On April 10, 2021 Zymeworks Inc. (NYSE: ZYME), a clinical-stage biopharmaceutical company developing multifunctional biotherapeutics, reported five presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Zymeworks, APR 10, 2021, View Source [SID1234577826]). The presentations highlight preclinical data that reveal new insights into the unique mechanisms of action of lead clinical candidate, zanidatamab, introduce Zymeworks’ fourth therapeutic platform, ProTECT, and describe two new preclinical assets focused on the cytokine, IL-12, and the immune-oncology target, 4-1BB.

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This press release features multimedia. View the full release here: View Source

Presentations are now available to registrants of the AACR (Free AACR Whitepaper) Annual Meeting and will also be archived on the Zymeworks website.

Zanidatamab Presentations

Super-resolution imaging studies of zanidatamab: providing insights into its bispecific mode of action

Abstract: 1032
Session Category: Experimental and Molecular Therapeutics
Session Title: Cellular Responses to Anticancer Drugs

The bispecific antibody zanidatamab’s (ZW25’s) unique mechanisms of action and durable anti-tumor activity in HER2-expressing cancers

Abstract: 1005
Session Category: Experimental and Molecular Therapeutics
Session Title: Cellular Responses to Anticancer Drugs

Zanidatamab, Zymeworks’ lead clinical candidate, is currently enrolling in a pivotal trial for refractory HER2-amplified biliary tract cancer (HERIZON-BTC-01) as well as several Phase 2 trials for HER2-expressing gastroesophageal and breast cancers. Zanidatamab is a bispecific antibody that simultaneously binds two distinct sites on HER2 resulting in multiple mechanisms of action. Research presented today at AACR (Free AACR Whitepaper) continues to demonstrate that zanidatamab induces the formation of HER2 receptor clusters and receptor internalization resulting in their downregulation, inhibits growth factor-dependent and -independent tumor cell proliferation, and potently activates the immune system via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). New findings from this research have revealed that zanidatamab can form complexes with HER2 with distinct higher order geometry on the cell surface. The potential for zanidatamab-induced HER2 localization may promote C1q engagement and is consistent with the additional finding that zanidatamab has the unique ability to promote complement dependent cytotoxicity (CDC). This was not observed with either of the HER2-targeted monospecific antibodies, trastuzumab and pertuzumab, or their combination and may contribute to zanidatamab’s promising clinical activity.

"In addition to the broad clinical validation of zanidatamab, we continue to value ongoing research designed to better understand its unique biparatopic mechanisms of action," said Ali Tehrani, Ph.D., Zymeworks’ President & CEO. "These findings provide important insights for our clinical development strategy and support our goal of developing zanidatamab in earlier lines of therapy where the combination of trastuzumab and pertuzumab are the backbone of the current standard of care."

ProTECT Presentation

ProTECT, a novel antibody platform for integrating tumor-specific immune modulation and enhancing the therapeutic window of targeted multispecific biologics

Abstract: 924
Session Category: Experimental and Molecular Therapeutics
Session Title: Antibody Technologies

The ProTECT platform is the first conditionally-active antibody technology that can simultaneously address both ends of the therapeutic window by potentially reducing toxicity and increasing efficacy. Functional, natural heterodimers (e.g. PD-1/PD-L1) are introduced to sterically block antigen binding outside the tumor. As a result, therapeutics utilizing ProTECT have limited activity in normal healthy tissue, avoiding on-target, off-tumor toxicities. Once in the tumor microenvironment, proteases cleave and release one half of the functional block activating both the targeting antibody and the immunomodulatory function. The resulting activated multifunctional therapeutic enables immune modulation in concert with antigen binding, leading to an overall increase in the therapeutic window through selective tumor activity and enhanced potency. This platform is also transferable with minimal engineering so it can be easily applied to different therapeutic targets. Data presented today at AACR (Free AACR Whitepaper) showcase the utility of the ProTECT platform for the generation of a first-in-class CD3-redirecting multispecific that also comprises PD-L1 checkpoint blockade.

IL-12 and 4-1BB Presentations

Increasing the therapeutic index of IL-12 by engineering for tumor-specific protease activation

Abstract: 1788
Session Category: Immunology
Session Title: Modifiers of the Tumor Microenvironment

IL-12 is a cytokine produced by innate immune cells that potently stimulates anti-tumor cytotoxic T cell, T helper cell, and natural killer cell-mediated immunity. The use of IL-12 as a therapeutic approach has historically been limited by systemic toxicity observed in clinical trials, and current approaches to address this toxicity have focused on reducing the potency of IL-12, which may also limit its anti-tumor activity. To broaden the therapeutic window of this highly potent cytokine, systemic IL-12 activity was blocked with an anti-IL-12 antibody which was designed to be cleaved and released by proteases in the tumor microenvironment. Data presented at AACR (Free AACR Whitepaper) show that the therapeutic window of IL-12 may be increased by the combination of antibody blockade and cytokine modifications that synergize to localize activity to the tumor.

Understanding the geometry and valency of bispecific antibodies in the optimization of tumor-dependent activation of 4-1BB

Abstract: 1737
Session Category: Immunology
Session Title: Immunomodulatory Agents and Interventions

4-1BB is a receptor expressed on the surface of tumor-infiltrating T cells that when activated, can enhance T cell function leading to tumor regression. Unfortunately, the clinical development of several 4-1BB targeting antibodies has been plagued by dose-limiting liver toxicity and subsequent lack of anti-tumor activity. To address this liability, multiple formats of 4-1BB x TAA (tumor associated antigen) bispecific candidates were developed to identify those that could selectively activate T cells within the tumor microenvironment. A promising bispecific format with bivalent 4-1BB targeting and monovalent TAA targeting demonstrated the highest potential for tumor selectivity across several different TAAs and was subsequently evaluated in an in vivo xenograft model where it showed robust anti-tumor activity.

"The presentations highlighted at the AACR (Free AACR Whitepaper) Annual Meeting showcase Zymeworks’ proprietary protein engineering capabilities and how they are being used to develop solutions for a broad set of therapeutic modalities," said Tony Polverino, Ph.D., Executive Vice President, Early Development and Chief Scientific Officer of Zymeworks. "Leveraging different approaches to achieve tumor selective activity, from the functional block of the ProTECT platform, to the antibody block used in our IL-12 cytokine candidates, to the use of format and valency in our 4-1BB program, we’ve demonstrated several versatile ways to increase the therapeutic window of our drug candidates. We continue to exploit these approaches along with our bispecific, antibody-drug conjugate, and immunomodulatory platforms to build a diverse therapeutic pipeline."

About Zanidatamab

Zanidatamab is a bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding, and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks is developing zanidatamab in multiple Phase 1, Phase 2, and pivotal clinical trials globally as a targeted treatment option for patients with solid tumors that express HER2. The FDA has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified Biliary Tract Cancer (BTC), and two Fast Track designations to zanidatamab, one as a single agent for refractory BTC and one in combination with standard of care chemotherapy, for first-line gastroesophageal adenocarcinoma (GEA). These designations mean zanidatamab is eligible for Accelerated Approval, Priority Review and Rolling Review, as well as intensive FDA guidance on an efficient drug development program. Zanidatamab has also received Orphan Drug designations for the treatment of biliary tract, gastric and ovarian cancers, as well as Orphan Drug designation for the treatment of gastric cancer from the European Medicines Agency.

On April 10, 2021 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that Phase 1 clinical data from studies exploring Rubraca in combination with Xtandi for the treatment of advanced prostate cancer (RAMP) and Rubraca monotherapy in advanced solid tumors in Japanese patients (RUCA-J) will be presented during week one of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (AACR) (Free AACR Whitepaper), taking place April 10-15, 2021 (Press release, Clovis Oncology, APR 10, 2021, View Source [SID1234577825]).

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"We remain committed to understanding how Rubraca may benefit patients with cancer, and the data presented at AACR (Free AACR Whitepaper) further enhance our understanding in different patient populations and solid tumor types," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "The Phase 1b RAMP data for the combination of Rubraca and Xtandi in unselected mCRPC patients help inform the Alliance for Clinical Oncology-sponsored CASPAR Phase 3 trial which is expected to begin enrolling patients soon, and we look forward to learning more about the combination."

Following are details of the Clovis-sponsored presentations at AACR (Free AACR Whitepaper) 2021:

Poster Presentation 445: Genomic Characteristics and Response to Rucaparib and Enzalutamide in the Phase 1b RAMP Study of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients

Lead author: Arpit Rao, MBBS, University of Minnesota, Minneapolis, USA
Session: Clinical Research
Date/Time: April 10, 2021, 8:30 a.m. – 11:59 p.m. ET
Key Takeaways: The results of this study demonstrated that unselected patients with mCRPC who had progressed on androgen receptor (AR)-directed therapies reported declines in prostate-specific antigen (PSA) following treatment with a combination of rucaparib 600 mg twice daily and enzalutamide 160 mg once daily, and these declines were observed even in the presence of AR alterations and the absence of DNA damage repair gene alterations. The safety profile was consistent with that associated with each drug as a monotherapy, with no clinically significant drug-drug interactions observed with the combination. These data support further study of the combination in this patient population and the Phase 3 CASPAR study (Alliance A031902; NCT04455750) is expected to begin enrolling biomarker-unselected patients with mCRPC shortly.
Poster Presentation CT124: Evaluation of Rucaparib in Japanese Patients with a Previously Treated Advanced Solid Tumor

Lead author: Kenji Tamura, MD, PhD, National Cancer Center Hospital, Tokyo, Japan
Session: Phase I Clinical Trials
Date/Time: April 10, 2021, 8:30 a.m. – 11:59 p.m. ET
Key Takeaways: This study suggests rucaparib 600 mg taken twice daily had a manageable safety profile for Japanese patients with advanced solid tumors, including ovarian, prostate, endometrial, and pancreatic cancer. The pharmacokinetic profile of rucaparib in Japanese patients overlapped with that of Western patients. Among patients with measurable disease, 18.5% (5/27) achieved an objective response rate and 51.9% (14/27) had stable disease per RECIST v1.1. These results support further exploration of rucaparib 600 mg twice daily in Japanese patients.
The presentations can also be viewed at View Source .

About Rubraca (rucaparib)

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Rubraca U.S. FDA Approved Indications

Ovarian Cancer

Rubraca is indicated for the maintenance treatment of adult women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Rubraca is indicated for the treatment of adult women with a deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca.

Prostate Cancer

Rubraca is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. Patients should be identified for treatment with Rubraca based on the presence of a deleterious BRCA mutation (germline and/or somatic) and selected for therapy based on an FDA-approved companion diagnostic for Rubraca. This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with Rubraca, and are potentially fatal adverse reactions. In 1146 treated patients, MDS/AML occurred in 20 patients (1.7%), including those in long term follow-up. Of these, 8 occurred during treatment or during the 28 day safety follow-up (0.7%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 53 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents. In TRITON2, MDS/AML was not observed in patients with mCRPC (n=209) regardless of homologous recombination deficiency (HRD) mutation.

Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca. For males on Rubraca treatment who have female partners of reproductive potential or who are pregnant, effective contraception should be used during treatment and for 3 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).

Most common adverse reactions in TRITON2 (≥ 20%; Grade 1-4) were fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT elevation (33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%).

Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.

Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose.

On April 10, 2021 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biopharmaceutical company focused on novel and targeted oncology therapies, reported a data update on the safety and tolerability of twice daily (BID) administered poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations (Press release, Spectrum Pharmaceuticals, APR 10, 2021, View Source [SID1234577824]). These preliminary data, from Cohort 5 of the ZENITH20 clinical trial, continue to show improved tolerability with BID dosing, reduced dose interruption compared to once daily (QD) dosing, and a reduction in treatment emergent Grade 3 or higher adverse events. The preliminary data also demonstrate improved anti-tumor activity with 8mg BID dosing. The presentation is part of the AACR (Free AACR Whitepaper) Virtual Meeting 2021 taking place April 10-15, 2021.

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"The 8mg BID dosing arm is showing the best performance we have seen across the various dosing arms for a mixed population of EGFR and HER2 exon 20 insertion mutations in NSCLC patients. There is clearly an improved therapeutic effect and a lower adverse event rate which is highly encouraging," said Francois Lebel, M.D., Chief Medical Officer of Spectrum Pharmaceuticals. "We are currently expanding the 8mg BID dataset and look forward to evaluating this dose in additional NSCLC patients and other solid tumors."

A copy of the AACR (Free AACR Whitepaper) presentation titled "Poziotinib administered twice daily improves safety and tolerability in patients with EGFR or HER2 exon 20 mutations" is available on Spectrum’s website at View Source

ZENITH20 Trial Design and Preliminary Safety and Efficacy Data for Cohort 5

Cohort 5 of the ZENITH20 trial includes previously treated NSCLC patients with EGFR or HER2 exon 20 insertion mutations. This cohort is investigating the efficacy of poziotinib with various dosing levels including BID administration. For the 38 patients randomized to poziotinib 16mg QD or 8mg BID in Cohort 5, improved responses were reported in the BID arm with 31.6% of patients (6/19) reaching a partial response. For the 38 patients randomized to poziotinib 12mg QD or 6mg BID, these dosing levels were not as active as 8mg BID but showed improved tolerance with BID dosing relative to QD dosing.

Improved tolerability was also observed for the typical TKI related adverse events, with a clinically meaningful reduction in Grade 3 or higher adverse events for the 8mg BID dose relative to 16mg QD. In addition, there were fewer dose interruptions and dose reductions for the BID arms relative to the same QD dose. Cohort 5 is now enrolling exclusively in the 8mg BID arm and data collection is ongoing.

About Poziotinib

Poziotinib is a novel, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that inhibits the tyrosine kinase activity of EGFR as well as HER2 and HER4. Importantly this, in turn, leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer. The company holds an exclusive license from Hanmi Pharmaceuticals to develop, manufacture, and commercialize poziotinib worldwide, excluding Korea and China. Poziotinib is currently being investigated by the company and Hanmi in several mid-stage trials in multiple solid tumor indications.

On April 10, 2021 Greenwich LifeSciences, Inc. (Nasdaq: GLSI) (the "Company"), a clinical-stage biopharmaceutical company focused on the development of GP2, an immunotherapy to prevent breast cancer recurrences in patients who have previously undergone surgery, reported a poster of the final 5 year GP2 Phase IIb clinical trial immune response data at the 2021 AACR (Free AACR Whitepaper) Annual Meeting (Press release, Greenwich LifeSciences, APR 10, 2021, View Source [SID1234577823]). Immune response is the primary mechanism of action for GP2 and is critical to developing dosing and booster treatment strategies that are designed to achieve and sustain peak immunity, as well as to prevent metastatic breast cancer recurrences.

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It has been previously reported that the completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients who had received a standard course of trastuzumab after surgery. The abstract and poster present the final immune response results over the 5 year follow-up period, assessing peak immunity compared to baseline and between patients treated with GP2+GM-CSF versus GM-CSF alone, including by HER2 status.

Summary of the Final 5 Year Immune Response Data as Previously Presented:

Potent immune response data supports the previously reported clinical outcome of 0% metastatic breast cancer recurrences over 5 years of follow up, if a patient completes the Primary Immunization Series over the first 6 months of GP2 treatment.
Statistically significant peak immunity was reached after 6 months of GP2 treatment as measured in both the Dimer Binding Assay and the DTH skin test.
HER2 3+ population immune response was similar to the HER2 1-2+ population immune response, suggesting the potential to treat the HER2 1-2+ population (including triple negative breast cancer) with GP2 immunotherapy in combination with trastuzumab (Herceptin) based products and other clinically active agents.
Broad based immune response suggests that GP2 immunotherapy and Herceptin based products may also have the potential to treat other HER2 1-3+ expressing cancers.
Dr. Thompson commented, "The analysis of the immune response data in the Phase IIb trial provides mechanistic confirmation of treatment effect correlated with the clinical response previously reported. GP2 treated patients, independent of their HER2 status, experienced a potent immune response to GP2, far greater than patients treated with placebo. In addition, this data has provided us with insight that will guide the upcoming Phase III trial. We believe that monitoring immune response will be an important aspect of the Phase III trial."

Excerpts from the AACR (Free AACR Whitepaper) Poster CT183:

Title: Final five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating a time series of immune responses using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Each GP2 treated patient was scheduled to receive 6 intradermal injections with GP2+GM-CSF over the first 6 months of treatment as part of the Primary Immunization Series and 4 boosters every 6 months thereafter. Placebo patients received intradermal injections with GM-CSF alone.

Immune responses to GP2 were measured over time using a CD8 T cell dimer binding assay (Dimer Binding Assay) and delayed-type-hypersensitivity (DTH) skin tests. The Dimer Binding Assay detects the percentage of GP2 specific killer T cells that can kill recurring cancer cells. The DTH skin test measures the diameter of the skin immune response to GP2 in millimeters 48-72 hours after injection of GP2 without GM-CSF.

Figure 1 of the poster shows that GP2 immunity peaked at 6 months in HER2 3+ patients after they completed their first 6 immunizations, as measured by the Dimer Binding Assay. The data also shows that for the 2.5 years that the immune response was measured, the immunity was sustained and remained above baseline, resulting in 100% disease free survival (0% recurrence rate) over 5 years. In the placebo arm, the immune response was not as robust, resulting in 89% disease free survival (11% recurrence rate). Immune response in GP2-treated patients increased quickly during the Primary Immunization Series and remained statistically significantly above baseline for 6 months after the completion of the Primary Immunization Series. Some patients received boosters beginning at 12 months and the immune response was assessed one month after the receiving the booster.

Dimer Binding Assay: The Dimer Binding Assay detects the percentage of GP2 specific killer T cells that can kill recurring cancer cells. Ex vivo immune response was assessed over 2.5 years with blood draws at baseline, then after the 3rd and 6th immunizations in the Primary Immunization Series, and then after each booster. Immune responses were assessed by phenotypic clonal expansion assays in the majority of patients (n=113). GP2-specific CTLs were quantified in patients treated with GP2 using the Ig:A2 Dimer Assay and demonstrated an expansion over time, showing an increase over baseline after the 3rd immunization and remaining elevated for the entire course of follow-up.

Figure 2 of the poster shows the same Dimer Binding Assay data for HER2 3+ patients as in Figure 1, where the GP2 treated patients showed statistically significant dimer readings versus baseline (pre-vaccination) at 3, 6, and 12-13 months.

DTH Skin Test: The DTH skin test measures the diameter of the skin immune response to GP2 in millimeters, 48-72 hours after intradermal injection of GP2 without GM-CSF. A DTH reaction was used to assess in vivo immune responses in patients (n=150). The DTH orthogonal mean of the skin wheal was measured 48-72 hours after injection using the sensitive ballpoint-pen method and is compared using a Wilcoxon Rank-Sum. For GP2 treated patients, there was a significant increase in DTH reactions after the PIS compared to baseline DTH reactions.

Figure 3A shows that after completion of the 6th immunization after 6 months, GP2 treated patients showed a robust immune response using the DTH skin test, while the placebo did not (p = 0.009). Within GP2 treated patients, the change from baseline after 6 months was a median of 4.8 mm (mean of 11.6 mm), which was a statistically significant increase over baseline (p < 0.0001). The change from baseline in DTH at 6 months was more robust in the GP2 treated patients. Those patients had an 11.6 mm mean increase in DTH after 6 months of exposure while patients treated with GM-CSF alone had a 5.2 mm mean increase (p = 0.023). This DTH data supports the Dimer Binding Assay data that shows a peak immune response after 6 months.

Figure 3B shows that the DTH immune response for GP2 treated patients was similarly robust in HER2 3+ patients and HER2 1-2+ patients, independent of prior trastuzumab treatment and HER2 expression levels. Thus, GP2’s robust immune response in the HER2 1-2+ population suggests the potential to apply GP2 immunotherapy to HER2 low to intermediate expressing breast cancers, as well as to other HER2 1-3+ expressing cancers.

AACR Abstract CT183:

Title: Final five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating a time series of immune responses using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Snehal S Patel, David B McWilliams, Mira S Patel, Christine T Fischette, Jaye Thompson and F Joseph Daugherty.

Greenwich LifeSciences, Stafford, TX

Background: The final analysis of the GP2 prospective, randomized, placebo-controlled, single-blinded, multicenter Phase IIb trial (NCT00524277) investigating GP2+GM-CSF versus GM-CSF alone in HLA-A02 patients administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with HER2 status (IHC 1-3+) is now complete with 5 year follow-up. It has been previously reported that completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients, who received a standard course of trastuzumab after surgery. Here we present the final immune response results, assessing peak immunity compared to baseline and between GP2 treated patients versus placebo, including by HER2 status. Interim analyses for this trial have been previously reported by Mittendorf et al.

Methods: Each GP2-treated patient was scheduled to receive 6 GP2+GM-CSF intradermal injections over the first 6 months as part of the PIS and 4 GP2+GM-CSF booster intradermal injections every 6 months thereafter. Placebo patients received GM-CSF only intradermal injections. Immune responses to GP2 were measured over time using delayed-type-hypersensitivity (DTH) skin tests and CD8 Tcell dimer binding assays.

Results: This basket trial explored HER2 3+ patients, who received a standard course of trastuzumab after surgery, and HER2 1-2+ patients, who did not receive trastuzumab after surgery. A DTH reaction was used to assess in vivo immune responses in patients (n=145). The DTH orthogonal mean was measured 48-72 hours after injection using the sensitive ballpoint-pen method and are compared using a Wilcoxon Rank-Sum. For GP2 treated patients, there was a significant increase in DTH reactions after the PIS compared to baseline DTH reactions. The DTH orthogonal mean in GP2 treated patients at baseline had a median 0.0mm versus 10.8mm after the PIS. For patients receiving GM-CSF alone, the DTH orthogonal mean prior to and after the PIS had a median of 0.0mm. In addition, the DTH reactions after the PIS were significantly greater in GP2 treated patients than in placebo patients (10.8mm vs. 0.0mm, p=0.009) and the DTH immune response in GP2 treated patients was similar between HER2 3+ and HER2 1-2+ patients. Ex vivo immune responses were assessed by phenotypic clonal expansion assays in the majority of patients (n=114). GP2-specific CTLs were quantified using the Ig:A2 dimer assay and demonstrated a gradual expansion over time reaching statistical significance approximately 6 months after the PIS compared to baseline in the GP2 treated patients (n=53, p=0.010) but not in the control patients (n=39, p=0.165).

Conclusions: Immunological data comparing peak immunity to baseline and GP2 treated patients to placebo showed that GP2 treated patients, independent of HER2 status, experienced a significant increase in their immune response while those receiving GM-CSF only did not. Future studies may explore the use of immune responses to assess: immunogenicity of GP2 by HLA type, timing of boosters to sustain immunity, clinical site performance, and the discontinuation of treatment for non-responders.

About the AACR (Free AACR Whitepaper) Annual Meeting 2021

The AACR (Free AACR Whitepaper) is the first and largest cancer research organization dedicated to accelerating the conquest of cancer and has more than 48,000 members residing in 127 countries and territories. The AACR (Free AACR Whitepaper) Annual Meeting program covers the latest discoveries across the spectrum of cancer research — from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy — and highlights the work of the best minds in research and medicine from institutions all over the world.

About Breast Cancer and HER2/neu Positivity

One in eight U.S. women will develop invasive breast cancer over her lifetime, with approximately 266,000 new breast cancer patients and 3.1 million breast cancer survivors in 2018. HER2/neu (human epidermal growth factor receptor 2) protein is a cell surface receptor protein that is expressed in a variety of common cancers, including in 75% of breast cancers at low (1+), intermediate (2+), and high (3+ or over-expressor) levels.

On April 10, 2021 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 a clinical data update from the phase 1 monotherapy study of cinrebafusp alfa (PRS-343), a 4-1BB/HER2 bispecific for the treatment of HER2-expressing solid tumors, in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Congress 2021 (Press release, Pieris Pharmaceuticals, APR 10, 2021, View Source [SID1234577822]). The Company also presented preclinical data for PRS-344/S095012, a 4-1BB/PD-L1 bispecific the Company is developing with Servier, at a poster session at the congress.

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Cinrebafusp Alfa (PRS-343):

Presented data demonstrated additional clinical benefit at the highest dose, including an additional, ongoing confirmed durable partial response, three additional patients with stable disease as best response, and overall durable benefit. Based on clinical benefit and pharmacodynamic correlates, cinrebafusp alfa showed a clear dose response and a 4-1BB-driven mechanism of action. Additionally, clinical benefit was observed in patients with "cold" tumors as well as those with HER2-low expressing tumors. Cinrebafusp alfa continues to be well-tolerated. The Company plans to initiate a phase 2 study in gastric cancer this summer that will evaluate both HER2-high and HER2-low patient settings.

As of the cut-off date of February 25, 2021, 8 patients in the monotherapy trial were evaluable for a response at the highest dose cohort (cohort 13b; 18 mg/kg Q2W) out of a total of 42 response-evaluable patients enrolled in the predicted active dose cohorts (cohort 9 and higher; ≥2.5 mg/kg) in the study.

In cohort 13b, one additional patient (cancer of unknown primary) achieved an ongoing confirmed durable partial response, for an updated overall response rate (ORR) of 25% in that cohort as compared to an ORR of 12% across active dose levels.
In cohort 13b, three additional patients experienced stable disease as best response, for an updated disease control rate (DCR) of 63% in that cohort as compared to a DCR of 52% across active dose levels.
Cinrebafusp alfa activates adaptive and innate immunity in the tumor microenvironment, consistent with intended mode of action as evidenced by post-treatment increases in CD8+ T cells, NK cells and cytotoxic activity.
Dose-dependent increases of CD8+ T cells in the tumor and soluble 4-1BB in the blood of patients demonstrate target engagement and a 4-1BB-driven mode of action.
Cinrebafusp alfa shows preliminary evidence of activity among "cold" tumor types as well as "hot" tumor types.
Activity in HER2-low expressing patients supports continued development of cinrebafusp alfa in that population, which the Company will evaluate in its phase 2 gastric cancer study.
Cinrebafusp alfa monotherapy appeared to be well-tolerated up to 18 mg/kg, with no significant specific anti-HER2 or anti-4-1BB safety signal and no dose limiting toxicity identified.
The cinrebafusp alfa data presented at AACR (Free AACR Whitepaper) can be found in an updated corporate presentation at View Source

PRS-344S095012:

The synergistic preclinical data presented for PRS-344/S095012 demonstrate PRS-344/S095012 is superior to the combination of PD-L1- and 4-1BB-targeting molecules. In an anti-PD-L1-resistant mouse model, the drug candidate induces a dose-dependent anti-tumor response and significantly extends survival. In vitro, PRS-344/S095012 enhances effective CD8+ T cell response and proinflammatory cytokine release.

PRS-344/S095012-mediated 4-1BB activation is strictly PD-L1 dependent, reducing the risk of peripheral toxicity. Furthermore, 4-1BB co-stimulation only occurs in combination with simultaneous TCR signaling, restricting its activity to antigen-specific T cells. PRS-344/S095012 also displays mAb-like pharmacokinetics in mice.

These data support further development of PRS-344/S095012, for which the phase 1 study is expected to begin this year.

A copy of the poster is available at this link.

"The matured data from the highest dose cohort of cinrebafusp alfa demonstrate a clear dose-dependent response that supports our recommended phase 2 dose, and the biomarker data generated across all active dose cohorts demonstrate that cinrebafusp alfa activity is 4-1BB-driven and that the drug candidate is active not only in HER2-high expressing tumors, but also HER2-low expressing tumors – a significant opportunity and unmet medical need that we are excited to pursue in our upcoming phase 2 study," said Stephen S. Yoder, President and Chief Executive Officer of Pieris. "Separately, we are pleased with the clear evidence of dose-dependent synergistic anti-tumor effects of PRS-344/S095012, as well as further evidence for its tumor-localized mechanism of action, and we look forward to moving this asset into the clinic this year. By its design, this bispecific has best-in-class potential in the 4-1BB/PD-L1 arena."

About Cinrebafusp Alfa:

Cinrebafusp alfa (PRS-343) is a 4-1BB/HER2 fusion protein comprising a 4-1BB-targeting Anticalin protein and a HER2-targeting antibody. The drug candidate is currently in development for the treatment of HER2-positive solid tumors. Based on encouraging phase 1 study results, which demonstrated clinical benefit as single agent and biomarker data indicative of a 4-1BB-driven mechanism of action, the Company is actively working towards initiating a phase 2 study of cinrebafusp alfa in combination with ramucirumab and paclitaxel for the treatment of HER2-high expressing gastric cancer and in combination with tucatinib in HER2-low expressing gastric cancer.