On September 18, 2020 Immutep Limited (ASX: IMM; NASDAQ: IMMP) reported further interim data from its ongoing INSIGHT-004 Phase I clinical trial (Press release, Immutep, SEP 18, 2020, View Source [SID1234565422]). The data were presented at the ESMO (Free ESMO Whitepaper) Virtual Congress 2020 on 17 September 2020, CEST (poster ID number 1032P) by trial investigator at Institute of Clinical Cancer Research, Krankenhaus Nordwest (IKF), PD Dr. Thorsten Götze.

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INSIGHT-004 is evaluating the combination of Immutep’s lead product candidate, eftilagimod alpha ("IMP321" or "efti") with avelumab (Bavenico), a human anti-PD-L1 antibody, in 12 patients with different solid tumours, primarily gastrointestinal. It is being conducted under Immutep’s collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer Inc., which are co-developing and co-commercialising avelumab. INSIGHT-004 is the fourth arm (Stratum D) of the investigator-initiated INSIGHT trial which is conducted by IKF in Frankfurt, Germany.

Prof Salah-Eddin Al-Batran, INSIGHT-004 trial investigator and Director of IKF said: "It is encouraging to see the range of patients with different solid cancers that are responding to the combination of efti and avelumab, including PD-L1-negative cervical cancer, squamous anal cell carcinoma and mesothelioma. These tumours are not typically responsive to immune checkpoint therapy and warrant further investigation."

Results Summary (data cut off 12 June 2020)

41.7% of patients (5 / 12) showed a partial response (PR) to the combination therapy according to RECIST 1.1. Previously 33% showed a PR (June 2020).

Encouraging durable deep responses in PD-L1 negative cancer.

Includes 2 patients with clinical progression

**
Response assessment not yet performed

Immutep Limited, Level 12, 95 Pitt Street, Sydney NSW 2000

ABN: 90 009 237 889

Safety

Interim results from INSIGHT-004 show that the combination of efti and avelumab is well tolerated with no dose limiting toxicities, building on efti’s strong safety profile to date.

IKF INSIGHT Trial Poster

IKF also presented data from the broader INSIGHT trial at ESMO (Free ESMO Whitepaper) showing that intratumoral and intraperitoneal administration of efti up to 30 mg displayed signals of clinical and cytokine responses. Both IKF posters are appended below and are available on the Company’s website at View Source

About INSIGHT-004

INSIGHT-004 is the fourth arm of the investigator-initiated INSIGHT trial which is being conducted by the Institute of Clinical Cancer Research IKF at Krankenhaus Nordwest in Frankfurt. It is being conducted under Immutep’s collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer Inc., and is evaluating the safety, tolerability and recommended Phase II dose of efti when given in combination with avelumab. It is the first combination trial of an approved and marketed anti-PD-L1 drug and efti.

Patients in cohort 1 receive 6mg doses of efti every two weeks with the standard dose of avelumab (800mg every two weeks), while patients in cohort 2 receive a higher dose of efti, 30mg, with avelumab.

On September 18, 2020 LinkDoc Technology, a Beijing oncology big data company, reported that it raised $103 million in a Series D+ funding round, primarily from new investors, CICC Capital, Youshan Capital and iFOF (Press release, LinkDoc, SEP 18, 2020, View Source [SID1234565413]). Founded in 2014, LinkDoc offers electronic medical records to hospitals, and it gathers medical data, using AI to develop clinical best-practice guidelines for cancer. Two years ago, LinkDoc completed a $143 million Series D round exclusively from state-owned China Investment Corporation.

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On September 18, 2020 EORTC reported that About 13% of lung cancer patients have Small Cell Lung Cancer (SCLC) (Press release, EORTC, SEP 18, 2020, View Source [SID1234565398]). The prognosis of this disease is very poor with 5-year survival rates of 31% for limited-stage SCLC (LS-SCLC) and 2% for extensive-stage SCLC (ES-SCLC). However, recent studies have shown that anti PD-L1 antibodies can extend overall survival of ES-SCLC patients when combined with platinum-etoposide treatment.

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Professor Benjamin Besse, Head of the Cancer Medicine Department at Gustave Roussy Cancer Campus and Professor of Medical Oncology at Paris-Saclay University, Orsay, presented the late breaking data from EORTC-1417-LCG REACTION study: a phase II study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive small cell lung cancer at the ESMO (Free ESMO Whitepaper) Virtual congress today.

All 125 patients (61 in experimental vs 64 in control arm) recruited previously responded to 2 cycles of platinum-etoposide. They were randomized into the control arm of 4 additional cycles of platinum-etoposide treatment or the experimental arm with 4 additional cycles of platinum-etoposide treatment combined with pembrolizumab and then up to 35 cycles of pembrolizumab. 119 (58 vs 61) patients were eligible and started at least one dose of the treatment. 19 patients had crossed over to the experimental arm at the time of progression. In the experimental arm, 43 % exhibited grade 3 to 5 adverse events vs 36% in the standard arm, median progression free survival was 4.7 vs. 5.4 months and overall survival was 12.3 vs 10.4 months respectively. Besse concluded that even though the combination of etoposide and platinum with pembrolizumab was well tolerated, it did not improve progression free survival compared to standard treatment. However, the data did elude to the potential increase in overall survival, it should be noted that pembrolizumab needs to be introduced as first line treatment in order to benefit from this improvement.

"In REACTION, immunotherapy was added from the third cycle of chemotherapy," said Besse. "Our results confirm the benefit of adding immunotherapy to first line chemotherapy in patients with extended SCLC. Our strategy is interesting for patient with PS2 at cycle 1 (thus unfit for immunotherapy) that will improve to PS 1 or 0 at cycle 3".

Mini Oral Session – Non-metastatic NSCLC and other thoracic malignancies

LATE BREAKING ABSTRACT: REACTION: A phase II study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive small cell lung cancer

On September 18, 2020 Merck reported that phase 2 data for a kidney cancer drug picked up in its $1.05 billion Peloton buyout, showing it shrank tumors in 28% of patients (Press release, Merck & Co, SEP 18, 2020, View Source [SID1234565373]). Now, that number has jumped to 36%, and the drug is showing promise at shrinking tumors outside of the kidney.

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The new data show the drug, a HIF-2α inhibitor dubbed MK-6482, reduced tumor size enough in 36% of patients for them to be considered responders. But that’s not all—another 38% of patients had stable disease, meaning their tumors had stopped growing, and 92% of patients saw at least some tumor shrinkage.

These numbers are in line with Merck’s expectations that the drug would work in more patients over time. The data, presented Friday at this year’s virtual annual meeting of the European Society for Medical Oncology, show that it takes at least three months for patients to see results, with some patients taking the drug for more than a year (62 weeks) before they start responding. The median time to response was nearly seven months. After one year, MK-6482 staved off cancer progression in virtually all 61 patients (98%).

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And when the treatment works, it continues to work. "I think it’s quite reassuring that these responses are durable. Sometimes, with new drugs, even though they might get an initial response, the tumors find a way to become resistant relatively quickly. What this says is that is just not true here," Eric Rubin, senior vice president of global clinical oncology at Merck Research Laboratories, said.

RELATED: Merck boosts late-phase cancer pipeline with $1.1B Peloton buy

The data are good news for patients with kidney cancer linked to Von Hippel-Lindau (VHL) disease, a genetic condition that causes tumors and cysts to grow throughout the body. Patients with VHL disease do not make a protein that binds to HIF-2α, (hypoxia-inducible factor-2 alpha), which plays a role in regulating tissue oxygen levels.

As a result, the HIF-2α is always on, which ramps up the production of red blood cells, stimulates formation of new blood vessels and causes certain cells to proliferate. This leads to the development of growths in places as diverse as the brain, retina, liver, pancreas and lungs.

Despite developing tumors in many organs, it’s usually kidney cancer that kills these patients. They undergo surgery to remove kidney tumors, but those often return, or new ones appear. At some point, those tumors get too big to remove without losing the whole kidney, Roy Baynes, Merck senior vice president and global head of clinical development, said in a previous interview.

RELATED: ASCO (Free ASCO Whitepaper): Merck backs up Peloton buyout with promising kidney cancer data

In addition to tackling dangerous kidney tumors, MK-6482 moved the needle in other areas. It shrank pancreatic tumors in 64% of patients, completely banishing them in 7% of them, and shrank a type of benign tumor in the brain or spinal cord in 30% of patients. Of the 16 patients who had retinal growths, none saw them get worse, with 69% of them logging improvement and 25% staying stable.

All 61 patients experienced side effects, but in most patients—75%—they were mild. The most common side effect was anemia, affecting 90% of patients, but that wasn’t a surprise considering HIF-2α’s role in forming new red blood cells.

"Patients are generally responsive to erythropoietin," a hormone involved in making red blood cells, Baynes said, adding that "it can be managed quite readily."

Eight patients (13%) had severe treatment-related side effects, including one patient who developed hypoxia, or low levels of oxygen. One patient died from "toxicity of various agents," but the investigator deemed the death unrelated to treatment.

Although VHL is a relatively uncommon disease, blocking HIF-2α could be useful more broadly. Patients with kidney cancer that can’t be surgically treated or has metastasized tend to receive an immuno-oncology drug, often alongside a kinase inhibitor. If they relapse, they might try a different kinase inhibitor, Baynes said.

"What we find as we look at clear cell kidney cancer is VHL function is lost or silenced in almost nine out of 10 kidney cancer patients," he noted. "The majority of patients, once they’ve failed all treatments, actually have a dysregulated VHL pathway."

Targeting that pathway with a drug like MK-6842 could become an option for those patients. Merck is already testing the drug against standard of care in a phase 3 kidney cancer trial and studying it in combination with Exelixis’ Cabometyx in a phase 2 study in clear cell kidney cancer.

On September 18, 2020 Phosplatin Therapeutics, a clinical stage pharmaceutical company focused on oncology therapeutics, reported that data from a Phase 1b dose escalation study (NCT 03409458) of lead candidate PT-112, an immunogenic cell death inducer, used in combination with avelumab, a PD-L1 immune checkpoint inhibitor, in patients with progressing solid tumors who previously exhausted all available treatment options (Press release, Phosplatin, SEP 18, 2020, View Source [SID1234565370]). Data were pre-released under the Mini Oral presentation format (session 1026MO) in the Investigational Immunotherapy category at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020, taking place September 19-21. Avelumab is co-developed and co-commercialized by Merck KGaA, Darmstadt, Germany and Pfizer Inc.

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The combination of PT-112 and avelumab was found to be safe and well tolerated in 36 heavily pre-treated solid tumor patients who have exhausted standard therapy options, the majority of whom had received prior immunotherapy. Common treatment-related adverse events (TRAEs) were nausea (47%), fatigue (31%), thrombocytopenia (28%), and decreased appetite (28%); 44% of patients had grade 3-4 TRAEs (most frequent was thrombocytopenia: 17%). Clinical benefit was observed in patients treated with PT-112 doses ranging from 150 to 360mg/m2. Sixty percent of patients with RECIST-evaluable disease achieved stable disease or better, including a durable RECIST response, PSA response and improvement in bone scan and bone pain in a patient with metastatic castration-resistant prostate cancer (mCRPC) with 8 prior therapies and no signature of likely response to immune checkpoint inhibition. Further activity signals were observed in patients with mCRPC, with 4 of 14 patients achieving a >50% PSA reduction, and consistent reduction in alkaline phosphatase (ALP) levels associated with bone metastatic site of disease.

"These results demonstrate that the PT-112 and avelumab combination is safe and well tolerated in heavily pre-treated patients. As in any advanced cancer population treated with numerous prior therapies, appropriate dose modifications are important. We are encouraged by activity observed thus far, and we look forward to confirming the combination dose in future studies as we seek treatment options for these patients who effectively have no other therapeutic alternatives remaining," said Daniel D. Karp, MD, Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.

No dose-limiting toxicities occurred during the study. The study enrolled 36 patients with progressing solid tumors across a range of tumor types, including 15 patients with mCRPC who were enrolled in a supplemental cohort. Phase 2 studies are planned to confirm the recommended dose, and to implement correlative immune-profiling assays.

"The results of this first combination study, including the evidence of activity among patients with prostate cancer, are indeed encouraging," said Robert Fallon, co-founder and Chief Executive Officer, Phosplatin Therapeutics. "Based upon these data, our immunotherapy combination appears feasible and active. These results add to the emerging body of evidence around the potential of PT-112, as an immunogenic cell death (ICD) inducer, to provide benefit to patients with advanced solid tumors, and to offer a potential treatment to patients who do not respond to current immunotherapy options."

The study was conducted under a collaboration agreement between Phosplatin Therapeutics, Pfizer Inc. and Merck KGaA, Darmstadt, Germany (EMD Serono in the US and Canada). Under the terms of the collaboration, Phosplatin Therapeutics is the Sponsor of Phase 1b/2a clinical trials in several indications. Pfizer and Merck KGaA, Darmstadt, Germany supply avelumab for the trials.

The ESMO (Free ESMO Whitepaper) presentation is available on-demand for the duration of the conference to registered attendees, and the underlying abstract is publicly available.

About PT-112

PT-112 is the first small molecule conjugate of pyrophosphate developed in oncology therapeutics. PT-112 promotes immunogenic cell death (ICD), or the release of damage associated molecular patterns (DAMPs), that lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents a potential best-in-class small molecule inducer of this immunological form of cancer cell death and is under Phase II development. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) 2018 Annual Congress. The novelty of its pyrophosphate moiety also results in osteotropism, or the propensity of the drug to reach the mineralized bone. This property is of interest in cancer types that originate in bone or frequently lead to metastatic bone involvement, such as metastatic castrate-resistant prostate cancer (mCRPC). The first human clinical results in mCRPC were presented at the 2020 Genitourinary Cancers Symposium.

Avelumab Approved Indications

Avelumab (BAVENCIO) is indicated in the US for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Avelumab in combination with axitinib is approved in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

Avelumab Important Safety Information from the US FDA-Approved Label

The warnings and precautions for avelumab (BAVENCIO) include immune-mediated adverse reactions (such as pneumonitis and hepatitis [including fatal cases], colitis, endocrinopathies, nephritis, and other immune-mediated adverse reactions as a single agent or in combination with axitinib [which can be severe and have included fatal cases]), infusion-related reactions, hepatotoxicity in combination with axitinib, major adverse cardiovascular events (MACE) in combination with axitinib [which can be severe and have included fatal cases], and embryo-fetal toxicity.

Common adverse reactions (reported in at least 20% of patients) in patients treated with BAVENCIO monotherapy include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction peripheral edema, decreased appetite, urinary tract infection and rash. Common adverse reactions (reported in at least 20% of patients) in patients receiving BAVENCIO in combination with axitinib include diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain and headache. Grade 3-4 hematology laboratory value abnormalities reported in at least 10% of patients with Merkel cell carcinoma treated with BAVENCIO monotherapy include lymphopenia; in patients receiving BAVENCIO in combination with axitinib, grade 3-4 clinical chemistry abnormalities include blood triglyceride increased and lipase increased.