Pembrolizumab in lung cancer: current evidence and future perspectives.

Pembrolizumab is a humanized monoclonal antibody against PD-1 capable of enhancing antitumor immune activity. The KEYNOTE-001 study showed that pembrolizumab has activity in advanced non-small-cell lung cancer patients and identified programmed death ligand 1 (PD-L1) as a companion test to select patients most likely to benefit from pembrolizumab. Five randomized clinical trials showed the efficacy of pembrolizumab in non-small-cell lung cancer: in second-line setting PD-L1 ≥1% (KEYNOTE-010), in first-line setting PD-L1 ≥50% (KEYNOTE-024 and KEYNOTE-042) and in first-line setting in combination with platinum doublets, any expression of PD-L1 (KEYNOTE-189 and KEYNOTE-407). Future challenges are the identification of the role of pembrolizumab in adjuvant, neoadjuvant, locally advanced disease or oncogene-addicted patients, in combination with radiotherapy or other biological agents.

Angiogenesis Inhibitors in NSCLC.

Angiogenesis is a complex biological process that plays a relevant role in sustaining the microenvironment, growth, and metastatic potential of several tumors, including non-small cell lung cancer (NSCLC). Bevacizumab was the first angiogenesis inhibitor approved for the treatment of patients with advanced NSCLC in combination with chemotherapy; however, it was limited to patients with non-squamous histology and first-line setting. Approval was based on the results of two phase III trials (ECOG4599 and AVAIL) that demonstrated an improvement of about two months in progression-free survival (PFS) in both trials, and in the ECOG4599 trial, an improvement in overall survival (OS) also. Afterwards, other antiangiogenic agents, including sunitinib, sorafenib, and vandetanib have been unsuccessfully tested in first and successive lines. Recently, two new antiangiogenic agents (ramucirumab and nintedanib) produced a significant survival benefit in second-line setting. In the REVEL study, ramucirumab plus docetaxel prolonged the median OS of patients with any histology NSCLC when compared with docetaxel alone (10.4 versus 9.1 months, hazard ratio (HR) 0.857, p = 0.0235). In the LUME-Lung 1 study, nintedanib plus docetaxel prolonged the median PFS of patients with any tumor histology (p = 0.0019), and improved OS (12.6 versus 10.3 months) in patients with adenocarcinoma. As a result, it became a new option for the second-line treatment of patients with advanced NSCLC and adenocarcinoma histology. Identifying predictive biomarkers to optimize the benefit of antiangiogenic drugs remains an ongoing challenge.

Extracerebral anaplastic meningioma.

Key Clinical Message: Conventional treatments of anaplastic meningioma include surgery and radiotherapy. Temozolomide is also an option. Metastases to extracerebral organs are very rare and hardly manageable. Antiangiogenic drugs could represent a salvage therapy. Abstract: Anaplastic meningioma is an unusual tumor subtype that rarely involves organs outside the brain. In our case, a patient with cerebral meningioma developed lung metastases after 19 years from the initial tumor appearance. This unpredictable behavior could make complex the diagnosis.

BRAF Inhibitors in Non-Small Cell Lung Cancer.

RAF family proteins are serine-threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5-3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.

Lurbinectedin in small cell lung cancer.

Few treatment options are available for patients with small cell lung cancer (SCLC) in progression after a first-line therapy. A novel therapeutic approach is represented by lurbinectedin, a synthetic derivative of trabectedin that works by inhibiting oncogenic transcription and promoting apoptosis in tumor cells. A phase II basket trial demonstrated the activity of lurbinectedin at the dose of 3.2 mg/m2 in patients with SCLC who had failed a previous chemotherapy, with a response rate of 35.2%, a median progression-free survival (mPFS) of 3.5 months, and a median overall survival (mOS) of 9.3 months. Common severe adverse events (grades 3-4) were hematological disorders, including anemia (9%), leukopenia (29%), neutropenia (46%), and thrombocytopenia (7%). On the basis of the positive results of this phase II study, on June 2020, lurbinectedin was approved by the Food and Drug Administration as second line for SCLC patients in progression on or after platinum-based therapy. The subsequent phase III trial comparing the combination of lurbinectedin plus doxorubicin vs. CAV (cyclophosphamide, Adriamycin, and vincristine) or topotecan did not demonstrate an improvement in overall survival, although the experimental arm showed a superior safety profile. Combinations of lurbinectedin with other drugs, cytotoxic agents and immune checkpoint inhibitors, are currently under investigation. The results of these studies should better define the optimal clinical application of lurbinectedin.

Gefitinib in non small cell lung cancer.

Gefitinib is an oral, reversible, tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) that plays a key role in the biology of non small cell lung cancer (NSCLC). Phase I studies indicated that the recommended dose of gefitinib was 250 mg/day. Rash, diarrhea, and nausea were the most common adverse events. The positive results obtained in early phase 2 clinical trials with gefitinib were not confirmed in large phase 3 trials in unselected patients with advanced NSCLC. The subsequent discovery that the presence of somatic mutations in the kinase domain of EGFR strongly correlates with increased responsiveness to EGFR tyrosine kinase inhibitors prompted phase 2 and 3 trials with gefitinib in the first line-treatment of EGFR-mutated NSCLC. The results of these trials have demonstrated the efficacy of gefitinib that can be now considered as the standard first-line treatment of patients with advanced NSCLC harbouring activating EGFR mutations.

Angiogenesis Inhibitors in Small Cell Lung Cancer.

Inhibition of angiogenesis has been demonstrated to be an efficacious strategy in treating several tumors. Vascular endothelial growth factor (VEGF) is the most important protein with proangiogenic functions and it is overexpressed in small cell lung cancer (SCLC). Bevacizumab, a monoclonal antibody directed against VEGF, showed a promising activity in combination with etoposide and cisplatin as first-line treatment of patients with extended stage (ES)-SCLC and two randomized studies confirmed that bevacizumab improved PFS, but failed to prolong OS. Instead, disappointing results have been observed with endostar, sunitinib, sorafenib, vandetanib, and thalidomide in combination with chemotherapy in the first-line setting, with sunitinib in the maintenance setting, with sunitinib, cediranib and nintedanib as single agents or ziv-aflibercept in combination with topotecan in second-line setting. Only anlotinib improved OS and PFS as third-line therapy in Chinese patients with SCLC, and it was approved with this indication in China. Future challenges are the evaluation of the role of angiogenesis inhibitors in combination with immune- checkpoint inhibitors and chemotherapy in SCLC patients and the identification of predictive biomarkers of response to both agents.

RET Inhibitors in Non-Small-Cell Lung Cancer.

RET rearrangements are observed in 1-2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.

Immunotherapy in Small Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive tumor type with limited therapeutic options and poor prognosis. Chemotherapy regimens containing platinum represent the cornerstone of treatment for patients with extensive disease, but there has been no real progress for 30 years. The evidence that SCLC is characterized by a high mutational burden led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy. Randomized phase III trials demonstrated that the combination of atezolizumab (IMpower-133) or durvalumab (CASPIAN) with platinum-etoposide chemotherapy improved overall survival of patients with extensive disease. Instead, the KEYNOTE-604 study demonstrated that the addition of pembrolizumab to chemotherapy failed to significantly improve overall survival, but it prolonged progression-free survival. The safety profile of these combinations was similar with the known safety profiles of all single agents and no new adverse events were observed. Nivolumab and pembrolizumab single agents showed anti-tumor activity and acceptable safety profile in Checkmate 032 and KEYNOTE 028/158 trials, respectively, in patients with SCLC after platinum-based therapy and at least one prior line of therapy. Future challenges are the identification predictive biomarkers of response to immunotherapy in SCLC and the definition of the role of immunotherapy in patients with limited stage SCLC, in combination with radiotherapy or with other biological agents.

Angiogenesis and epidermal growth factor receptor inhibitors in non-small cell lung cancer.

Several preclinical studies suggested a potential benefit from combined treatment with inhibitors of epidermal growth factor receptor (EGFR) and angiogenesis, both effective in patients with advanced non-small-cell lung cancer (NSCLC). In pretreated patients with advanced EGFR wild type NSCLC, bevacizumab plus erlotinib improved progression-free survival as second-line therapy in the BeTa study and as maintenance therapy in the ATLAS trial, although the benefit was modest and did not translate into an advantage in overall survival. Disappointing results were reported with oral VEGF inhibitors plus erlotinib in pretreated patients with EGFR wild type NSCLC. On the contrary, erlotinib plus bevacizumab or ramucirumab showed a clinically relevant improvement of progression-free survival in naïve patients with EGFR mutations, leading to the approval of these two regimens as first-line treatment of NSCLC patients with EGFR mutant tumors. Several clinical studies are evaluating the feasibility and activity of osimertinib plus bevacizumab or ramucirumab. However, limits that could affect its use in clinical practice are the need of an intravenous infusion for angiogenesis inhibitors, the increased incidence of treatment associated adverse events, the exclusion of patients with tumors located in central position or at risk of hemorrhage. The identification of predictive biomarkers is an important goal of research to optimize the combined use of these agents.

The safety of atezolizumab plus chemotherapy for the treatment of metastatic lung cancer.

INTRODUCTION: Atezolizumab is a humanized monoclonal antibody against PD-L1 capable of enhancing antitumor immune activity, with a demonstrated activity as single agent in patients with advanced non-small-cell lung cancer (NSCLC). AREAS COVERED: This review summarizes the clinical data emerging from randomized clinical studies with atezolizumab in NSCLC and small-cell lung cancer (SCLC), focusing in particular on the efficacy and safety data regarding the combinations of atezolizumab plus chemotherapy in the IMpower studies. EXPERT OPINION: A significant improvement in progression-free survival and in overall survival was observed in IMpower 130 and 150 (NSCLC non-squamous) and 133 (SCLC), with an acceptable safety profile. In particular, the most common immune-related adverse events were rash (18-28% of patients), hypothyroidism (8-15%), hepatitis (5-17%), pneumonitis (2-7%), and colitis (1.5-2.3%). The safety profile of atezolizumab in combination with chemotherapy was consistent with the known adverse events related to single-agent atezolizumab and no new adverse events were observed. Ongoing studies will evaluate the role of atezolizumab in other settings (adjuvant and neoadjuvant) and in combination with chemotherapy and radiotherapy for patients with locally advanced NSCLC and the role of predictive factors (B-FAST study).

Classic Kaposi's sarcoma with an initial solitary colon lesion.

Kaposi's sarcoma involving the digestive tract in isolated form before the appearance of diffuse skin lesions is very rare in HIV-negative patients and is a condition requiring watchful waiting.

Unusual metastases of melanoma.

Malignant melanoma is a very aggressive tumor. Immune and targeted therapy could prolong patient's clinical benefit and survival, but the correct sequence of therapies has still to be defined.

Response to ibrutinib in chronic lymphocytic leukemia improves in quality with time.

Unlike chemoimmunotherapy regimens, which are given for a defined period, ibrutinib, a first-in-class Bruton's kinase inhibitor, allows most patients with CLL to remain on treatment for an extended period. Our experience, supported by sequential CT scan images, suggests that long-term ibrutinib promotes a high response rate that improves in quality with time.

Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpressing metastatic breast cancer.

The aim of this study was to evaluate the safety and efficacy of combined treatment with trastuzumab (T), gemcitabine (gem) and vinorelbine (vin) as second-line therapy for HER-2 overexpressing metastatic breast cancer, pretreated with anthracyclines and/or taxanes and/or trastuzumab. Eligible patients had HER-2/neu-positive disease (IHC 2+ or 3+), performance status (PS) or=2 metastatic sites. Of the patients, 7 (23.3%) had received trastuzumab as first-line therapy. Treatment was well-tolerated with grade 4 neutropenia in 6 patients, grade 3 thrombocytopenia and grade 3 anemia in 1 patient, and grade 3 asthenia in 4 patients. Fifteen patients obtained an objective response (response rate, 50%; C.I. 95%, range, 31.3-68.7%). Among the patients with HER-2/neu 3+, the response rate was 73.3%. Noteworthy were 4 objective responses observed in patients with brain metastasis. Also, 7 patients had stable disease (23.3%). Median progression-free survival was 7 months (range 5-10), and median overall survival was 15 months (range 5-33). T-gem-vin is a safe and active regimen in this subgroup of patients with poor prognosis, and the efficacy of such a schedule was particularly satisfactory in patients with HercepTest 3+.

Multiorganic dissemination of a colorectal signet ring cell carcinoma with fulminant clinical course.

Mucinous colorectal cancer with signet ring cell aspects is a rare form of adenocarcinoma representing about 2-5% of large bowel neoplasms. The tumor frequently presents with late-stage or peritoneal spreading. It can often affect young patients and diffusely infiltrate through all layers of the intestinal wall. Local recurrence and distant metastases are common in spite of surgical operation and adjuvant treatment, conditioning a poor prognosis. At the present, early diagnosis and complete resection are the most important approaches to improve the outcome. In our report we describe a case of a 41-yr-old patient with very aggressive untreated metastatic colorectal signet ring cell carcinoma. The fulminant tumor progression was really unexpected and misled every possible medical interpretation, leading to rapid worsening of the patient's clinical conditions and no chance for chemotherapy treatment. The tumor mimicked the picture observed in the acute leukemia, developing diffuse infiltration in all serosal membranes, liver, lung, kidneys, multiple lymph nodes, and meninges, as revealed by the post-mortem medical report.

Focus on Nintedanib in NSCLC and Other Tumors.

Nintedanib is a new triple angiokinase inhibitor that potently blocks the proangiogenic pathways mediated by vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and fibroblast growth factor receptors. Evidence about its efficacy in addition to second-line chemotherapy in non-small cell lung cancer (NSCLC) has been produced by two large randomized phase III clinical trials (LUME-Lung 1 and LUME-Lung 2), conducted in patients with pretreated NSCLC, without major risk factors for bleeding. In the LUME-Lung 1, the addition of nintedanib to docetaxel significantly improved progression-free survival, which was the primary end point of the trial (3.4 vs. 2.7 months, hazard ratio: 0.79; p = 0.0019). Furthermore, a significant improvement in median overall survival (from 10.3 to 12.6 months) was observed in patients with adenocarcinoma histology, with a greater advantage in patients who progressed within 9 months after start of first-line treatment (from 7.9 to 10.9 months) and in patients who were most refractory to first-line chemotherapy (from 6.3 to 9.8 months). Adverse events were more common in the docetaxel plus nintedanib group, and they included diarrhea and increased liver enzymes, while no statistically significant increase in the incidence of bleeding and hypertension events by the addition of nintedanib was observed. On these bases, the combination of docetaxel and nintedanib can be considered a new option for the second-line treatment for patients with advanced NSCLC with adenocarcinoma histology. Future challenges are the identification of predictive factors to help the decision of using nintedanib in eligible patients.

Afatinib: An overview of its clinical development in non-small-cell lung cancer and other tumors.

Afatinib is an oral, irreversible, tyrosine kinase inhibitor (TKI) of EGFR, HER2 and HER4. According to phase I studies, the recommended dose of afatinib was 50mg daily. Rash, acne, diarrhea and stomatitis were the most common adverse events. Afatinib failed to demonstrate an improvement in overall survival in unselected heavily pretreated NSCLC patients (Lux-Lung-1). On the contrary, the Lux-Lung-3 and -6 trials met the primary end point, demonstrating a significant increase in terms of PFS with afatinib compared with chemotherapy in the first line treatment of EGFR mutant patients. Moreover, in both studies, afatinib improved overall survival in patients with exon 19 EGFR deletion (31.7 vs 20.7 months; HR: 0.59, p=0.0001). The results of ongoing randomized trials should further clarify the efficacy of afatinib compared with first-generation TKIs in advanced NSCLC, its activity in the adjuvant and neoadjuvant settings, as well as its efficacy in other tumors.

An unusual case of three synchronous tumors in a young woman.

The occurrence in the same young patient of three synchronous tumors deriving from different embryogenic tissues and without a clear correlation with a common etiopathogenic factor is very unusual. We report a case of a Caucasian woman submitted to wide resection of a large retroperitoneal liposarcoma and right radical nephrectomy for suspected tumor infiltration. Histological examination of the right ureter and renal pelvis showed the presence of a multifocal urothelial carcinoma that was clinically asymptomatic. Two months later, during follow-up, chest X-ray and computed tomography documented a coin lesion of the upper left lung, confirmed by positron emission tomography. This nodule was surgically removed and examined histologically, resulting in a diagnosis of sclerosing hemangioma. The patient is alive without evidence of recurrent disease.