On June 6, 2022 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a clinical stage biotechnology company developing the next generation of therapeutics based on its proprietary self-delivering RNAi (INTASYL) therapeutic platform, reported a trial-in-progress poster describing the study outline of its Phase 1b clinical trial of PH-762, a self-delivering RNAi targeting PD-1, for the treatment of advanced melanoma at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, which is being held June 3-7, 2022 in Chicago, IL (Press release, Phio Pharmaceuticals, JUN 6, 2022, View Source [SID1234615623]).

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Immunotherapy with antibodies targeting immune checkpoints, such as PD-1, has shown significant benefit in late stage melanoma patients. However, further improvements in therapeutic options are still needed. Treatment given as a first step prior to surgery, or neoadjuvant treatment, and local intratumoral (IT) injection are two alternative approaches for improving the outcome of immunotherapy for melanoma patients.

"We are pleased to share the details for the ongoing clinical trial of our lead product, PH-762. As the first-in-human study for an INTASYL immunotherapy compound, the initiation of this study earlier this year marks an important milestone for our broader pipeline and platform," said Dr. Simon Fricker, Phio’s VP of Research and Development. "Neoadjuvant therapy may stimulate significant responses that appear to be associated with a decrease in the risk of relapse after surgery. As there is currently no neoadjuvant standard of care for resectable advanced melanoma patients, neoadjuvant treatment with PH-762 provides an alternative therapeutic option to treat these patients."

IT administration of PH-762 to the tumor can stimulate a local immune response in the tumor microenvironment by silencing PD-1 and generating an immune response in distant untreated tumors. Studies conducted by the Company have shown potent silencing of PD-1 and a robust, dose-dependent inhibition of tumor growth. Further, IT injection of PH-762 also has the potential to minimize systemic effects and off-target toxicity, which has been seen with the use of antibodies.

The poster presented at ASCO (Free ASCO Whitepaper) outlines the design of the Phase 1b study with PH-762 for the treatment of patients with advanced melanoma. The clinical study is being conducted at the Gustave Roussy Institute, one of the largest cancer centers in Europe. The purpose of this study is three-fold: to evaluate the safety and pharmacokinetics of neoadjuvant use of PH-762 administered by IT injection in subjects with resectable advanced melanoma; to determine the recommended Phase 2 dose; and to determine the potential immunologic and pathologic tumor responses. Study treatment will feature a dose escalation of once weekly IT injections of PH-762 for four weeks prior to surgical excision of tumor lesion(s) after treatment with PH-762. Up to five dose levels will be tested in a serial fashion in cohorts of three or more subjects. A Bayesian optimal interval (BOIN) design will be employed to evaluate escalating doses of PH-762 to determine the maximum tolerated dose level and the dose of PH-762 will be normalized to tumor volume to ensure an equivalent local dose (tumor tissue concentration). Tumor changes will be evaluated per RECIST criteria, adapted for use with IT therapy, and by pathological response.

The poster being presented at ASCO (Free ASCO Whitepaper), titled, "A First-in-Human, Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of Neoadjuvant Use of PH-762 Administered Intratumorally in Subjects with Advanced Melanoma" will be made available on the "Investors – Events and Presentations" section of the Company’s website (click here).

About PH-762

PH-762 activates immune cells to better recognize and kill cancer cells. It does so by reducing the expression of PD-1, a clinically validated target for immunotherapy. PD-1 is expressed by T cells and prevents them from killing cancer cells. When PH-762 reduces PD-1 expression, the "brakes" on the immune system are released and activates the T cells to kill the cancer cells. PH-762 is being developed as a standalone drug therapy with local IT administration to a tumor. In addition, it is also being developed as a critical component of cellular immunotherapy, more specifically to improve tumor cell killing capability of adoptively transferred tumor infiltrating lymphocyte (TIL) therapy.

On June 6, 2022 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for people living with cancer, reported an update from an interim analysis of its international Phase 2 RAMP 201 trial evaluating VS-6766 ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC), regardless of KRAS status (Press release, Verastem, JUN 6, 2022, View Source [SID1234615639]).

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Verastem recently completed a planned interim analysis of its RAMP 201 trial with the goal of selecting a go forward treatment regimen of either VS-6766 monotherapy or VS-6766 in combination with defactinib. The analysis indicated encouraging efficacy results with confirmed responses by independent review in patients treated with VS-6766 monotherapy and patients treated with VS-6766 in combination with defactinib. The findings also include confirmed responses by independent review in both KRAS mutant and KRAS wild-type LGSOC. To date, there have been no additional safety signals with a continued favorable safety profile in both the monotherapy and combination treatment arms with approximately 6% of patients discontinuing due to adverse events.

With a substantial majority (approximately 80%) of patients remaining on study treatment with a median duration of follow-up of four months, the Company has concluded that the data from the interim analysis are not mature enough to make a final decision on the go forward treatment regimen at this time and the trial will continue with all four cohorts (VS-6766 ± defactinib in KRAS mutant and KRAS wild type patient populations).

"We are encouraged by the positive anti-tumor activity that we have seen to date in the RAMP 201 trial in patients with both KRAS mutant and KRAS wild-type tumors. We look forward to evaluating a more mature data set and expect to provide an update on progress once the go forward treatment regimen has been determined," said Brian Stuglik, Chief Executive Officer, Verastem Oncology. "This interim analysis adds to our optimism about the potential for VS-6766 with or without defactinib and our commitment to advancing the first new treatment specifically developed and approved for women with low-grade serous ovarian cancer where a high medical need remains."

The Company plans to complete enrollment of all four cohorts of the trial in the second half of this year. Each cohort is expected to have approximately 36 patients for a total of 144 patients.

Both VS-6766 and defactinib are in late-stage development and the combination has received Breakthrough Therapy Designation by the U.S. Food and Drug Administration for the treatment of all patients with recurrent low-grade serous ovarian cancer regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.

About the VS-6766/Defactinib Combination

VS-6766 is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS pathway inhibition. In contrast to currently available MEK inhibitors, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The combination of VS-6766 and FAK inhibitor, defactinib provides RAF/MEK vertical blockade and FAK parallel inhibition to overcome key resistance mechanisms. Both VS-6766 and defactinib are in late-stage development.

Verastem Oncology is conducting Phase 2 registration-directed trials of VS-6766 alone and with defactinib in patients with recurrent LGSOC and in patients with recurrent KRAS G12V-mutant NSCLC as part of its RAMP (Raf And Mek Program) clinical trials, RAMP 201 and RAMP 202, respectively (www.ramp201study.com and www.ramp202study.com). Verastem Oncology has also established clinical collaborations with Amgen, Inc. and Mirati Therapeutics, Inc. to evaluate LUMAKRAS (sotorasib) and adagrasib in combination with VS-6766 in KRAS G12C-mutant NSCLC as part of the RAMP 203 and RAMP 204 trials, respectively.

About Low-Grade Serous Ovarian Cancer

Low-grade serous ovarian cancer is a highly recurrent, chemotherapy-resistant cancer, associated with slow tumor growth and high mortality rate.1 Approximately 6,000 women in the U.S. and 80,000 worldwide are living with this disease. Mutations in the KRAS gene are present in 35-57% cases of LGSOC.2 LGSOC is most often diagnosed in women between the ages of 45-55 years and has a median survival of approximately ten years.2 The majority of patients experience severe pain and complications as the disease progresses. Chemotherapy is the standard of care for this disease, with limited treatment options currently available.2

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.