Epidermal growth factor receptor-mutated lung carcinomas with insufficient response to epidermal growth factor receptor inhibitors.

Administration of single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a standard treatment option for metastatic non-small cell lung carcinomas with EGFR exon 19 deletions (ex19del) and L858R substitutions. However, there is a significant interpatient heterogeneity with regard to the degree of the response and its duration. Patients with EGFR ex19del mutation, TP53 wild-type, good performance status, low tumor burden and no circulating tumor DNA (ctDNA) at baseline have the best chances to derive pronounced benefit from TKI therapy. In contrast, subjects with EGFR L858R substitution, mutated TP53, poor overall condition, high tumor volume and detectable ctDNA are generally poor responders to EGFR inhibitors. ctDNA dynamics in the first days or weeks of treatment allows reliable identification of patients, who are very unlikely to derive clinically meaningful benefit from single-agent TKIs. These patients are candidates for clinical trials, which may involve the addition of chemotherapy and antiangiogenic drugs to patients, who failed to achieve immediate benefit from TKI monotherapy.

[Box: see text].

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial.

PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS: In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Evidence blocks for effective presentation of genomic findings at molecular tumor boards: Single institution experience.

Genomic profiling, or molecular profiling of the tumor, is becoming a key component of therapeutic decision making in clinical oncology, and is typically carried out via next generation sequencing. However, the interpretation of the results and evaluation of rationale for targeting the uncovered alterations is challenging and requires a deep understanding of cancer biology, genetics, genomics and oncology. Multidisciplinary molecular tumor boards represent a promising strategy in the facilitation of molecularly-informed therapeutic decisions, and usually consist of specialists with various fields of expertise. To effectively communicate the biological and clinical significance of genomic findings, as well as to make molecular tumor board discussions more productive, we developed and implemented evidence blocks into case discussions in our center. We found that this approach facilitated clinicians' understanding of the results of genomic profiling, and resulted in shorter yet more efficient case discussions within the molecular tumor board. Here, we discuss our experience with evidence blocks and how their implementation influenced the molecular tumor board practice.

Utility of public knowledge bases for the interpretation of comprehensive tumor molecular profiling results.

With the growing use of comprehensive tumor molecular profiling (CTMP), the therapeutic landscape of cancer is rapidly evolving. NGS produces large amounts of genomic data requiring complex analysis and subsequent interpretation. We sought to determine the utility of publicly available knowledge bases (KB) for the interpretation of the cancer mutational profile in clinical practice. Analysis was performed across patients who previously underwent CTMP. Independent interpretation of the CTMP was performed manually, and then, the recommendations were compared to ones present in KBs (OncoKB, CIViC, CGI, CGA, VICC, MolecularMatch). A total of 222 CTMP reports from 222 patients with 932 genomic alterations (GA) were identified. For 368 targetable GA identified in 171 (77%) of the patients, 1381 therapy recommendations were compiled. Except for CGA, therapy ESCAT LOE I, II, IIIA and IIIB therapy options were equally represented in the majority of KB. Personalized treatment options with ESCAT LOE I-II were provided for 35 patients (16%); MolecularMatch/CIViC allowed to collect ESCAT I-II treatment options for 34 of them (97%), OncoKB/CGI-for 33 of them (94%). Employing VICC and CGA 6 (17%) and 20 (57%) of patients were left without ESCAT I or II treatment options. For 88 patients with ESCAT level III-B therapy recommendations: only 2 (2%), 3 (3%), 4 (5%) and 6 (7%) of patients were left without options with CIViC, MolecularMatch, CGI and OncoKB, and with VICC-12 (14%). Highest overlap ratio was observed for IIIA (0.81) biomarkers, with the comparable results for LOE I-II. Meanwhile, overlap ratio for ESCAT LOE IV was 0.22. Public KBs provide substantial information on ESCAT-I/R1 biomarkers, but the information on ESCAT II-IV and resistance biomarkers is underrepresented. Manual curation should be considered the gold standard for the CTMP interpretation.

Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study.

BACKGROUND: Trifluridine-tipiracil plus bevacizumab has shown efficacy in previous phase 2 studies including patients with unresectable metastatic colorectal cancer. We aimed to investigate first-line trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab in patients with unresectable metastatic colorectal cancer ineligible for intensive treatment. METHODS: In this open-label, randomised, phase 3 study, we enrolled patients aged 18 years and older with histologically confirmed metastatic colorectal cancer, ineligible for full-dose doublet or triplet chemotherapy and curative resection across 25 countries and regions. Participants were randomly allocated (1:1) to trifluridine-tipiracil plus bevacizumab or capecitabine plus bevacizumab until disease progression or unacceptable toxicity using an interactive web response system, stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), primary tumour location (right vs left colon), and the main reason for not being a candidate for intensive therapy (clinical condition vs non-clinical condition). The primary endpoint was investigator-assessed progression-free survival, defined as the time from randomisation to radiological progression or death from any cause, in the intention-to-treat population. Safety was assessed in all patients having taken at least one dose of the study drug. The trial is ongoing, findings presented here are those of the primary analysis of progression-free survival, conducted after 629 events had occurred. This study is registered with ClinicalTrials.gov, NCT03869892. FINDINGS: Between March 21, 2019, and Sept 14, 2020, 856 patients (54% male, 46% female) were randomly assigned to trifluridine-tipiracil plus bevacizumab (n=426) or capecitabine plus bevacizumab (n=430). After a median follow-up of 16·6 months (95% CI 16·5-17·1), the hazard ratio for progression-free survival for trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab was 0·87 (0·75-1·02; p=0·0464; protocol-defined significance level of p=0·021 not met). Investigator-assessed median progression-free survival was 9·4 months (95% CI 9·1-10·9) with trifluridine-tipiracil plus bevacizumab versus 9·3 months (8·9-9·8) with capecitabine plus bevacizumab. The most common grade 3 and higher treatment-emergent adverse events were neutropenia (220 [52%] of 423 patients in the trifluridine-tipiracil plus bevacizumab group vs six [1%] of 427 in the capecitabine plus bevacizumab group), decreased neutrophil count (78 [18%] vs four [<1%]), anaemia (60 [14%] vs 16 [4%]), and hand-foot syndrome (none vs 61 [15%]). Nine deaths (five in the trifluridine-tipiracil plus bevacizumab group and four in the capecitabine plus bevacizumab group) were treatment related. INTERPRETATION: First-line trifluridine-tipiracil plus bevacizumab was not superior to capecitabine plus bevacizumab in this population. As expected, the safety profile differed between the two treatments, but there were no new safety concerns. Trifluridine-tipiracil plus bevacizumab represents a feasible alternative to capecitabine plus bevacizumab in this population. FUNDING: Servier International Research Institute, Suresnes, France.

Management and Treatment of Non-small Cell Lung Cancer with MET Alteration and Mechanisms of Resistance.

OPINION STATEMENT: MET-driven tumors are a heterogenous group of non-small cell lung cancers (NSCLC) with activating mutations. Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions. Besides its role as primary driver, MET activation might also mediate resistance to kinase inhibitors in NSCLC with various other actionable alterations. While checkpoint inhibitors have modest efficacy in MET-driven tumors, several approaches of targeted blockade are available. Among them the most promising are small tyrosine kinase inhibitors, antibody-drug conjugates, and bispecific antibodies. Unfortunately, resistance is virtually inevitable. Resistance to small kinase inhibitors might be mediated by kinase domain mutations or activation of shunting cascades. Various resistance mechanisms might be present in one patient, making it overcoming an unresolved problem.

Tumor acidity: From hallmark of cancer to target of treatment.

Tumor acidity is one of the cancer hallmarks and is associated with metabolic reprogramming and the use of glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid acid stress major by the activation and expression of proton and lactate transporters and exchangers and have an inverted pH gradient (extracellular and intracellular pHs are acid and alkaline, respectively). The shift in the tumor acid-base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, and treatment resistance. For example, weak-base chemotherapeutic agents may have a substantially reduced cellular uptake capacity due to "ion trapping". Lactic acid negatively affects the functions of activated effector T cells, stimulates regulatory T cells, and promotes them to express programmed cell death receptor 1. On the other hand, the inversion of pH gradient could be a cancer weakness that will allow the development of new promising therapies, such as tumor-targeted pH-sensitive antibodies and pH-responsible nanoparticle conjugates with anticancer drugs. The regulation of tumor pH levels by pharmacological inhibition of pH-responsible proteins (monocarboxylate transporters, H+-ATPase, etc.) and lactate dehydrogenase A is also a promising anticancer strategy. Another idea is the oral or parenteral use of buffer systems, such as sodium bicarbonate, to neutralize tumor acidity. Buffering therapy does not counteract standard treatment methods and can be used in combination to increase effectiveness. However, the mechanisms of the anticancer effect of buffering therapy are still unclear, and more research is needed. We have attempted to summarize the basic knowledge about tumor acidity.

Candidate Bevacizumab Biosimilar CT-P16 versus European Union Reference Bevacizumab in Patients with Metastatic or Recurrent Non-Small Cell Lung Cancer: A Randomized Controlled Trial.

BACKGROUND: CT-P16 is a candidate bevacizumab biosimilar. OBJECTIVE: This double-blind, multicenter, parallel-group, phase III study aimed to establish equivalent efficacy between CT-P16 and European Union-approved reference bevacizumab (EU-bevacizumab) in patients with metastatic or recurrent non-squamous non-small cell lung cancer (nsNSCLC). PATIENTS AND METHODS: Patients with stage IV or recurrent nsNSCLC were randomized (1:1) to receive CT-P16 or EU-bevacizumab (15 mg/kg every 3 weeks; ≤ 6 cycles) with paclitaxel (200 mg/m2) and carboplatin (area under the curve 6.0; both for 4-6 cycles), as induction therapy. Patients with controlled disease after induction therapy continued with CT-P16 or EU-bevacizumab maintenance therapy. The primary endpoint was objective response rate (ORR) during the induction period. Time-to-event analyses, pharmacokinetics, safety, and immunogenicity were also evaluated. Results obtained after 1 year of follow-up are presented. RESULTS: Overall, 689 patients were randomized (CT-P16, N = 342; EU-bevacizumab, N = 347). ORR was 42.40% (95% confidence interval [CI] 37.16-47.64) and 42.07% (95% CI 36.88-47.27) for CT-P16 and EU-bevacizumab, respectively. The risk difference (0.40 [95% CI - 7.02 to 7.83]) and risk ratio (1.0136 [90% CI 0.8767-1.1719]) for ORR fell within predefined equivalence margins (- 12.5 to + 12.5%, and 0.7368 to 1.3572, respectively), demonstrating equivalence between CT-P16 and EU-bevacizumab. Median response duration, time to progression, progression-free survival, and overall survival were comparable between treatment groups. Safety profiles were similar: 96.2% (CT-P16) and 93.0% (EU-bevacizumab) of patients experienced treatment-emergent adverse events. Pharmacokinetics and immunogenicity were comparable between groups. CONCLUSIONS: Equivalent efficacy and similar pharmacokinetics, safety, and immunogenicity support bioequivalence of CT-P16 and EU-bevacizumab in patients with nsNSCLC. TRIAL REGISTRATION NUMBER: NCT03676192.

Case Report: Multiple Causes of Cardiac Death After the First Infusion of Atezolizumab: Histopathological and Immunohistochemical Findings.

Immune checkpoint inhibitors are promising agents for anticancer therapy. But despite their high efficacy in the treatment of solid tumors, there is still a problem with immune-related adverse events, especially cardiovascular complications with a very high mortality rate. Myocarditis or ischemic heart disease progression is not the only possible cause of cardiovascular death in patients treated with checkpoint inhibitors. We report a case of a patient with mucinous carcinoma of the lung, with a previous history of hypertension and moderate left ventricular dysfunction. The patient was prescribed atezolizumab, but the first atezolizumab infusion resulted in the patient cardiovascular death. Postmortem histopathological evaluation of myocardium revealed several possible reasons for hemodynamic instability: tumor embolism of the coronary arteries, micrometastases of mucinous carcinoma in the myocardium, and myocarditis diagnosed by both Dallas and immunohistochemistry criteria. In addition, testing for expression of PD-L1 detected the high levels of membranous and cytoplasmic PD-L1 protein even in the myocardium area free from tumor cells. The present clinical case demonstrates a problem of cardiovascular death in patients treated with checkpoint inhibitors and actualizes the need for future research of potential risk factors for cardiovascular complications.

Real-World Experience with Targeted Therapy in BRAF Mutant Advanced Melanoma Patients: Results from a Multicenter Retrospective Observational Study Advanced Melanoma in Russia (Experience) (ADMIRE).

Clinical trials of targeted therapy (TT) and immunotherapy (IT) for highly aggressive advanced melanoma have shown marked improvements in response and survival rates. However, real-world data on treatment patterns and clinical outcomes for patients with advanced BRAF V600 mutant melanoma are ultimately scarce. The study was designed as an observational retrospective chart review study, which included 382 patients with advanced BRAF V600 mutant melanoma, who received TT in a real-world setting and were not involved in clinical trials. The data were collected from twelve medical centers in Russia. The objective response rates (ORRs) to combined BRAFi plus MEKi and to BRAFi mono-therapy were 57.4% and 39.8%, respectively. The median progression-free survival (PFS) and median overall survival (OS) were 9.2 months and 22.6 months, respectively, for the combined first-line therapy; 9.4 months and 16.1 months, respectively, for the combined second-line therapy; and 7.4 months and 17.1 months, respectively, for the combined third- or higher-line therapy. Analysis of treatment patterns demonstrated the effectiveness of the combined TT with BRAF plus MEK inhibitors in patients with brain metastases, rare types of BRAF mutations, and across lines of therapy, as well as a well-tolerated and manageable safety profile.

Efficacy of immune checkpoint blockade in MUTYH-associated hereditary colorectal cancer.

Colorectal carcinomas (CRCs) caused by hereditary biallelic MUTYH gene mutations are characterized by elevated mutation load and high lymphocyte infiltration. Given that these tumor features are associated with the response to immune checkpoint inhibitors, we administered nivolumab to a CRC patient who carried two inactive MUTYH alleles (p.Y179C and p.G396D) and previously experienced failure of chemotherapy. This experimental treatment resulted in a pronounced tumor response. We further compared tumor lymphocyte infiltration in MUTYH-associated (n = 3), high-level microsatellite instability (MSI-H, n = 8) and microsatellite stable (MSS, n = 6) CRCs. Both MUTYH-driven and MSI-H CRCs showed noticeably higher lymphocyte densities than those of microsatellite stable tumors; this difference reached the level of statistical significance for the comparison of central areas of the tumors (p = 0.02 and 0.03, respectively) but not for the invasive tumor margins. Although MUTYH-associated tumors are exceptionally rare among unselected CRC cases, their share in CRC patients with somatic KRAS p.G12C substitution approaches 5-25%. These observations provide a rationale for further evaluation of the efficacy of the immune checkpoint blockade in MUTYH-driven CRC.

Overall Survival of Patients With ALK-Positive Metastatic Non-Small-Cell Lung Cancer in the Russian Federation: Nationwide Cohort Study.

PURPOSE: The overall survival (OS) results in patients with ALK-positive metastatic non-small-cell lung cancer (NSCLC) have rarely been reported. The aim of this prospective-retrospective cohort study was to obtain real-world data on the use of crizotinib or chemotherapy in patients with ALK-positive metastatic NSCLC in Russia. PATIENTS AND METHODS: Patients with epidermal growth factor receptor-negative metastatic NSCLC were screened in 23 cancer centers. To be eligible, patients were required to have confirmation of ALK rearrangement. Patients were treated with crizotinib (250 mg twice daily; n = 96) or the investigator's choice of platinum-based chemotherapy (n = 53). The primary end point was OS. RESULTS: A total of 149 ALK-positive patients were included. Mean age was 53 years in both groups. Patients were predominately women (59%) and never-smokers (74%), and most patients had adenocarcinoma histology (95%). At a median follow-up time of 15 months, 79 of the 149 patients included in the analysis had died. Median OS from the start of treatment was 31 months (95% CI, 28.5 to 33.5 months) in the crizotinib group and 15.0 months (95% CI, 9.0 to 21.0 months) in the chemotherapy group (P < .001). The objective response rate was 34% in the crizotinib group. Among patients with brain metastasis, one complete response (6%) and five partial responses (31%) were achieved. Grade 3 adverse events were observed in three patients (3%) in the crizotinib group. CONCLUSION: The improved OS observed in crizotinib clinical trials in ALK-positive NSCLC was also observed in the less selective patient populations treated in daily practice in Russia. The use of standard chemotherapy in these patients remains common but seems inappropriate as a result of the effectiveness of newer treatments, such as crizotinib.

Crystal structures of a llama VHH antibody BCD090-M2 targeting human ErbB3 receptor.

Background: The ability of ErbB3 receptor to functionally complement ErbB1-2 and induce tumor resistance to their inhibitors makes it a unique target in cancer therapy by monoclonal antibodies. Here we report the expression, purification and structural analysis of a new anti-ErbB3 single-chain antibody. Methods: The VHH fragment of the antibody was expressed in E. coli SHuffle cells as a SUMO fusion, cleaved by TEV protease and purified to homogeneity. Binding to the extracellular domain of ErbB3 was studied by surface plasmon resonance. For structural studies, the antibody was crystallized by hanging-drop vapor diffusion in two different forms. Results: We developed a robust and efficient system for recombinant expression of single-domain antibodies. The purified antibody was functional and bound ErbB3 with K D =15±1 nM. The crystal structures of the VHH antibody in space groups C2 and P1 were solved by molecular replacement at 1.6 and 1.9 Å resolution. The high-quality electron density maps allowed us to build precise atomic models of the antibody and the putative paratope. Surprisingly, the CDR H2 existed in multiple distant conformations in different crystal forms, while the more complex CDR H3 had a low structural variability. The structures were deposited under PDB entry codes 6EZW and 6F0D. Conclusions: Our results may facilitate further mechanistic studies of ErbB3 inhibition by single-chain antibodies. Besides, the solved structures will contribute to datasets required to develop new computational methods for antibody modeling and design.

Resistance mechanisms to drug therapy in breast cancer and other solid tumors: An opinion.

Cancer is an important contributor to mortality worldwide. Breast cancer is the most common solid tumor in women. Despite numerous drug combinations and regimens, all patients with advanced breast cancer, similarly to other solid tumors, inevitably develop resistance to treatment. Identified mechanisms of resistance could be classified into intra- and extracellular mechanisms. Intracellular mechanisms include drug metabolism and efflux, target modulations and damage restoration. Extracellular mechanisms might be attributed to the crosstalk between tumor cells and environmental factors. However, current knowledge concerning resistance mechanisms cannot completely explain the phenomenon of multi-drug resistance, which occurs in the vast majority of patients treated with chemotherapy. In this opinion article, we investigate the role of these factors in the development of drug-resistance.

Abnormal expression of ATP1A1 and ATP1A2 in breast cancer.

Breast cancer is the first in incidence and the second in death among all solid tumors occurring in women. The identification of molecular genetic abnormalities in breast cancer is important to improve the results of treatment. In the present study, we analyzed microarray data of breast cancer expression profiling (NCBI GEO database, accession GSE65194), focusing on Na +/K +-ATPase coding genes. We found overexpression of the ATP1A1 and down-regulation of the ATP1A2. We expect that our research could help to improve the understanding of predictive and prognostic features of breast cancer.

Pulse mode of laser photodynamic treatment induced cell apoptosis.

One of the factors limiting photodynamic therapy (PDT) is hypoxia in tumor cells during photodynamic action. PDT with pulse mode irradiation and appropriate irradiation parameters could be more effective in the singlet oxygen generation and tissue re-oxygenation than continuous wave (CW) mode. We theoretically demonstrate differences between the cumulative singlet oxygen concentration in PDT using pulse mode and CW mode of laser irradiation. In vitro experimental results show that photodynamic treatment with pulse mode irradiation has similar cytotoxicity to CW mode and induces mainly cell apoptosis, whereas CW mode induces necrotic cell death. We assume that the cumulative singlet oxygen concentration and the temporal distribution of singlet oxygen are important in photodynamic cytotoxicity and apoptosis initiation. We expect our research may improve irradiation protocols and photodynamic therapy efficiency.