Bright scientific events in oncology in 2020

Author: Alexey Tikhonov

2020 was marked by a large number of striking events in the oncology field, and in this material, I would like to highlight a number of studies that, in my opinion, can both bring us closer to a more detailed understanding of the tumor biology, and may change approaches to the diagnosis and treatment of cancer in the future.

Due to the pandemic, most of the largest oncology conferences were held online, and this undoubted advantage made it possible to immediately recognize and evaluate the presented studies. In April 2020, at the Annual Meeting of the American Association for Cancer Research AACR 2020 , two important studies were presented focused on the minimally-invasive detection of circulating biomarkers in the blood which could potentially be useful for early cancer diagnosis. In a prospective trial of 10 thousand women using the DETECT-A test (analysis of 16 genes and 9 proteins), it was shown that a blood test can detect cancer in women who did not have a history of cancer and who did not have symptoms. There were 26 cases of cancer in 10 organs, with 17 cases diagnosed at an early stage of the disease . In other study , funded by GRAIL , the authors using developed minimally-invasive test based on the determination of circulating DNA methylation patterns have shown that this approach allows to detect cancer with a specificity of more than 99%, as well as successfully determine the tumor site in a cohort of people at high risk of developing cancer, but without symptoms. However, the sensitivity of the test was about 50% .

One of the major achievements of recent years has been the successful use of low-molecular-weight inhibitors targeted KRAS G12C in cancer patients. This mutation is most common in lung cancer patients (~ 13%), and this year the results of the Phase I Clinical Study CodeBreaK100 were published , the efficacy and safety profile of Sotorasib, a KRAS G12C inhibitor were tested. The study included 129 metastatic patients with various solid tumors, who received, on average, 3 lines of therapy by the time of inclusion. 32.2% of patients with non-small cell lung cancer (NSCLC) had a confirmed response, and 88.1% had disease control for months or more, resulting in a median progression-free survival of 6.3 months. Similarly, for the majority of patients in the colorectal cancer subgroup, disease control was observed in 73% of patients, with a median progression-free survival of 4.0 months. Currently, the survival of such patients using the recommended treatment options is lower compared to the results obtained in this trial, and the response rate and disease control with Sotorasib are encouraging.

Another KRAS G12C inhibitor, Adagrasib, also showed promising results in the KRYSTAL-1 study . In 45% of highly pretreated NSCLC patients, the response rate was 45%, with 14 patients with the longest follow-up (9.6 months), 6 responding to treatment and 4 continuing treatment after more than 11 months.

Traditionally, great progress has been made in the field of immunotherapy. For example, more than 80% of active clinical trials of antibodies against PD-1 / PD-L1 in 2020 were combinations in which these monoclonal antibodies were tested together with other immunooncological drugs, targeted therapy, chemotherapy or radiotherapy, and the number of clinical trials with -PD-1 / PD-L1 has tripled since 2017. And therefore, any negative or controversial research in this area is of great interest.

These include the results of the phase III trial IMbassador250, in which the addition of Atezolizumab (anti-PD-L1 antibody) to Enzalutamide compared to Enzalutamide alone did not lead to an increase in the survival of patients with metastatic prostate cancer . In addition, no benefit was observed for any of the key secondary endpoints (including response rate, disease stability, disease progression, duration of response, and PSA response). This phase III randomized trial enrolled 759 patients with metastatic castration-resistant prostate cancer who progressed on Abiraterone and who did not meet criteria or who refused the taxane regimen. Overall survival was 15.2 months with the combination versus 16.6 months with Enzalutamide alone. One of the reasons for the addition of a PD-L1 inhibitor was to convert prostate cancer from an immunologically «cold» tumor with fewer T cells to a «hot» tumor, but this was not successful, possibly due to the interaction of the microenvironment and immunosuppressive pathways of such tumors and therapy.

Other interesting results related to the Atezolizumab combination were reported at the ESMO 2020 Virtual Congress of the European Society for Medical Oncology. In contrast to the overall survival benefit demonstrated for Atezolizumab plus nab-Paclitaxel in the IMpassion130 study, Atezolizumab plus Paclitaxel did not show an overall survival benefit in the IMpassion131 trial for the treatment of patients with metastatic triple negative breast cancer. The median progression-free survival in IMpassion131 in the PD-L1-positive cohort was 6.0 versus 5.7 months (HR = 0.82) and overall survival was 22.1 versus 28.3 months (HR = 1.12). In contrast, the IMpassion130 overall survival analysis confirmed the superiority of Atezolizumab plus nab-Paclitaxel over nab-Paclitaxel alone, reducing mortality by 33%. One of the reasons for the negative result of the IMpassion131 trial could be the increased use of steroids, which have an immunosuppressive effect, but in a similar trial KEYNOTE 355, which compared combinations of Pembrolizumab with different chemotherapy regimens in similar cohorts, such an effect was not demonstrated. Another reason can be in the discrepancy in the PD-L1 positivity testing assays. And so far, there is no definite answer to the question why Atezolizumab + nab-Paclitaxel showed an advantage in overall survival, but the combination of Atezolizumab and Paclitaxel did not.

We can also note positive trials of immunotherapeutic drugs combinations, including those aimed at new targets, for example, TIGIT, a receptor that is expressed on some T cells and natural killer cells (NK cells). TIGIT can suppress the immune response by binding to its ligand, PVR, which is found on tumor cells and antigen-presenting cells. TIGIT can also block the activation of CD226 or DNAM-1, which is a positive regulator of the immune response. Thus, at the annual meeting of the American Society of Clinical Oncology ASCO 2020, the results of a randomized phase II trial  were demonstrated, which compared Atezolizumab plus anti-TIGIT antibody Tiragolumab with Atezolizumab plus placebo in PD-L1-positive patients with locally advanced or metastatic NSCLC, as first-line therapy. The combination showed an advantage in objective response rate (31.3 percent versus 16.2 percent) and median progression-free survival (5.4 months versus 3.6 months) compared to Atezolizumab alone. A similar phase III test has already begun.

I cannot fail to note research in the field of oncology using the CRISPR-Cas9 system, for the development of a method for using which the Nobel Prize in Chemistry was awarded this year. In February 2020, the first article on the treatment of cancer patients with CRISPR-modified T cells was published. The idea was to remove genes encoding endogenous T-cell receptor and PD-1 to improve efficacy, increase lymphocyte persistence and reduce toxicity, and introduce a synthetic NY-ESO-1 transgene to improve tumor cell recognition. In addition to two myeloma patients, using adoptive immunotherapy with genetically modified T lymphocytes the first patient with a solid tumor drug-resistant metastatic sarcoma was cured. Already in June, the following article was published, continuing the topic, on the use of CRISPR-modified T cells in patients with refractory NSCLC. In this phase I trial, 12 patients were treated with engineered-T lymphocytes. All treatment-related adverse events were grade 1/2. The median progression-free survival was 7.7 weeks and the median overall survival was 42.6 weeks. These results show the safety and the possibility of using the approach in the treatment of cancer patients, including those with solid tumors.

And I would like to end with an interesting clinical observation published in January 2021 in the New England Journal of Medicine. This article describes 2 cases of transmission of cancer cells from a mother with cervical cancer to a child during childbirth through the birth canal, and the further development of lung cancer in children. In 23-month-old and 6-year-old boys, tumors were detected at the time of diagnosis at the onset of complaints, and therapy with an immune checkpoint inhibitor (Nivolumab) resulted in a strong regression of all remaining tumors in the first child. Surprisingly.