Immunotherapy in small cell lung cancer:One step at a time: A narrative review

Chemotherapy with or without radiotherapy has been the standard of care for many years for patients with small cell lung cancer (SCLC). Despite exceptionally high responses (up to 80%) with chemotherapy, the majority of patients relapse rapidly within weeks to months after treatment completion. Therefore, new and better treatment options are necessary. Recently, synergistic activity has been reported for the addition of immune checkpoint inhibitors (ICI) to standard platinum-based chemotherapy in the therapeutic strategy of advanced SCLC. For the first time after several decades, a significant survival improvement was achieved for this population. However, the overwhelming majority of patients do not respond to ICI, or relapse rapidly. There is need for better knowledge about the biology, histopathologic features, and molecular pathways of SCLC. This can probably help to identify the optimal predictive biomarkers, which are warranted to develop an individual therapeutic strategy including the rational use of a combination of immunotherapeutic agents. Here, we provide an overview of the rationale for and clinical results of the completed and ongoing trials using different strategies of immunotherapy in SCLC. In addition, opportunities for further improvement of therapies will be discussed, including the addition of radiotherapy, co-stimulatory antibodies, and other immune modifying agents.</p

A brief report on combination chemotherapy and anti–programmed death (ligand) 1 treatment in small-cell lung cancer: Did we choose the optimal chemotherapy backbone?

Extensive-stage small-cell lung cancer (ES-SCLC) is an aggressive cancer that remains very hard to treat. The life expectancy of a patient diagnosed with this disease has not changed over the past three decades. Recently, three large clinical studies showed a survival benefit by adding an anti–programmed death (ligand) 1 (PD-(L)1 antibody to the current chemotherap

Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes

BACKGROUND: Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: more than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. METHODS: Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. RESULTS: The median age at onset was 67.8 years (SD 8.4) with a female predominance (n = 17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2–11). Most patients had subacute sensory neuronopathy (n = 15, 75%), with a median mRS of 4 at baseline. Thirteen patients had a tumor, all small cell lung cancer. After natalizumab treatment, two patients (10%) showed functional improvement. Of the remaining patients, 60% had a stable functional outcome, while 30% showed further deterioration. Treatment response was classified as positive in nine patients (45%). CONCLUSIONS: Natalizumab may ameliorate the disease course in Hu-PNS, but no superior effects above other reported immunosuppressive and immunomodulatory were observed. More effective treatment modalities are highly needed. TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000675-13/N

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer

Background: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. Objective: We aimed to develop alternative dosing regimens to reduce drug expenses. Methods: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. Results: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. Conclusions: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.</p

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19:an update from the Dutch Oncology COVID-19 Consortium

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic

Rare thoracic cancers: a comprehensive overview of diagnosis and management of small cell lung cancer, malignant pleural mesothelioma and thymic epithelial tumours

Despite the progress in outcomes seen with immunotherapy in various malignancies, including nonsmall cell lung cancer, the benefits are less in small cell lung cancer, malignant pleural mesothelioma and thymic epithelial tumours. New effective treatment options are needed, guided via more in-depth insights into the pathophysiology of these rare malignancies. This review comprehensively presents an overview of the clinical presentation, diagnostic tools, staging systems, pathophysiology and treatment options for these rare thoracic cancers. In addition, opportunities for further improvement of therapies are discussed

Long-term follow-up of mesothelioma patients treated with dendritic cell therapy in three phase i/ii trials

Background: Malignant pleural mesothelioma (MPM) is a fatal neoplasm with, if un-treated, poor survival of approximately nine months from diagnosis. Until recently, phase II–III immunotherapy trials did not show any significant benefit. The lack of immunotherapy efficacy can be explained by the fact that mesothelioma is a tumor with an “immune desert” phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of DCs, which were ex-vivo cultured, exposed to (tumor-associated) antigens, and subsequently activated, this “immune desert” phenotype might be turned into an “inflamed” phenotype. Three phase I/II studies have been performed and published using activated DCs, which support this concept. We here report on the long-term survival of patients treated with DCs in three phase I/II studies. Methods: Survival data of the phase I/II trials using DC therapy in MPM patients were obtained and subsequently analyzed. In the first two trials, DCs were loaded with autologous tumor lysate. In the third trial, DCs were loaded with allogeneic mesothelioma tumor cell line lysate. Results: In the three studies combined, 29 patients with MPM were treated with DC vaccination between 2006 and 2015. At data cut-off, the median OS was 27 months (95% CI: 21–47 months). OS at 2 years was 55.2% (95% CI: 39.7–76.6%), and OS at 5 years was 20.7% (95% CI: 10.1–42.2%). Conclusions: The long-term survival of DC therapy in MPM in these three trials is promising, which is the basis for the randomized phase II/III DENIM study. This DENIM study is currently enrolling, and the results of which have to be awaited for definite conclusions