On November 9, 2019 Nektar Therapeutics (Nasdaq: NKTR) reported the presentation of five clinical and preclinical data abstracts focused on its immuno-oncology portfolio at the 2019 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (Press release, Nektar Therapeutics, NOV 9, 2019, View Source [SID1234550836]).

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New clinical results from the PIVOT-02 Phase 1/2 study were shared in an oral presentation titled, "Clinical activity of BEMPEG plus NIVO in previously untreated patients with metastatic melanoma: updated results from the Phase 1/2 PIVOT-02 Study" by Adi Diab, MD, Associate Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center during the Combination Phase 1-2 Clinical Trials Session on Saturday, November 9th.

Additional preclinical data presented at the annual meeting highlighted NKTR-255, an IL-15 agonist discovered by Nektar. The presentations demonstrated that NKTR-255 enhanced activity of antibody-dependent cellular cytotoxicity (ADCC) against tumor cells in vitro, and that it also enhanced in vivo efficacy of ADCC-inducing antibodies in models of human solid tumors. NKTR-255 is designed to engage the IL-15 pathway to stimulate and expand natural killer (NK) cells and promote the survival and expansion of memory CD8+ T cells without inducing suppressive regulatory T cells. NKTR-255 is currently being evaluated in a Phase 1/2 clinical trial in patients with either relapsed or refractory Non-Hodgkin’s lymphoma or multiple myeloma.

"The data presented at this year’s SITC (Free SITC Whitepaper) meeting continue to showcase the potential of our I-O portfolio, most notably our key IL-2 pathway program, bempeg, and our new IL-15 pathway program, NKTR-255," said Jonathan Zalevsky, Ph.D., Senior Vice President and Chief Research & Development Officer at Nektar. "The 18-month follow-up data presentation for the Stage IV melanoma patients in our PIVOT-02 study reinforces the promise of BEMPEG and NIVO to work synergistically to achieve a deepening of response over time, while maintaining a favorable safety and tolerability profile. We’re pleased that at this 18 month timepoint, 85% of patients who achieved responses have ongoing responses and median PFS has not yet been reached."

Highlights from Dr. Diab’s oral presentation include:

18.6 Month Median Follow-Up for First-Line Stage IV Melanoma Cohort in PIVOT-02:
(Response measured by RECIST v1.1 by blinded independent central radiology (BICR) review for 38 efficacy-evaluable patients per protocol, which were treated at the recommended Phase 2 dose in PIVOT-02 and with >1 on treatment scan. Data cut as of September 25, 2019):

At a median time of follow-up of 18.6 months, confirmed objective response rate (ORR) was 53% (20/38) in efficacy-evaluable patients, with 34% (13/38) of patients achieving confirmed complete responses (CR). 42% (16/38) of patients achieved a maximum reduction of 100% in target lesions. DCR, also known as disease control rate (CR+ Partial Response + Stable Disease), was 74% (28/38).
Median time to response was 2.0 months and median time to complete response was 7.9 months.
Median percent reduction of target lesions from baseline was 61.5%.
At a median time of follow-up of 18.6 months, median duration of response has not been reached and 85% (17/20) of patients with responses had ongoing responses.
Among the 35 patients with known baseline PD-L1 status, ORR in PD-L1 negative patients was 5/13 (39%) and in PD-L1 positive patients was 14/22 (64%).
At a median time of follow-up of 18.6 months, the Kaplan-Meier estimate of median progression-free survival (PFS) was not reached (95% CI: 5.3, NE).
BEMPEG plus NIVO is well tolerated, and treatment-related adverse events are predictable and transient, similar to what was previously reported at ASCO (Free ASCO Whitepaper) 2019.
In August of 2019, Bristol-Myers Squibb and Nektar Therapeutics announced that the U.S. Food and Drug Administration has granted Breakthrough Therapy Designation for investigational agent bempegaldesleukin in combination with nivolumab for the treatment of patients with previously untreated unresectable or metastatic melanoma. A Phase 3 trial evaluating bempegaldesleukin in combination with nivolumab, versus nivolumab in first-line advanced melanoma patients, is currently recruiting patients (NCT03635983).

A copy of Dr. Diab’s presentation of PIVOT-02 data is available on Nektar’s corporate website at View Source

Analyst Call with Melanoma Specialist:

Date and Time: Sunday, November 10, 2019 at 9:00 a.m. Eastern Standard Time

Dial-in: 877-881-2183 (toll-free) or 970-315-0453 (international), enter conference ID code 9059428
Investors and analysts can also view slides and listen to the live audio webcast of the presentation at View Source The event will also be available for replay for two weeks on the company’s website, www.nektar.com.

Details of the preclinical poster presentations at SITC (Free SITC Whitepaper) are as follows and each will be available for download at the time of presentation at View Source

Abstract P619: "NKTR-255, a polymer-conjugated IL-15 receptor agonist, enhances efficacy of therapeutic monoclonal antibodies with ADCC activity in solid tumor models", Kivimäe, S., et al.

NKTR-255 treatment of NK cells enhanced activity of antibody-dependent cellular cytotoxicity (ADCC) against tumor cells in vitro, and in vivo efficacy of ADCC-inducing antibodies in human solid tumor xenograft models.
In tumor models resistant to single agent treatment (cetuximab or trastuzumab), combination treatment with NKTR-255 showed tumor growth inhibition, suggesting potential for increased response rates of ADCC targeted therapies.
Abstract P622: "Characterization and comparison of NKTR-255, a polymer-conjugated IL-15 versus IL-15 superagonist", Miyazaki, T., et al.

NKTR-255, a novel IL-15R alpha-dependent cytokine, demonstrated enhanced pharmacokinetic and pharmacodynamic properties relative to the native IL-15 cytokine, and may have the potential to capture the full spectrum of native IL-15 biology.
NK cells treated with NKTR-255 showed more rounds of division than those treated with the IL-15 superagonist at the highest concentration.
Abstract P623: "Bempegaldesleukin in combination with local radiation and systemic checkpoint blockade induces a robust systemic anti-tumor immunity", Pieper, A., et al.

Bempeg in combination with low-dose radiation therapy (RT) and checkpoint blockade with anti-CTLA-4 caused primary tumor regression and resulted in greater overall survival than pairing bempeg with anti-CTLA-4 or RT, or combining bempeg, RT and anti-CTLA-4 with T cell depleting antibodies.
Bempeg with RT and anti-CTLA-4 could mount a T cell-dependent anti-tumor response capable of regressing large, unresectable tumors and disseminated, heterogenous metastatic disease in murine melanoma models.
Details of the Trials in Progress poster presentation are as follows:
Abstract P387: "A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-resistant Prostate Cancer (PORTER)", Nissola, L., et al.

PORTER is an open-label, non-randomized, exploratory platform study designed to assess the safety and antitumor activity of multiple immunotherapy combinations of bempeg plus NIVO vs. CDX-301 (Flt3L), poly-ICLC (PAMP-adjuvant), NIVO and stereotactic body radiation therapy in participants with metastatic castration-resistant prostate cancer who have received prior secondary androgen inhibition.
The primary endpoint will be safety, as assessed by the incidence and severity of adverse events. The secondary endpoint will be a composite efficacy endpoint. Exploratory endpoints will be responses associated with tissue, blood, and stool biomarkers.
About Bempegaldesleukin (BEMPEG, NKTR-214)
Bempeg is an investigational, first-in-class, CD122-preferential IL-2 pathway agonist designed to provide rapid activation and proliferation of cancer-killing immune cells, known as CD8+ effector T cells and natural killer (NK) cells, without over activating the immune system. The agent is designed to stimulate these cancer-killing immune cells in the body by targeting CD122-specific receptors found on the surface of these immune cells. CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these effector T cells.1 In clinical and preclinical studies, treatment with bempegaldesleukin resulted in expansion of these cells and mobilization into the tumor micro-environment.2,3 Bempegaldesleukin has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.

About NKTR-255
NKTR-255 is an IL-15 receptor agonist designed to activate the IL-15 pathway and expand NK cells and promote the survival and expansion of memory CD8+ T cells without inducing suppressive regulatory T cells. Through optimal engagement of the IL-15Rα/IL-2Rβγ receptor complex, NKTR-255 enhances formation of long-term immunological memory, which may lead to sustained anti-tumor immune response. NKTR-255 is uniquely designed to overcome the challenges of recombinant IL-15, which is rapidly cleared from the body and must be administered frequently and in high doses, limiting its utility due to toxicity and convenience of use.

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