Signs of efficacy of new targeted agents and immunotherapies for multiple cancers

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Data from early clinical trials presented at ESMO Congress 2021 suggest that new anti-cancer treatments with a clear focus on precision medicine are imminent. Despite the recession of medical research in the early days of the COVID-19 pandemic, the abundance of promising new drugs and innovative therapeutic approaches currently under development is an annual renewal of the oncology field for the future. This is the proof that concludes the rendezvous. An oncology community with a message of hope.

New molecular target on the way to be struck

As personalized medicine matures, the number of genetic mutations in cancer cells continues to grow and is identified as a potential target for new therapies. One example is a mutation that causes the loss of function of the tumor suppressor gene ARID1A, which is found in an estimated 10-50% of solid tumors, including endometrial cancer, bladder cancer, colorectal cancer, and cholangiocarcinoma. In a phase II trial of the target drug Celaracertib, whose interim results were presented at this year’s ESMO conference, 3 out of 10 patients with advanced solid tumors showing ARID1A loss are defined as stable disease for at least 6 months. Clinical benefits were observed. Functional. Two participants with endometrial cancer continued treatment and showed continuous complete response 16 and 21 months after initiation, respectively.

According to Dr. Rodrigo Dienstmann of Oncoclinicas, Brazil, an early drug development expert who is not involved in the study, this data is promising and tumors with this type of change have potential for targeted therapies that exploit cancer defects. Increasing evidence of sensitivity to DNA: Cell’s ability to repair damage to DNA: “Is this dependent on the type of tumor because ARID1A mutations are found in many cancers, from gynecological to malignant tumors of the esophagus? Please understand if other changes in the tumor need to be considered, but currently it is not known if they behave the same in each disease. It is important to obtain a complete genome image of the cancer through next-generation sequencing in the early stages, “he said. ..

The hope that a drug targeting a particular mutation can effectively treat multiple different diseases in which it plays has been approved for the treatment of PIK3CA mutant breast cancer among patients with PIK3CA-related overgrowth. It also motivated the compassionate use of the drug Alperisib. Spectra (PROS)-A rare life caused by sporadic mutations in the same gene, causing malformations and overgrowth in different parts of the body. A syndrome that threatens. A retrospective analysis of patient charts from this compassionate use program reported reduced overgrowth in 23 (74%) of 31 evaluable cases, with PROS-related signs in the majority of patients. A clinically meaningful and permanent improvement in symptoms was reported (55-91%). The drug has proven safe, primarily in the pediatric population, with 91% of participants continuing treatment at the end of the study.

Professor Alessandra Curioni-Fontecedro, an oncologist at the University of Zurich Hospital in Switzerland and not involved in the study, commented: Alpericib administration is a very interesting approach for this rare group of illnesses for which there are no previously approved treatment options. ”

Deliver anti-cancer drugs directly to the core of tumor cells

According to Professor Andrés Cervantes of the University of Valencia Hospital Clinic in Spain, another promising new therapeutic approach at ESMO 2021 is represented by antibody-drug conjugates (ADCs). It utilizes antibodies that bind to proteins that are known to be overproduced by a wide range of cells. Various tumors penetrate cancer cells and release cytotoxic agents. This kills cells in a highly targeted way while maintaining healthy tissue in the body. “Because the proteins of interest are so common, in Phase I / II clinical trials of the antibody-drug conjugate DS-7300, researchers did not select patients based on the expression of the associated protein B7-H3. We have decided, “said Cervantes.

The antitumor activity of DS-7300 was suggested by a partial response to the drug seen in 15 (21%) of the 70 patients enrolled in the study, with participants being highly pretreated (4). Median of one pretreatment line) Achieved a reduction in tumor size It was observed to last up to 40 weeks after the start of treatment. Early signs of efficacy were similarly reported in the first human trial of the antibody-drug conjugate SKB264, with 6 of 17 patients (35%) with locally advanced or metastatic solid tumors treated. It reacted. Both trials are currently recruiting additional patients to further determine their efficacy in tumors, including breast, ovarian, gastric, lung, esophageal, and prostate cancers.

“Despite these early clinical trials, no dose-limiting toxicity was observed, so it is surprising that reactions were seen in a variety of cancers using seemingly well-tolerated drugs. That is why it emphasizes the future value of ADCs for a wider cancer population. Patients. Study this promising therapeutic approach in large trials and what other tumor types are effective against It’s time to know, “says Cervantes.

Expanding the field of view of immunotherapy

In the well-known field of immunotherapy, new technologies and disease mechanisms are being utilized to improve the effectiveness of this therapeutic approach among patients with solid tumors, making it an existing immune checkpoint inhibitor. Only 15-20% respond persistently to it. Curioni-Fontecedro is seen in TC-210, a new type of cell therapy that adapts patients’ own T cells to recognize the target protein mesocellin present on the surface of tumor cells in diseases such as ovarian cancer and mesothelioma. Emphasized the exceptional results that can be achieved. In a dose-escalation study presented at ESMO 2021, all but one of 16 patients experienced tumor size reduction, with 6 participants having 50% tumor after a single injection of TC-210. I confirmed that it was reduced above. In patients with mesothelioma, who make up three-quarters of the study population, median overall survival was 337 days.

“There’s not much else happening when it comes to treating mesothelioma, so this type of cell therapy can ultimately make a real difference to the patient,” said Curioni-Fontecedro. Curioni-Fontecedro cites the current complex and time-consuming manufacturing process of cell therapy as a practical and economical hurdle for further development, while targeting multiple molecular targets for tumor heterogeneity in the future. He also suggested that the approach may be needed.

This is a long-term follow-up of 75 patients with human papillomavirus (HPV) -related cancer enrolled in Phase I and Phase II trials to run out of standard treatment options and administer the drug Bintrafuspalpha. It was an example of another study that presented the data. Designed to activate the body’s immune response to cancer by blocking the well-known immune checkpoint protein PD-L1 and inhibiting the activity of the immunosuppressive molecule TGF-β produced by cancer cells. I am. The median response to treatment was 17 months, some patients continued to respond much longer, the median overall survival was 21 months, and 40% of patients survived more than 4 years after the start of treatment. was doing.

Professor Sebastian Kobold of the University of Munich, Germany, an expert in immuno-oncology unrelated to research, commented: This one drug alone has four patients, which is very encouraging for early-stage trials. ”

Kobold said, “We need more of these alternative immunotherapeutic approaches. In parallel, we are the patients who will benefit most from this type of therapy, including immune checkpoint inhibition, so that we can focus on the future. , Needs more work to understand. Efforts to them. ”

“The ESMO Congress 2021 has strongly confirmed that cancer research works, including rare cancers, which are usually orphans with new treatments,” added Antonio Passaro, ESMO 2021 Press Officer at Istituto Europeo di Oncologia, Italy. rice field. “The ESMO Conference provides a promising stage of development presented to the oncology community, going beyond the development of new drugs for both biomarker-driven and agnostic approaches to molecular or post-immunotherapy resistance. We also hope to improve management. These prospects encourage oncologists and cancer Researchers around the world continue to explore ways to significantly improve the survival and quality of life of patients. ”

Antibody-drug conjugates show impressive activity in patients with non-small cell lung cancer with mutations in the HER2 gene

For more information:
Interim results from R. Aggarwal et al, 512O are the results of a phase II trial of the ATR inhibitor seraracertib in ARID1A deficient and ARID1A intact advanced solid tumor malignancies. Annual Tumor Report (2021). DOI: 10.1016 / j.annonc.2021.08.1034

G. Canaud et al, LBA23 EPIK-P1: A retrospective chart review study of patients (pts) with PIK3CA-related overgrowth spectrum (PROS) who received alpericive (ALP) as part of a compassionate use program, Annual Tumor Report (2021). DOI: 10.1016 / j.annonc.2021.08.2097

ML Johnson et al, 513O Phase I / II multicenter clinical trial of DS-7300 (B7-H3 DXd-ADC) in patients with advanced solid tumors (pts). Annual Tumor Report (2021). DOI: 10.1016 / j.annonc.2021.08.1035

J. Rodon et al, 514O First open-label, global, human study of SKB264 in patients with locally advanced or metastatic solid tumors, Annual Tumor Report (2021). DOI: 10.1016 / j.annonc.2021.08.1036

DS Hong et al, 959O Gavocabtagene autoleucel (gavo-cel, TC-210) Dose escalation in refractory mesocellin-expressing solid tumors, Annual Tumor Report (2021). DOI: 10.1016 / j.annonc.2021.08.1344

J. Strauss et al, 957 Long-term follow-up of patients with human papillomavirus (HPV) -related malignancies (pts) treated with bintrafuspalpha, a bifunctional fusion protein that targets OTGF-β and PD-L1. Annual Tumor Report (2021). DOI: 10.1016 / j.annonc.2021.08.1342

Quote: Https: // New for multiple cancers (September 24, 2021) obtained on September 24, 2021 Signs of Effectiveness of Targeted Drugs and Immunotherapy

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