On November 9, 2019 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical stage targeted oncology company, reported the presentation of initial data from its ongoing Phase 2 clinical trial of sitravatinib in combination with nivolumab (OPDIVO) in metastatic urothelial cancer (mUC) patients with documented progression on a platinum-chemotherapy and checkpoint inhibitor (Press release, Mirati, NOV 9, 2019, View Source [SID1234550835]). The data were presented in an oral presentation at the Society of Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 34th Annual Meeting in National Harbor, MD. Preliminary results from the ongoing Phase 1 study of neoadjuvant sitravatinib combined with nivolumab in patients with resectable squamous cell carcinoma of the oral cavity (SNOW trial) were also presented in a poster session.

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"Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, Mer), that has the potential to increase responsiveness in patients whose tumors are resistant to checkpoint inhibitors. The initial efficacy data from the Phase 2 clinical trial presented today in patients with checkpoint refractory mUC is promising and extends the clinical benefit data beyond what has already been demonstrated by sitravatinib combined with nivolumab in checkpoint refractory non-small cell lung cancer (NSCLC)," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer of Mirati. "In addition, we are evaluating sitravatinib in patients who have progressed on checkpoint therapy, including those with NSCLC and renal cell cancer, and we continue to expand development efforts of sitravatinib through our collaboration with BeiGene in multiple indications including NSCLC, renal cell cancer, hepatocellular cancer, ovarian cancer, and gastric cancer."

The ongoing Phase 2 clinical trial, an open-label, multi-cohort trial, is enrolling patients with advanced or metastatic urothelial cancer who had been previously treated with a platinum-chemotherapy and checkpoint inhibitor and had documented disease progression. Data from Cohort 1 of the trial were presented, where patients must have also received prior platinum-based chemotherapy. Trial objectives included tumor regression, safety and pharmacokinetics.

As of the data cut-off date of October 17, 2019, 22 patients were evaluable for response with at least one radiographic scan:

6/22 evaluable patients achieved a confirmed Complete Response (CR, 1 patient) or Partial Response (PR, 5 patients).
21/22 evaluable patients achieved a CR, PR or stable disease.
4 responding patients have been treated for more than 6 months.
The combination has been well-tolerated and most adverse events (AEs) were Grade 1 or 2.

Additionally, preliminary results from the Phase 1 SNOW trial (sitravatinib and nivolumab in oral cavity cancer window of opportunity study) were shown in a poster presentation. The preliminary data suggest that the combination of neoadjuvant sitravatinib and nivolumab is safe and active in patients with squamous cell carcinoma of the oral cavity who are candidates for resection. As of the data cut-off date of October 9, 2019, 9 patients had been enrolled (1 is active and 8 are in follow-up). Tumor reduction was observed in all eight patients who were eligible for evaluation, including one complete pathological response. All patients received postoperative radiation therapy, and none required postoperative chemotherapy. With a median follow-up of 31.4 weeks, all patients are alive with no disease recurrence to date. In most patients, treatment with sitravatinib led to a decrease in myeloid-derived suppressor cells and a shift towards M1-type macrophages in the tumor microenvironment, supporting previous preclinical findings.

About Sitravatinib

Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being evaluated in combination with nivolumab (OPDIVO), an anti-PD-1 checkpoint inhibitor, in patients whose cancers have progressed despite treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.

On November 9, 2019 -Five Prime Therapeutics, Inc. (NASDAQ: FPRX), a clinical-stage biotechnology company focused on developing immune modulators and precision therapies for solid tumor cancers, reported initial safety data from the Phase 1 clinical trial of FPT155 in patients with advanced solid tumors in a poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 34th Annual Meeting in National Harbor, Maryland (Press release, Five Prime Therapeutics, NOV 9, 2019, View Source [SID1234550830]). The poster can be found on the Publications Page of the Five Prime Therapeutics website.

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"FPT155 is a first-in-class CD80 fusion protein with potential dual mechanisms to activate T cells," said Helen Collins, M.D., Executive Vice President and Chief Medical Officer of Five Prime Therapeutics. "Importantly, the initial safety results for FPT155 suggest that it may not cause the same safety issues seen with a prior molecule targeting CD28. This allows us to continue enrolling patients to study additional dose escalation cohorts and identify a dose for future studies."

The FPT155 data presented at SITC (Free SITC Whitepaper) included initial safety results from the Phase 1a dose escalation portion of the trial, which is designed to characterize the safety and pharmacokinetic (PK)/pharmacodynamic (PD) profile of FPT155 and identify a recommended dose for the Phase 1b portion of the trial. This included data from 15 patients with solid tumors that were treated with FPT155 at doses of 0.07 mg, 0.21 mg, 0.7 mg, 2.1 mg, 7 mg, 21 mg, and 42 mg. The key highlights from the presentation include:

FPT155 was well tolerated at all dose levels, with no dose-limiting toxicities and no grade 4 or higher adverse events.
There is no evidence of clinical or laboratory cytokine release syndrome, an adverse event associated with a prior therapy targeting CD28.
Dose escalation with FPT155 is ongoing with the study currently enrolling patients at the 70 mg dose level.
The Phase 1a/1b open-label, multicenter, dose escalation, dose exploration and dose expansion study will evaluate the safety and tolerability of FPT155 in patients with advanced solid tumors. The Phase 1a dose escalation portion of the trial will characterize the safety and PK/PD profile of FPT155 and will identify a recommended dose for the Phase 1b portion of the trial. The Phase 1b portion of the trial is intended to further characterize the safety, PK/PD profile, and preliminary efficacy of FPT155.

About FPT155

FPT155 is a first-in-class CD80 fusion protein that (i) directly engages CD28 to enhance its co-stimulatory T-cell activation activity without inducing super agonism, and (ii) blocks CTLA-4 from competing for endogenous CD80, allowing CD28 signaling to prevail in T-cell activation in the tumor microenvironment. FPT155 has also demonstrated its ability to retain anti-tumor activity independent of its engagement with CTLA-4, suggesting a differentiated mechanism of action from CTLA-4-blocking antibodies. Studies in preclinical models suggest FPT155 has the potential to be a potent T-cell co-stimulator with strong monotherapy anti-tumor activity.

On November 9, 2019 Bolt Biotherapeutics, Inc., a private biotechnology company focused on using its Immune-Stimulating Antibody Conjugate (ISAC) platform technology to unleash the power of the immune system to treat cancer, reported new preclinical data demonstrating profound antitumor efficacy for its lead HER2 ISAC therapeutic program, when administered as a monotherapy, resulting in the complete eradication of large tumors (Press release, Bolt Biotherapeutics, NOV 9, 2019, View Source [SID1234550814]). The poster presentation entitled "HER2-targeting TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation and anti-tumor immune responses in a TLR- and FcR- dependent manner" was presented at the 34th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) in National Harbor, Maryland.

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"These exciting preclinical data provide a strong rationale for moving our ISAC cancer immunotherapy platform into clinical testing and I’m pleased to report that we expect to initiate our first clinical trial for our HER2 monotherapy in early 2020," stated Randall Schatzman, Ph.D., chief executive officer of Bolt. "While much progress has been made in cancer immunotherapy, there still remains a significant need for single-agent therapies that can impact well-established tumors and provide durable efficacy in tumors that are refractory to standard of care therapies. Our proprietary Boltbody ISACs embody all of these components, and we are highly optimistic about the future of this platform to impact cancer."

"We believe such profound antitumor activity is unprecedented, including complete tumor eradication in large tumors, with an immunotherapeutic systemically administered as a monotherapy," stated David Dornan, Ph.D., senior vice president of research at Bolt Biotherapeutics. "Our data define the details of the mechanism of action by which our Boltbody technology is able to eliminate these hard to treat solid tumors, while generating immunological memory to suppress recurrence."

In the series of studies presented at SITC (Free SITC Whitepaper), key preclinical data show:

ISAC antitumor activity requires tumor target expression, interaction with Fc gamma receptors on immune cells, and TLR7/8 engagement
Single-agent anti-HER2 ISAC treatment led to in vivo tumor regression and clearance in models with large tumor burden and are resistant to anti-HER2 naked antibody treatment
Immunological memory was achieved as measured by protection from subsequent tumor growth. In syngeneic tumor models in which anti-HER2 ISAC treatment led to tumor clearance, hosts that were re-challenged with the parental tumor cell line lacking HER2 antigen expression were resistant to tumor growth. This protection was mediated by T cells as evidenced by the ability to re-establish tumors after the deletion of CD4 and CD8 T cells.
About Bolt Biotherapeutics’ Immune-Stimulating Antibody Conjugate (ISAC) Platform Technology
The Boltbody platform consists of Immune-Stimulating Antibody Conjugates (ISAC) that harness the ability of innate immune agonists to convert cold tumors into immunologically hot tumors thereby illuminating tumors to the immune system and allowing them to be invaded by tumor killing cells. Boltbody ISACs have demonstrated the ability to eliminate tumors following systemic administration in preclinical models and have also led to the development of immunological memory, which is predicted to translate into more durable clinical responses for patients.

On November 9, 2019 Rakuten Medical, Inc. (RMI) a clinical-stage, global biotechnology company developing precision-targeted cancer therapies based on Rakuten Medical’s Illuminox, its proprietary, anti-cancer treatment platform, reported new preclinical data suggesting CD25 photoimmunotherapy (PIT) treatment, combined with an anti-PD1 therapy, may stimulate the immune system, and lead to a synergistic, anti-cancer activity in targeted tumors (Press release, Rakuten Medical, NOV 9, 2019, View Source [SID1234550813]).

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"These exciting data suggests that anti-CD25 photoimmunotherapy may alter the immune tumor environment and unlock the potential of combination immunotherapies for patients living with certain types of cancers for which there are few treatment options," said Miguel Garcia-Guzman, Ph.D., Vice Chairman and Chief Scientific Officer at Rakuten Medical. "We are committed to harnessing the full potential of the immune system through modulation of the cancer tumor environment, and these results support our clinical development program based on our anti-cancer treatment platform, Rakuten Medical’s Illuminox."

The preclinical data were showcased during a poster presentation during the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 34th annual meeting:

"Intratumoral depletion of regulatory T-cells using CD25 targeted photoimmunotherapy elicits anti-cancer immune activity and synergizes with PD1 checkpoint blockade in immunocompetent mouse models." (Abstract P774), presented by Jerry J. Fong, Cancer Biology and Pharmacology, Rakuten Medical.

The poster discusses intratumoral depletion of regulatory T-cells (Tregs), a significant source of immune suppression, with an anti-CD25-IR700 conjugate therapy using PIT. Anti-cancer activity and subsequent immune responses following anti-CD25-IR700 PIT treatment, administered alone or in combination with anti-PD1 treatment, were evaluated in immunocompetent mouse models. Key highlights from the studies include:

Rapid and significant reduction of intratumoral Tregs, eliciting significant anti-cancer activity
An increase of non-exhausted T-cells following a single treatment, suggesting systemic activation and intratumoral recruitment of new CD8 T-cells from the periphery
Significant enhancement of anti-cancer activity in vivo, as demonstrated by percentage of mice achieving complete responses (CRs) with combination treatment in comparison to animals receiving one treatment alone
Durable increase of intratumoral CD8 T-cell/Treg ratio
Enhanced systemic adaptive immune responses and induced abscopal anti-cancer effects in a CD8 T-cell dependent manner
Tumor-specific immune memory response as demonstrated by systemic tumor-antigen-specific cytotoxic lymphocytes expansion and prevention of new tumor growth in CR mice
Combination treatment enhanced systemic adaptive immune responses and induced abscopal anti-cancer effects in a CD8 T-cell dependent manner

On November 9, 2019 Pieris Pharmaceuticals, Inc. (NASDAQ: PIRS), a clinical-stage biotechnology company advancing novel biotherapeutics through its proprietary Anticalin technology platform for respiratory diseases, cancer, and other indications, reported the presentation of data from the phase 1 dose-escalation monotherapy study of PRS-343, a 4-1BB/HER2 bispecific for the treatment of HER2-positive solid tumors, in a late-breaking oral presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting. PRS-343 demonstrated single-agent anti-tumor activity, including partial responses, in heavily pre-treated patients across multiple HER2-positive tumors (Press release, Pieris Pharmaceuticals, NOV 9, 2019, View Source [SID1234550812]). Beyond demonstrating clinical benefit, PRS-343 showed a potent increase in CD8+ T cell numbers and proliferative index in the tumor microenvironment of responders, indicative of 4-1BB agonism on T cells. PRS-343 was safe and well tolerated at all doses and schedules tested.

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"The data presented today demonstrate PRS-343’s potential to make a meaningful difference for patients with tumors that are difficult to treat with currently-available therapies," said Geoffrey Y. Ku, medical oncologist at Memorial Sloan Kettering and the principal investigator for the PRS-343 monotherapy trial. "Beyond today’s presentation, I look forward to sharing some of these case studies at Pieris’ upcoming R&D day alongside emerging data from the study of PRS-343 in combination with atezolizumab."

The ongoing phase 1 first-in-human, open-label multicenter trial has enrolled 53 patients, including 19 patients with gastric cancer, 14 patients with breast cancer, 6 patients with gynecological cancers, and 14 patients with other tumor types. Eleven dose cohorts have been evaluated at a Q3W dosing schedule, with the 11th dose level (8 mg/kg) also being evaluated at a Q2W dosing schedule. Pre- and post- treatment biopsies were obtained from many of the patients. Trial objectives include evaluation of safety and tolerability, characterizing the pharmacokinetic profile, assessing pharmacodynamic and potential immunogenicity effects, and investigating clinical response.

As of the cut-off date of October 23, 2019, 18 patients were evaluable for a response at active dose levels, which began at cohort 9 (2.5 mg/kg).

At the 8 mg/kg Q2W dose level, one patient with stage 4 gastric adenocarcinoma and one patient with stage 4 gynecological carcinoma achieved confirmed partial responses; the remaining patients experienced stable disease, for an overall disease control rate of 100% in this cohort as best response.
Across the remaining active dose levels and schedules, an additional five patients experienced stable disease.
Biomarker data from post-treatment tumor biopsies in patients receiving active dose levels and showing clinical benefit reflected a pronounced increase in CD8+ T cell numbers.
As of the cutoff date, treatment duration across active dose levels is over 30 weeks.
Treatment-related adverse events (AEs) were primarily grade 1 and 2. The most common AEs were infusion related reactions and fatigue. No patients experienced a dose-limiting toxicity and a maximum tolerated dose has not been reached.
"In addition to being the first 4-1BB bispecific to enter the clinic, PRS-343 is our lead immuno-oncology asset, and we believe this dataset serves as early clinical validation of our 4-1BB-targeting immuno-oncology approach and the Anticalin bispecific platform," said Stephen S. Yoder, President and Chief Executive Officer of Pieris. "PRS-343 shows promising signs of efficacy linked to clear biomarker evidence of 4-1BB agonism, in addition to being safe and well tolerated. We look forward to concluding this escalation trial in the near term and initiating an expansion trial informed by the emerging data. We also look forward to initiating clinical development of our 4-1BB/PD-L1 bispecific, PRS-344, with Servier in the first half of next year."