3) Table 1. Demographics and Baseline Characteristics (Phase 1b/2) ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; Q1 = first quartile; Q3 = third quartile; ULN = upper limit of normal; * Expression determined by tumor proportion score using Dako 22C3 antibody
RESULTS CONT. Page
RESULTS CONT. Page
Subgroup Analyses Favor 2 mg Dose CI = confidence interval; ECOG = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; ORR = objective response rate; RR = risk ratio; ULN = upper limit of normal . 2 mg 8 mg N ORR N ORR RR (95% CI) Overall 47 70% 40 48% 1.5 (1.0. 2.2) Age, year < 65 17 71% 17 59% 1.2 (0.7, 2.0) ≥ 65 30 70% 23 39% 1.8 (1.0, 3.1) Sex Male 33 76% 26 50% 1.5 (1.0, 2.3) Female 14 57% 14 43% 1.3 (0.6, 2.8) ECOG PS 0 30 73% 30 47% 1.6 (1.0, 2.4) 1 17 65% 10 50% 1.3 (0.6, 2.6) LDH ≤ ULN 39 72% 30 50% 1.4 (1.0, 2.2) > ULN 8 63% 10 40% 1.6 (0.6, 4.0) Stage at screening IIIC 10 60% 8 25% 2.4 (0.7, 8.8) M1a-c 37 73% 32 53% 1.5 (1.0, 2.1) M1a 16 88% 11 64% 1.4 (0.8, 2.2) M1b 9 56% 9 67% 0.8 (0.4, 1.8) M1c 12 67% 12 33% 2.0 (0.8, 4.9) Number of prior lines of therapy 0 34 74% 28 43% 1.7 (1.0, 2.8) 1+ 13 62% 12 58% 1.1 (0.6, 2.0) Favors 8 mg Favors 2 mg CONFIDENTIAL 0 2 4 6 8 10 Risk Ratio
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IMMUNE-RELATED BIOMARKERS Page Values above the graphs represent the means and 95% confidence intervals. Methods: biopsies of the injected tumor were collected at screening (prior to dosing) and post-dose. Biopsies were analyzed by the nCounter® PanCancer Immune Profiling Panel (NanoString Technologies, Inc., Seattle WA) to evaluate the immunophenotype of the tumor environment. Nanostring data were analyzed using the nSolver™ Analysis Software
CONCLUSIONS Page The addition of 2 mg/lesion of SD-101 to pembrolizumab appears to increase immune activity in the tumor microenvironment and efficacy compared with 8 mg/lesion in similar patient populations The ORR and PFS were significantly better in the 2 mg/lesion SD-101 group than in the 8 mg/lesion SD-101 group Responses occurred in patients with PD-L1 negative tumors and PD-L1 positive tumors Tumor shrinkage occurred in injected lesions, and non-injected visceral lesions including in the liver and lung The combination of SD-101 and pembrolizumab was well tolerated, consistent with previous reports AEs associated with SD-101 were transient, mild to moderate flu-like symptoms that were manageable with over-the-counter medications No increase in immune-related AEs over pembrolizumab monotherapy was observed Clinical responses were supported by immunologic data consistent with the mechanism of SD-101 Increases in CD8+ cells, NK cells, cytotoxic cells, and Th1 cells in the tumor microenvironment were observed in both SD-101 dose groups but were higher in the 2 mg group and appeared to correlate with enhanced clinical efficacy
Abstract 3560: Phase 1b/2, Open-Label, Multicenter Study of Intratumoral SD-101 in Combination With Pembrolizumab in Anti-PD-1 Treatment-Naïve Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (SYNERGY-001/KEYNOTE-184, NCT02521870) Ezra Cohen,1 Alain Algazi,2 Douglas Laux,3 Deborah Wong,4 Asim Amin,5 Lisle Nabell,6 Michael Chisamore,7 Erick Gamelin,8 Robert Janssen,8 Sarwan Bishnoi9 1Moores Cancer Center, University of California San Diego, La Jolla, CA USA; 2University of California San Francisco, CA USA; 3University of Iowa, Iowa City, IA USA; 4Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA USA; 5Levine Cancer Institute, Charlotte, NC USA; 6University of Alabama at Birmingham, Birmingham, AL USA; 7Merck & Co., Inc., Kenilworth, NJ USA; 8Dynavax, Berkeley, CA USA; 9Adelaide Cancer Centre, Kurralta Park, Australia
RESULTS Page Characteristics 8 mg (n=23) 2 mg (n=10) Median age, years (Min, Max) 65 (43, 91) 60 (38, 84) Male/female sex, % 91/9 50/50 ECOG PS 1, N (%) 22 (84.6) 24 (75.0) Primary tumor location, n (%) Hypopharyngeal 1 (4.3) 1 (10.0) Nasopharyngeal 1 (4.3) 0 Oral 10 (43.4) 4 (40.0) Oropharyngeal 5 (21.7) 2 (20.0) Laryngeal 3 (13.0) 1 (10.0) Unknown 3 (13.0) 2 (20.0) 0/1/2/≥ 3 prior lines of therapy, n 4/11/5/3 4/6/0/0 Prior radiotherapy, n (%) 18 (78.3) 5 (50.0) Prior surgery, n (%) 21 (91.3) 8 (80.0) Prior systemic therapy,* n(%) 19 (82.6) 6 (60.0) Table 1. Demographics and Baseline Characteristics ECOG PS = Eastern Cooperative Oncology Group performance status; HPV = human papillomavirus * No patient received prior anti-PD-1/L1 or anti-CTLA-4 therapy
RESULTS CONT. Page Table 3. Objective Response Rate: SD-101 8 mg or 2 mg/injection
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HNSCC CONCLUSIONS Page The combination therapy showed encouraging efficacy in patients with HNSCC, with an ORR of 27% Median DOR has not been reached. Some prolonged responses Responses observed in both SD-101 injected and non-injected lesions
SD-101 + PEMBROLIZUMAB CONCLUSIONS Page Why we think SD-101 adds meaningful clinical benefit to pembrolizumab therapy SD-101 in combination with local low dose radiation induced abscopal responses in 80% of patients with indolent non-Hodgkin’s lymphoma 8 mg of SD-101 induces responses in anti-PD-1/L1 refractory and resistant melanoma tumors in 21% of patients In 2 similar patient populations with melanoma naïve to anti-PD-1/L1 therapy treated with the same dose of pembrolizumab, the difference in the groups was the dose of SD-101 they received. In this setting, 2 mg/lesion of SD-101 induces a significantly higher ORR and longer PFS than 8 mg/lesion With responses in PD-L1 negative tumors And biomarker activity that suggests 2 mg is the biologically optimal dose in melanoma compared with 8 mg. In HNSCC, 8 mg of SD-101 appears to induce a higher ORR than pembrolizumab monotherapy SD-101 adds little additional toxicity to pembrolizumab
SD-101 + PEMBROLIZUMAB CONCLUSIONS Page Moving forward: Currently recruiting patients to receive 2 mg in 1 to 4 lesions: Advanced melanoma who have tumors that are refractory or resistant to anti-PD-1/L1 therapy Recurrent or metastatic HNSCC with no prior anti-PD-1/L1 therapy
ACKNOWLEDGEMENTS Page This study was sponsored by Dynavax Technologies Corporation in collaboration with Merck & Co., Inc., Kenilworth, NJ USA. We thank the patients and their families and caregivers for participating in the study; the participating principal investigators and their study teams; Albert Candia, Kavya Kazipeta and Tripta Dahiya for contributions to the analysis of the data (Dynavax Technologies Corporation).