On June 6, 2022 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported that results from the Phase II SUMMIT trial, assessing the efficacy of combined neratinib, fulvestrant, and trastuzumab in patients with hormone receptor positive, HER2-negative, HER2-mutant metastatic breast cancer, at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting held in person from June 3-7 in Chicago, IL, and online (Press release, Puma Biotechnology, JUN 6, 2022, View Source [SID1234615656]). The poster, entitled "Neratinib + fulvestrant + trastuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): outcomes and biomarker analysis from the SUMMIT trial," was presented at the Breast Cancer — Metastatic Poster Session (poster #1028) by Komal L. Jhaveri, MD, FACP, Medical Oncologist at Memorial Sloan Kettering Cancer Center on June 6 at 9:00 a.m. ET.

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Earlier genomic analyses from a cohort treated with a combination of neratinib and fulvestrant suggest that resistance to neratinib may occur via mutant allele amplification or secondary HER2 mutations. The addition of trastuzumab to the combination of neratinib and fulvestrant in this trial demonstrated positive durable responses in patients with HR-positive, HER2-mutant MBC who had received prior CDK4/6 inhibitors (CDK4/6i).

The Phase II SUMMIT basket trial is an open-label, multicenter, multinational study that included a cohort evaluating the efficacy of the triplet combination of neratinib (N), plus fulvestrant (F), plus trastuzumab (T), in patients with HR-positive, HER2-negative, HER2-mutant metastatic breast cancer, as identified by local genomic sequencing, who had previously received CDK4/6 inhibitors. In order to confirm the contribution of neratinib to the combination, a small, randomized cohort comparing neratinib plus fulvestrant plus trastuzumab versus fulvestrant plus trastuzumab versus fulvestrant was also included. A range of HER2 allelic variants was represented in the cohort. Patients who received the triplet regimen were enrolled in the non-randomized cohort and received 240 mg of neratinib per day intramuscularly, 500 mg intravenous fulvestrant on days 1 and 15 of Cycle 1 and then every 4 weeks, 8mg/kg body weight trastuzumab initially and then 6mg/kg every 3 weeks. Patients in the randomized cohort received either a combination of neratinib, fulvestrant, and trastuzumab, or fulvestrant and trastuzumab, or fulvestrant alone in a 1:1:1 ratio. To counter the side effects of diarrhea, loperamide prophylaxis was mandatory for the first two treatment cycles. Patients who were randomized to the combination of fulvestrant and trastuzumab, or fulvestrant alone, could cross over to receive neratinib, fulvestrant, and trastuzumab at progression. Efficacy was assessed using objective response rate (ORR) and clinical benefit rate (CBR). Tumor tissue was retrospectively assessed by central next-generation sequencing (NGS).

The table below summarizes the efficacy of SUMMIT MBC patients who received neratinib plus fulvestrant plus trastuzumab, those who received fulvestrant plus trastuzumab, and those who received fulvestrant alone; and also those who received fulvestrant plus trastuzumab or fulvestrant and then crossed over to neratinib plus fulvestrant plus trastuzumab upon progression. Patients who received neratinib plus fulvestrant plus trastuzumab (non-randomized + randomized) had a 35.3% investigator-assessed objective response rate, 14.3-month duration of response, 41.7% clinical benefit rate, and 8.2-month median progression-free survival. Neratinib appears to be a critical component of the combination therapy, as demonstrated by lack of response in the small cohort of patients treated with fulvestrant or fulvestrant plus trastuzumab, and by response in a subset of those patients upon crossover to neratinib plus fulvestrant plus trastuzumab.

Table: Efficacy Findings from HR+ Metastatic Breast Cancer Patients

Data cut-off: 15 April 2022. Tumor response based on: investigator tumor assessments (RECIST v1.1)
CR, confirmed response; PR, partial response; CI, confidence interval; DOR, duration of response; NA, not applicable; NE, not estimable; PFS, progression-free survival
a Objective response defined as either a complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met;
b Kaplan-Meier analysis. For crossover patients, calculated from time of crossover to N+F+T.
c Clinical benefit is defined as confirmed CR or PR or stable disease (SD) for ≥24 weeks (within +/– 7-day visit window)
These results suggest that the combination of neratinib, fulvestrant, and trastuzumab together is promising for treating HR+ and HER2-mutated MBC with prior exposure to CDK4/6i across a range of HER2 mutations.

Dr. Jhaveri, an investigator of the trial, said, "Patients with hormone receptor-positive, HER2-negative, HER2-mutant metastatic breast cancer who had received prior treatment with CDK4/6 inhibitors demonstrated encouraging clinical activity with durable responses when treated with the triplet combination of neratinib with fulvestrant and trastuzumab. These responses were observed in patients whose tumors harbored a wide spectrum of HER2 mutations, including those with co-occurring HER3 mutations, regardless of ductal or lobular histology, and with a range of HER2 protein expression."

Alan H. Auerbach, Chief Executive Officer, and President of Puma Biotechnology added, "HER2 mutations can be readily and accurately identified and are clinically actionable for targeted therapy in metastatic breast cancers. We are very pleased with the updated activity seen with the combination of neratinib plus trastuzumab plus fulvestrant therapy in this heavily pretreated metastatic breast cancer patient population with HER2-mutated disease."

On June 6, 2022 Linnaeus Therapeutics, Inc. (Linnaeus), a privately held clinical-stage biopharmaceutical company focused on the development and commercialization of novel small-molecule oncology therapeutics, reported the presentation of clinical data from its phase 1/2 clinical trial of LNS8801 in combination with pembrolizumab in patients who have developed secondary resistance to anti–PD-1/L1 therapy at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Linnaeus Therapeutics, JUN 6, 2022, View Source [SID1234615672]).

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The poster is entitled, "Phase 1b study of the novel first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in combination with pembrolizumab in patients with immune checkpoint inhibitor (ICI)-relapsed and refractory solid malignancies."

In the dose-escalation portion of the study, LNS8801 demonstrated exceptional safety and tolerability. With monotherapy, no dose-limiting toxicities (DLTs) or treatment-related serious adverse events were observed, and the combination of LNS8801 and pembrolizumab was confirmed to be safe and tolerable with no DLTs observed. The recommended phase 2 dose of LNS8801 was identified as 125 mg daily as a monotherapy and in combination with pembrolizumab (200 mg every 3 weeks). Predictive, prognostic, and confirmatory biomarkers have been shown to correlate well with anticancer activity and clinical benefit. These biomarkers are being further validated and will aid in the selection of patients in future clinical studies.

The combination of LNS8801 with pembrolizumab has demonstrated strong signals of activity in patients with metastatic cancer who had previously benefited from and then developed secondary resistance to ICI therapy. An objective response rate of 15.4% was achieved, with 2 of 13 evaluable patients achieving confirmed partial responses. A disease control rate of 69.2% was observed, with 9 of 13 evaluable patients achieving partial responses or stable disease. Four patients have already remained on study longer than 6 months with ongoing benefit for the duration of therapy. The combination of LNS8801 and pembrolizumab is tolerable without unanticipated toxicities.

"We are very pleased to showcase these data at ASCO (Free ASCO Whitepaper)," commented Patrick Mooney, MD, CEO of Linnaeus. "LNS8801 continues to be extremely safe and well tolerated and shows very promising activity in combination with pembrolizumab. It is important to note that the disease control rate of ICI therapy alone in this patient population is expected to be very low, so it is exciting to see that the addition of LNS8801 to pembrolizumab is stopping progression in almost 70% of patients without any additional toxicity. We look forward to further exploration of LNS8801 alone and in combination, and we are encouraged by the continuing data we are seeing from these open cohorts."

About LNS8801
LNS8801 is an orally bioavailable, highly specific, and potent agonist of GPER whose activity is dependent on the expression of GPER. GPER activation by LNS8801 rapidly and durably depletes c-Myc protein levels. In preclinical cancer models, LNS8801 displays potent antitumor activities across a wide range of tumor types, rapidly shrinking tumors and inducing immune memory.

In the ongoing phase 1/2a study in humans, LNS8801 monotherapy has been safe and well tolerated. Additionally, LNS8801 has demonstrated target engagement, c-Myc protein depletion, and clinical benefit in some patients with advanced cancer.

On June 6, 2022 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported that senior management will participate in a fireside chat at the 2022 Jefferies Global Healthcare Conference in New York City on Wednesday, June 8, 2022 at 8:30 a.m. ET (Press release, Celldex Therapeutics, JUN 6, 2022, View Source [SID1234615708]).

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A webcast of the presentation will be available on the "Events & Presentations" (opens in a new tab)page of the "Investors & Media(opens in a new tab)" section of the Celldex website. A replay will be available for 30 days following the event.

On June 6, 2022 Enterome, a clinical stage biopharmaceutical company developing first-in-class immunomodulatory drugs based on its bacterial Mimicry drug discovery platform, reported proof-of-concept immune response data and first clinical data from its Phase 1/2 clinical trial of EO2401 in combination with an immune checkpoint inhibitor (nivolumab, Opdivo) +/- an anti-VEGF therapy (bevacizumab, Avastin), for the treatment of patients with first progression/recurrence of glioblastoma (the ROSALIE trial, EOGBM1-18, NCT04116658) (Press release, Enterome, JUN 6, 2022, View Source [SID1234615607]). The data1 were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, on June 5, 2022 in Chicago and virtually.

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EO2401 is Enterome’s first-in-class off-the-shelf OncoMimics cancer immunotherapy. It combines three OncoMimics peptides that closely mimic IL13Ra2, BIRC5 and FOXM1, all of which are known driver antigens present on aggressive solid tumors. In addition, EO2401 contains a CD4 helper peptide UCP2. Enterome selected these OncoMimics using its Mimicry platform, which applies best-in-class biocomputational tools and bioassays to identify novel therapeutics from its proprietary database of 20+ million bioactive gut microbiome peptides and proteins.

Key highlights from the EO2401 poster presentation covering the Phase 1/2 ROSALIE trial were:

Proof-of-concept immune response data

Immune monitoring demonstrated the ability of the individual microbiome-derived peptides that comprise EO2401 to induce a strong CD8+ T cell response in patients with strong cross-reactivity against the human tumor antigens that they mimic.

Positive responses against the three OncoMimics peptides were demonstrated for 26 of the 27 patients investigated, and sustained for more than 44 weeks in the longest-followed patient.

Promising clinical outcomes

The combination of EO2401 plus nivolumab in study part 1 (Cohorts 1/2a/2b, n=29), despite short treatment durations, showed promising survival with a possible plateau at around 30% after 1 year. The short treatment durations were thought to be a result of a higher than expected rate of "pseudoprogression" leading to neurological symptoms (infiltration of tumor by immune cells and edema).

In study part 2, the addition of time-limited, low-dose bevacizumab as a symptom-driven anti-edema treatment (to counteract edema due to tumor infiltration of immune cells) supported prolonged treatment durations, which could also potentially impact efficacy (efficacy not yet presented due to short follow-up).

The triple combination of EO2401 plus nivolumab and bevacizumab (Cohort 3, n=11) demonstrated interesting directly measurable anti-tumor efficacy (objective tumor shrinkage) as compared with that observed in Cohort 1/2a/2b from study part 1 (EO2401 plus nivolumab without any bevacizumab) (below), and also with previous results shown with a checkpoint inhibitor (pembrolizumab or nivolumab) plus bevacizumab in contemporary trials2,3:

Objective response rates (ORR) – Cohort 3: 54.5% (95% CI 23.4; 83.3) vs Cohorts 1/2a/2b: 3% (95% CI 2.2; 27.4)

Disease control rates (DCR) – Cohort 3: 81.8% (95% CI 48.2; 97.7) vs Cohorts 1/2a/2b: 5% (95% CI 17.9; 54.3)
The encouraging efficacy seen with the triplet, including longer treatment durations, supports the hypothesis that the addition of symptomatic anti-edema treatment with time-limited, low-dose bevacizumab to the EO2401 plus nivolumab combination might influence efficacy positively.

Safety

The combination of EO2401, administered sub-cutaneously with the adjuvant Montanide ISA 51 VG, with nivolumab +/- bevacizumab was well tolerated. The safety profile was consistent with the profile of nivolumab, and, when applicable, the profile of bevacizumab, except the addition of local administration site reactions (occurring in 48% of patients, all Grade 1-2).

Professor Wolfgang Wick, Universitätsklinikum Heidelberg and German Cancer Research Center, Heidelberg, Germany commented, "I am pleased to be part of the ROSALIE trial, the first clinical study to evaluate Enterome’s novel therapeutic vaccine EO2401, which is based on the OncoMimics concept. In contrast to tumor antigens, the OncoMimic peptides in EO2401 are recognized by the immune system as "non-self" and, as we have seen in this study, generate strong human cytotoxic CD8+ responses. Based on the immune response and early clinical data that we have seen so far in this extremely challenging patient propulation, I am hopeful that more mature data from the trial might support further development steps in glioblastoma."

Jan Fagerberg, Chief Medical Officer of Enterome said, "I am very pleased that we have been able to present these very encouraging data from the ROSALIE trial, evaluating EO2401 in combination with checkpoint blockade, and checkpoint blockade plus anti-VEGF therapy. Most importantly, this first presentation of data from a clinical trial of EO2401 show proof-of-concept with regard to immune response, and also encouraging clinical data. We are looking forward to sharing a more mature set of data from ROSALIE at ESMO (Free ESMO Whitepaper) in September, which we hope will reinforce the positive findings that we have communicated at ASCO (Free ASCO Whitepaper)."

EO2401 in adrenal malignancies

At ASCO (Free ASCO Whitepaper), and separately announced today, Enterome presented the first clinical data from its Phase 1/2 clinical trials of EO2401 in combination with nivolumab for the treatment of patients with adrenal tumors (the SPENCER trial, EOADR1-19). View press release here.

About ROSALIE

ROSALIE (EOGBM1-18, NCT04116658) is a multicenter, open-label, Phase 1/2 trial investigating EO2401 in combination with nivolumab, and in combination with nivolumab/bevacizumab in patients with glioblastoma at first progression/recurrence after surgery and adjuvant radiotherapy/temozolomide. The trial is assessing safety, tolerability, immunogenicity and preliminary efficacy in approximately 80 patients at centers in the US and Europe

On June 6, 2022 Clarity Pharmaceuticals (ASX: CU6) ("Clarity"), a clinical-stage radiopharmaceutical company developing next-generation products to address the growing needs in oncology, reported the approval of its Investigational New Drug (IND) application by the United States Food and Drug Administration (US FDA) to evaluate its SAR-Bombesin product as an imaging agent in prostate cancer patients that are Prostate-Specific Membrane Antigen (PSMA)-negative (Press release, Clarity Pharmaceuticals, JUN 6, 2022, View Source [SID1234615624]).

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Clarity’s Executive Chairman, Dr Alan Taylor, commented, "Receiving clearance from the FDA on the imaging trial with SAR-Bombesin is yet another significant milestone for Clarity. It shows our ability to develop cutting-edge theranostics from the lab, through preclinical studies and into clinical trials, with SAR-Bombesin being Clarity’s fourth IND across five products which are clear for investigation in the US."

This IND gives Clarity clearance to proceed with a US-based Phase II 64Cu SAR-Bombesin Positron Emission Tomography (PET) imaging trial in participants with PSMA-negative biochemical recurrence (BCR) of prostate cancer following definitive therapy (such as surgery or radiation).

SABRE, which derives from "Copper-64 SAR-Bombesin in Biochemical REcurrence of Prostate Cancer trial", is a multi-center, single arm, non-randomised, open-label trial in up to 50 PSMA-negative patients with known or suspected prostate cancer. The primary objectives of the trial are to investigate the safety and tolerability of 64Cu SAR-Bombesin, as well as its ability to correctly detect the recurrence of prostate cancer.

The SABRE trial builds upon the promising clinical data from the pilot trial assessment of 64Cu SAR-Bombesin in breast cancer led by Prof Louise Emmett of St Vincent’s Hospital Sydney. The data from this trial was recently presented at the prestigious American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting. The SABRE trial was developed in response to the strong demand for this product from clinicians with prostate cancer patients whose cancer was not visible with currently approved PSMA diagnostic agents or conventional imaging (such as CT and/or MRI). Their patients were successfully imaged with 64Cu SAR-Bombesin under a Special Access Scheme.

Approximately 20% of prostate cancers with BCR are PSMA-PET negative1-4. These patients are therefore unlikely to respond to therapeutic PSMA-targeted products and currently have few treatment options available to them. Given the prostate cancer indication is one of the largest in oncology, there is a significant unmet medical need in this segment. The SAR-Bombesin product targets the Gastrin Releasing Peptide receptor (GRPr) found on prostate and many other cancers. As such, the product could offer valuable imaging and therapeutic options for not only PSMA negative patients, but also the large number of patients that have the target receptor on their cancers.

"We look forward to further progressing the development of SAR-Bombesin and hope it will provide a new and effective diagnostic option for prostate cancer patients. Building on the promising clinical and preclinical data acquired to date, we are also planning an IND submission for a theranostic trial in prostate cancer participants, using 67Cu SAR-Bombesin therapy paired with the imaging agent, 64Cu SAR-Bombesin. Combined with the clinical, environmental and logistical benefits enabled by the copper isotope pairing, SAR-Bombesin has potential to provide this large patient population with accurate and precise detection and treatment of prostate cancer. We anticipate the SABRE trial to commence shortly and the theranostic trial to commence in 2023," Dr Taylor added.

This announcement has been authorised for release by the Executive Chairman.