Immunotherapy for non-small cell lung cancer (NSCLC) is incorporated increasingly in first line treatments protocols. Multiple phase 3 studies have tested different medications targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), with or without chemotherapy. The inclusion criteria differ between the various clinical trials, including the cut-off levels of PD-L1 expression on tumor cells, and the tumor histology (squamous or non-squamous). Patients with tumor expression levels of PD-L1 ≥ 50% are candidates for treatment with single agent Pembrolizumab or Atezolizumab. Patients with PD-L1 < 50% are candidates for immunotherapy with pembrolizumab as a single agent if PL-1 > 1%; immunotherapy doublet, Nivolumab and Ipilimumab, or single agent immunotherapy combined with chemotherapy. Here we review phase 3 clinical trials utilizing immunotherapy in the first line for treatment of NSCLC, including Pembrolizumab in KEYNOTE-024, KEYNOTE-042, KEYNOTE-189 and KEYNOTE-407; Nivolumab and Ipilimumab in CHECKMATE-227 and CHECKMATE 9LA; and Atezolizumab in IMpower110, IMpower130 and IMpower150.

The association between cancer and thrombosis has been known for over a century and a half. However, the mechanisms that underlie this correlation are not fully characterized. Hypercoagulability in cancer patients can be classified into two main categories: Type I and Type II. Type I occurs when the balance of endogenous heparin production and degradation is disturbed, with increased degradation of endogenous heparin by tumor-secreted heparanase. Type II hypercoagulability includes all the other etiologies, with factors related to the patient, the tumor, and/or the treatment. Patients with poor performance status are at higher risk of venous thromboembolism (VTE). Tumors can result in VTE through direct pressure on blood vessels, resulting in stasis. Several medications for cancer are correlated with a high risk of thrombosis. These include hormonal therapy (e.g., tamoxifen), chemotherapy (e.g., cisplatin, thalidomide and asparaginase), molecular targeted therapy (e.g., lenvatinib, osimertinib), and anti-angiogenesis monoclonal antibodies (e.g., bevacizumab and ramucirumab).

The BNT162b2 vaccine was shown to be highly effective in reducing the risk of COVID-19 infection in healthy individuals and patients with chronic disease. However, there are little data regarding its efficacy in patients treated for cancer. We analyzed the humoral response following vaccination with the second dose of BNT162b2 in 140 patients with solid malignancies who were receiving anti-cancer therapy at the time of vaccination and 215 participants who had not been diagnosed with cancer. Multivariate analysis was performed, followed by matching the two groups by age, gender and days from vaccination. The humoral response in the cancer patient group was significantly lower than in the non-cancer group: 20/140 seronegative (14.3%) vs. 3/215 (1.4%), p < 0.001; median IgG levels 2231 AU/mL (IQR 445-8023) vs. 4100 (IQR 2231-6774) p = 0.001 respectively. The odds ratio for negative serology results in cancer patients adjusted by age and gender was 7.35 compared to participants without cancer. This effect was observed only in chemotherapy treated patients: 17/73 seronegative (23.3%) vs. 3/215 (1.4%), p < 0.001; median IgG 1361 AU/mL vs. 4100, p < 0.001 but not in patients treated with non-chemotherapeutic drugs. Reduced immunogenicity to COVID-19 vaccine among chemotherapy-treated cancer patients, raises the need to continue exercising protective measures after vaccination in these patients.

Lung cancer is worldwide the most common malignancy. Standard of care treatments for early-stage non-small-cell lung cancer (NSCLC) include surgery and adjuvant chemotherapy. However, these patients continue to have poor prognosis due to systemic or local relapse. Immunotherapy has been considered as a novel approach to improve survival in patients with early-stage NSCLC. Since immune checkpoint inhibitors have transformed the treatment of advanced NSCLC, there is a growing interest in the role of immunotherapy in early-stage NSCLC. In this review, we summarize reported and ongoing clinical trials of immunotherapy in both neoadjuvant and adjuvant settings. We also highlight unaddressed issues in this field of research, such as the predictive markers, the optimal combination therapy, and the need for adjuvant immunotherapy. More studies are needed to optimize the treatment regimen of immunotherapy in patients with early-stage NSCLC.

Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC).

Background. FGFR1/2/3 fusions have been reported infrequently in aNSCLC, including as a rare, acquired resistance mechanism following treatment with EGFR TKIs. Data regarding their prevalence and therapeutic implications are limited. Methods. The Guardant Health (GH) electronic database (ED) was evaluated for cases of aNSCLC and FGFR2/3 fusions; FGFR2/3 fusion prevalence with and without a co-existing EGFR mutation was assessed. The ED of Tel-Aviv Sourasky Medical Center (TASMC, June 2020–June 2021) was evaluated for cases of aNSCLC and de novo FGFR1/2/3 fusions. Patients with EGFR mutant aNSCLC progressing on EGFR TKIs and developing an FGFR1/2/3 fusion were selected from the ED of Davidoff Cancer Center (DCC) and Oncology Department, Bnei-Zion hospital (BZ) (April 2014–April 2021). Clinicopathological characteristics, systemic therapies, and outcomes were assessed. Results. In the GH ED (n = 57,445), the prevalence of FGFR2 and FGFR3 fusions were 0.02% and 0.26%, respectively. FGFR3-TACC3 fusion predominated (91.5%). In 23.8% of cases, FGFR2/3 fusions co-existed with EGFR sensitizing mutations (exon 19 del, 64.1%; L858R, 33.3%, L861Q, 2.6%). Among samples with concurrent FGFR fusions and EGFR sensitizing mutations, 41.0% also included EGFR resistant mutations. In TASMC (n = 161), 1 case of de novo FGFR3-TACC3 fusion was detected (prevalence, 0.62%). Of three patients from DCC and BZ with FGFR3-TACC3 fusions following progression on EGFR TKIs, two received EGFR TKI plus erdafitinib, an FGFR TKI, with clinical benefit duration of 13.0 and 6.0 months, respectively. Conclusions. Over 23% of FGFR2/3 fusions in aNSCLC may be associated with acquired resistance following treatment with EGFR TKIs. In this clinical scenario, a combination of EGFR TKIs and FGFR TKIs represents a promising treatment strategy.