KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma.

BACKGROUND: Predictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information. METHODS: The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations. Additionally, two previously published immunotherapy and two surgical patient cohorts were analyzed. Therapy benefit was stratified by KRAS and TP53 mutations. Molecular characteristics underlying KRASmut/TP53mut tumours were revealed by the analysis of TCGA data. RESULTS: An interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses of overall survival (Hazard ratio [HR] = 0.56, p = 0.0044 and HR = 0.53, p = 0.0021) resulting in a stronger benefit for KRASmut/TP53mut tumours (HR = 0.71, CI 0.55-0.92). This observation was confirmed in immunotherapy cohorts but not observed in surgical cohorts. Tumour mutational burden, proliferation, and PD-L1 mRNA were significantly higher in TP53-mutated tumours, regardless of KRAS status. Genome-wide expression analysis revealed 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristic of KRASmut/TP53mut tumours. CONCLUSIONS: KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumour features. Mutation testing of the two genes can be easily implemented using small NGS panels.

Real-world data for precision cancer medicine-A European perspective.

Leveraging real-world data (RWD) for drug access is necessary to overcome a key challenge of modern precision oncology: tackling numerous low-prevalence oncogenic mutations across cancers. Withholding a potentially active medication in patients with rare mutations for the sake of control chemotherapy or "best" supportive care is neither practicable nor ethically justifiable anymore, particularly as RWD could meanwhile be used instead, according to scientific principles outlined by the US Food and Drug Administration, European Medicines Agency and other stakeholders. However, practical implementation varies, with occasionally opposite recommendations based on the same evidence in different countries. In the face of growing need for precision drugs, more transparency of evaluation, a priori availability of guidance for the academia and industry, as well as a harmonized framework for health technology assessment across the European Union (EU) are imperative. These could in turn trigger infrastructural changes in national and pan-European registries, cancer management guidelines (e.g., frequency of routine radiologic restaging, inclusion of patient-reported outcomes), and the health data space, to ensure conformity with declared standards and facilitate extraction of RWD sets (including patient-level data) suitable for approval and pricing with minimal effort. For an EU-wide unification of precision cancer medicine, collective negotiation of drug supply contracts and funding solidarity would additionally be required to handle the financial burden. According to experience from pivotal European programs, off-label use could potentially also be harmonized across EU-states to accelerate availability of novel drugs, streamline collection of valuable RWD, and mitigate related costs through wider partnerships with pharmaceutical companies.

Protocol of the TREASURE study: Thoracic RadiothErapy with Atezolizumab in Small cell lUng canceR Extensive disease - a randomized, open-label, multicenter phase II trial.

BACKGROUND: Recently, the combination of the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab with first-line chemotherapy has demonstrated to improve outcome for patients with advanced small cell lung cancer (SCLC), leading to approval of this regimen. At the same time, accumulating (pre-)clinical data suggest synergisms of radiotherapy and immunotherapy via the radiation-mediated induction of anti-tumor immunogenicity. Combining the recent findings, the TREASURE trial aims at further enhancing response to upfront chemo-immunotherapy by the addition of thoracic radiotherapy (TRT). METHODS/DESIGN: The TREASURE trial is a randomized, multicenter, phase II clinical trial ( ClinicalTrials.gov identifier, NCT04462276). One hundred four patients suffering from extensive disease (ED) SCLC, with any response to the standard of care induction chemo-immunotherapy will be randomized to receive atezolizumab maintenance therapy with or without TRT. The primary endpoint of this study is overall survival (OS). Secondary endpoints include further measures of efficacy, safety, and the collection of biomarker samples. A safety interim analysis will take place after n = 23 patients receiving TRT have been observed for three months after the end of TRT. DISCUSSION: This trial will investigate whether treatment efficacy can be improved by adding TRT to atezolizumab maintenance therapy in ED SCLC patients with any response after chemo-immunotherapy. Safety and feasibility of such a regimen will be evaluated, and biomaterials for a translational research project will be collected. Together, the results of this trial will deepen our comprehension of how checkpoint inhibition and radiotherapy interact and contribute to the evolving landscape of SCLC therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04462276 (Date of initial registration: 8th July 2020), https://clinicaltrials.gov/ct2/show/NCT04462276 Eudra-CT Number: 2019-003916-29 (Date of initial registration: 30th March 2020), https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003916-29/DE.

Brigatinib versus other second-generation ALK inhibitors as initial treatment of anaplastic lymphoma kinase positive non-small cell lung cancer with deep phenotyping: study protocol of the ABP trial.

BACKGROUND: Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. METHODS/DESIGN: In this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. DISCUSSION: Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a "chronic disease" will be distinguished from "high-risk" cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019-001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36.

Thoracic radiotherapy plus Durvalumab in elderly and/or frail NSCLC stage III patients unfit for chemotherapy - employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy: study protocol of the TRADE-hypo trial.

BACKGROUND: Non-small cell lung cancer is the most common cause of cancer death worldwide, highlighting the need for novel therapeutic concepts. In particular, there is still a lack of treatment strategies for the group of elderly and frail patients, who are frequently not capable of receiving standard therapy regimens. Despite comprising the majority of lung cancer patients, this group is underrepresented in clinical trials. This applies also to elderly and frail patients suffering from unresectable stage III NSCLC, who are unfit for chemotherapy, and, therefore, cannot receive the standard therapy comprising of radiochemotherapy and the recently approved subsequent durvalumab consolidation therapy. These patients often receive radiotherapy only, which raises the concern of undertreatment. The TRADE-hypo trial aims at optimizing treatment of this patient group by combining radiotherapy with concomitant durvalumab administration, thereby employing the immune-promoting effects of radiotherapy, and determining safety, feasibility, and efficacy of this treatment. METHODS/ DESIGN: In this prospective phase II clinical trial, durvalumab therapy will be combined with either conventionally fractionated (CON-group) or hypofractionated (HYPO-group) thoracic radiotherapy. A safety stop-and-go lead-in phase will assess safety of hypofractionated radiotherapy with respect to severe pneumonitis in small patient cohorts before opening full enrollment. Tumor tissue, blood and stool samples will be collected before and during the study period to investigate the immunological mechanisms responsible for checkpoint inhibitor efficacy and immune-promoting effects of radiotherapy. DISCUSSION: Preclinical data suggests that irradiation-induced immunogenicity can be further increased if applied in a hypofractionated setting, potentially boosting the expected synergistic effect with immune checkpoint inhibition in restoring the immune anti-tumor response. If proven safe and efficient, a hypofractionated radiation schedule can provide a considerably more practicable option for the patient. Taking into consideration the intend to develop a combination treatment strategy that can be made available to patients soon after proving to be efficient and the potentially elevated toxicity of a hypofractionated radiotherapy approach, this trial was designed as a two-trials-in-one design. An accompanying translational research program is planned striving to gain insights into the tumor-host biology and to identify suitable biomarkers to predict therapy response. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04351256 . Registered 17 April 2020, Eudra-CT, 2019-002192-33 . Registered 24 October 2019.

Re-irradiation in locally recurrent lung cancer patients.

PURPOSE: Lung cancer remains one of the tumour diagnoses with high lethality, although innovative treatment approaches have yielded improvements in local control and survival rates. There is still no consensus on how to treat local relapse in patients after first-line treatments. Radiotherapy may be considered in this situation; however, data supporting its effectiveness are rare. The purpose of this retrospective analysis was to evaluate outcomes of patients re-irradiated for thoracic tumours in terms of overall survival (OS), local progression-free survival (LPFS), toxicity and dose-volume parameters. PATIENTS AND METHODS: Sixty-two patients with locally recurrent previously irradiated lung cancer were analysed retrospectively (NSCLC n = 52, SCLC n = 10). Target volumes both in lung and mediastinum were re-irradiated with conventional three-dimensional or intensity-modulated radiotherapy techniques. Median overall dose of re-irradiation was 38.5 Gy (range 20-60 Gy) with a median single dose per fraction of 2 Gy (1.8-3.0 Gy). Clinical documents and treatment plans were evaluated. RESULTS: Median follow-up was 8.2 months (range 0-27 months). OS following re-irradiation was 9.3 months (range: 0-27 months) and LPFS was 6.5 months (range: 0-24 months). OS and LPFS were not affected by histology, total dose or patient age and gender. OS was improved in patients whose re-irradiation volumes included less than two mediastinal lymph node stations (p = 0.016). Twelve patients suffered from pneumonitis ≥grade II (19%) and two from pneumonitis grade III. One patient presumably died from pneumonitis grade V. A slight decline in forced expiratory volume (FEV1) was detected in post-re-irradiation lung function testing. CONCLUSIONS: Re-irradiation is an option for patients with tumour recurrence to control local progression and lower the symptom burden. Oncological outcome appears to be affected by size, location of mediastinal target volumes and lung function. Prospective clinical trials are warranted to substantiate the role of re-irradiation in recurrent lung cancer.

Fostering efficacy of anti-PD-1-treatment: Nivolumab plus radiotherapy in advanced non-small cell lung cancer - study protocol of the FORCE trial.

BACKGROUND: Hypofractionated palliative radiotherapy for metastatic lung cancer patients is frequently used in order to ease pain, to increase bone stability, to treat local mass effects, or to prolong progression-free survival at critical sites. Recently introduced, immunotherapy for patients with non-squamous non-small cell lung carcinoma (NSCLC) has significantly improved outcome in this cohort. Preclinical and early clinical data suggest that the combination of photon radiation with programmed death-1 (PD-1) targeting immunotherapies may promote a strong and durable immune response against tumor manifestations both within and beyond radiation targets. METHODS/DESIGN: In the present prospective, two-group, non-randomized, open-label phase II trial, 130 patients with stage IV non-squamous NSCLC in 2nd-line or 3rd-line treatment will be included. 65 patients with a clinical indication for palliative radiotherapy to non-cerebral/non-pulmonary metastatic sites will receive 240 mg nivolumab followed by palliative radiotherapy with 5 × 4 Gray (Gy) = 20 Gy photon radiation, which will be initiated within 72 h after first nivolumab administration (Group A). 65 patients without an indication for radiotherapy will only receive nivolumab (Group B). Nivolumab will be further administered every two weeks in both groups and will be continued until progression and loss of clinical benefit or until occurrence of limiting toxicities. The primary endpoint will be the objective response rate (ORR) according to response evaluation criteria in solid tumors (RECIST) 1.1. Secondary endpoints will be progression-free survival (PFS) according to RECIST 1.1, overall survival, descriptive subgroup analyses according to PD-L1 expression, toxicity and quality of life. Since response patterns following immunotherapies differ from those after conventional cytostatic agents, both objective response rate and progression-free survival will additionally be assessed according to immune-related RECIST (irRECIST) criteria. DISCUSSION: The FORCE study will prospectively investigate response rates, progression-free and overall survival (OS), and toxicity of nivolumab with and without hypofractionated palliative radiotherapy in a group of 130 patients with metastatic non-small cell lung cancer (non-squamous histology) in 2nd-line or 3rd-line treatment. This trial will contribute prospective data to the repeatedly published observation that the combination of hypofractionated photon radiotherapy and medical immunotherapy is not only safe but will also promote antitumoral immune responses. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03044626 (Date of initial registration: 05 January 2017). Eudra-CT Number: 2015-005741-31 (Date of initial registration: 18 December 2015).

EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non-small cell lung cancer.

In order to identify anaplastic lymphoma kinase-driven non-small cell lung cancer (ALK+ NSCLC) patients with a worse outcome, who might require alternative therapeutic approaches, we retrospectively analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants V1, V2 and V3 as detected by next-generation sequencing or reverse transcription-polymerase chain reaction (n = 67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4-ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases, respectively. Patients with V3-driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, p = 0.005), which suggests increased disease aggressiveness. Furthermore, V3-positive status was associated with earlier failure after treatment with first and second-generation ALK TKI (median progression-free survival [PFS] by RECIST in the first line 7.3 vs. 39.3 months, p = 0.01), platinum-based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, p = 0.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first-line treatment, p = 0.028), and with inferior overall survival (39.8 vs. 59.6 months in median, p = 0.017). Thus, EML4-ALK fusion variant V3 is a high-risk feature for ALK+ NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies.

Outcome and prognostic factors in single brain metastases from small-cell lung cancer.

PURPOSE: Whole brain radiation therapy (WBRT) is historically the standard of care for patients with brain metastases (BM) from small-cell lung cancer (SCLC), although locally ablative treatments are the standard of care for patients with 1-4 BM from other solid tumors. The objective of this analysis was to find prognostic factors influencing overall survival (OS) and intracranial progression-free survival (iPFS) in SCLC patients with single BM (SBM) treated with WBRT. METHODS: A total of 52 patients were identified in the authors' cancer center database with histologically confirmed SCLC and contrast-enhanced magnet resonance imaging (MRI) or computed tomography (CT), which confirmed SBM between 2006 and 2015 and were therefore treated with WBRT. A Kaplan-Meier survival analysis was performed for OS analyses. The log-rank (Mantel-Cox) test was used to compare survival curves. Univariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS and iPFS. RESULTS: The median OS after WBRT was 5 months and the median iPFS after WBRT 16 months. Patients that received surgery prior to WBRT had a significantly longer median OS of 19 months compared to 5 months in the group receiving only WBRT (p = 0.03; HR 2.24; 95% confidence interval [CI] 1.06-4.73). Patients with synchronous disease had a significantly longer OS compared to patients with metachronous BM (6 months vs. 3 months, p = 0.005; HR 0.27; 95% CI 0.11-0.68). Univariate analysis for OS revealed a statistically significant effect for metachronous disease (HR 2.25; 95% CI 1.14-4.46; p = 0.019), initial response to first-line chemotherapy (HR 0.58; 95% CI 0.35-0.97; p = 0.04), and surgical resection (HR 0.36; 95% CI 0.15-0.88; p = 0.026). OS was significantly affected by metachronous disease in multivariate analysis (HR 2.20; 95% CI 1.09-4.45; p = 0.028). CONCLUSIONS: Univariate analysis revealed that surgery followed by WBRT can improve OS in patients with SBM in SCLC. Furthermore, synchronous disease and response to initial chemotherapy appeared to be major prognostic factors. Multivariate analysis revealed metachronous disease as a significantly negative prognostic factor on OS. The value of WBRT, stereotactic radiosurgery (SRS), or surgery alone or in combination for patients with a limited number of BM in SCLC should be evaluated in further prospective clinical trials.

Synonymous EGFR variant p.Q787Q is neither prognostic nor predictive in patients with lung adenocarcinoma.

Patients with non-small cell lung cancer (NSCLC) harboring activating mutations in the Epidermal Growth Factor Receptor (EGFR) benefit from targeted therapies. A synonymous polymorphism (rs1050171, p.Q787Q) was shown to be associated with improved overall survival (OS) in colorectal cancer patients. As data in NSCLC are limited, we retrospectively analyzed associations of p.Q787Q with clinicopathological parameters including clinical response and outcome in patients with lung adenocarcinoma (ADC) who received tyrosine kinase inhibitor (TKI) therapy. Of 642 ADC patients whose tumors were profiled by next generation sequencing, 102 (15.9%) carried EGFR mutations targetable by TKIs (30.4% male patients, median age 65.1 y, 19.6% smokers with 12.8 median pack years). Seventy-nine patients (77.5%) received TKI therapy either as a first- or second-line therapy. Of the 102 EGFR-mutant tumors, 72 (70.6%) exhibited the p.Q787Q polymorphism and another 12 (11.8%) cases with p.Q787Q harbored an additional TKI insensitive mutation (p.T790M). The polymorphism was neither associated with classic clinicopathological parameters nor with overall survival (21.1 months vs. 20.1 months; P-value = 0.91) or clinical response (P-value = 0.122). The patients with p.T790M had worse survival compared to EGFR activating mutation carriers with and without p.Q787Q when analyzed as a separate group (27.5 months, P-value = 0.02). In conclusion, p.Q787Q is neither a suitable prognostic nor predictive biomarker for ADC patients receiving anti-EGFR therapy in first- or second-line of therapy. © 2016 Wiley Periodicals, Inc.

Outcome and prognostic factors in patients with brain metastases from small-cell lung cancer treated with whole brain radiotherapy.

The purpose of this study was to evaluate prognostic factors associated with overall survival (OS) and neurological progression free survival (nPFS) in small-cell lung cancer (SCLC) patients with brain metastases who received whole-brain radiotherapy (WBRT). From 2003 to 2015, 229 SCLC patients diagnosed with brain metastases who received WBRT were analyzed retrospectively. In this cohort 219 patients (95%) received a total photon dose of 30 Gy in 10 fractions. The prognostic factors evaluated for OS and nPFS were: age, Karnofsky Performance Status (KPS), number of brain metastases, synchronous versus metachronous disease, initial response to chemotherapy, the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class and thoracic radiation. Median OS after WBRT was 6 months and the median nPFS after WBRT was 11 months. Patients with synchronous cerebral metastases had a significantly better median OS with 8 months compared to patients with metachronous metastases with a median survival of 3 months (p < 0.0001; HR 0.46; 95% CI 0.31-0.67). Based on RPA classification median survival after WBRT was 17 months in RPA class I, 7 months in class II and 3 months in class III (p < 0.0001). Karnofsky performance status scale (KPS < 70%) was significantly associated with OS in both univariate (HR 2.84; p < 0.001) and multivariate analyses (HR 2.56; p = 0.011). Further, metachronous brain metastases (HR 1.8; p < 0.001), initial response to first-line chemotherapy (HR 0.51, p < 0.001) and RPA class III (HR 2.74; p < 0.001) were significantly associated with OS in univariate analysis. In multivariate analysis metachronous disease (HR 1.89; p < 0.001) and initial response to chemotherapy (HR 0.61; p < 0.001) were further identified as significant prognostic factors. NPFS was negatively significantly influenced by poor KPS (HR 2.56; p = 0.011), higher number of brain metastases (HR 1.97; p = 0.02), and higher RPA class (HR 2.26; p = 0.03) in univariate analysis. In this series, the main prognostic factors associated with OS were performance status, time of appearance of intracranial disease (synchronous vs. metachronous), initial response to chemotherapy and higher RPA class. NPFS was negatively influenced by poor KPS, multiplicity of brain metastases, and higher RPA class in univariate analysis. For patients with low performance status, metachronous disease or RPA class III, WBRT should be weighed against supportive therapy with steroids alone or palliative chemotherapy.

Retrospective study in 23 patients of the self-expanding sinus-XL stent for treatment of malignant superior vena cava obstruction caused by non-small cell lung cancer.

PURPOSE: To evaluate retrospectively the self-expanding nitinol Sinus-XL stent (OptiMed, Ettlingen, Germany) for the treatment of superior vena cava (SVC) obstruction caused by non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Between October 2009 and December 2012, 23 patients (7 women and 16 men; age, 62.5 y ± 8.5) with stage IIIA (1 patient), IIIB (4 patients) or IV (18 patients) NSCLC and acute SVC obstruction were scheduled for urgent stent implantation. The primary study endpoints were technical success (defined as accurate stent placement with complete coverage of the obstructed SVC), residual stenosis < 30%, and clinical efficacy. Complications were assessed as a secondary study endpoint. RESULTS: There were 26 stents implanted in 23 patients. The technical success was 100%. Stent dilation was performed after deployment in 18 cases (78%). Stent migration into the right atrium occurred immediately after deployment in one patient; however, this stent was successfully repositioned and stabilized by a second stent. The clinical symptoms improved at least one category according to the International Consensus Committee on Chronic Venous Disease after stent implantation in all but one patient. The mean clinical follow-up was 66 days ± 83 (range, 1-305 d). Three minor complications (13%) and one major complication (4%) occurred. CONCLUSIONS: Implantation of the self-expanding Sinus-XL stent for treatment of SVC obstruction caused by NSCLC is a safe and effective urgent treatment in this palliative setting.

Immune checkpoint inhibitors in non-small cell lung cancer - When should we dare to stop treatment?

Over the last years, the emergence of immune checkpoint inhibitors (ICI) has revolutionized the treatment of non-small cell lung cancer (NSCLC). Patients in a palliative setting with previously very poor prognosis may now show remarkable responses over years. Yet, ICI therapy is very cost-intensive and involves frequent contacts with healthcare resources. Some of the early trial protocols restricted ICI treatment duration to two years. Now follow-up data of these studies is available and reveal the possibility of a persistent response after two or more years without further treatment for patients having successfully completed two years of therapy. May we now dare to think (and speak) of cure in the palliative setting? Does it mean we can stop ICI therapy after an initial two-year treatment? In this review, we try to improve confidence in clinical decision-making for this patient group. To this end, trials with a restricted treatment duration of two years and other data considering potential ICI discontinuation in responding patients were evaluated. Up to 25% of patients successfully complete an initial two-year course of ICI. Within this group about 40-46% of patients are alive at five years without further treatment with five-year survival rates of up to 83%. Data on ICI rechallenge are scarce, yet it does not seem to provide the same level of efficacy as at first exposure. At present there are no established biomarkers to help with decision-making. Possible future (bio-)markers, such as PD-L1, mutations, circulating tumor DNA (ctDNA) or Positron emission tomography (PET) need to be evaluated further in a prospective setting. In conclusion, we propose that the concept of discontinuing ICI therapy in patients with tumor response has to be seriously taken into consideration as it may be of benefit to our patients and health care systems.

Pembrolizumab Alone or With Chemotherapy for 70+ Year-Old Lung Cancer Patients: A Retrospective Study.

OBJECTIVE: First-line pembrolizumab alone, as approved for PD-L1 ≥50%, or with chemotherapy was analyzed in older non-small-cell lung cancer (NSCLC) patients, for whom evidence is scarce. MATERIALS AND METHODS: A total of 156 consecutive ≥70 year-old patients treated between January 2016 and May 2021 were retrospectively analyzed. Tumor progression was verified through radiologic review, while toxicity was captured from records. RESULTS: Pembrolizumab plus chemotherapy (n = 95) caused higher rates of adverse events (91% vs. 51%, P < .001), treatment discontinuation (37% vs. 21%, P = .034), and hospitalization (56% vs. 23%, P < .001), but similar rates of immune-related adverse events (irAEs, mean 35%, P = .998) compared to pembrolizumab monotherapy (n = 61). Progression-free (PFS) and overall survival (OS) were similar between the 2 groups (7 vs. 8 months, and 16 vs. 14 months in median, P > .25). Occurrence of irAEs was associated with longer survival in a 12-week landmark analysis (median PFS 11 vs. 5 months, hazard ratio [HR] 0.51, P = .001; median OS 33 vs. 10 months, HR 0.46, P < .001), but occurrence of other AEs not (both P > .35). A worse ECOG performance status (PS) ≥2, presence of brain metastases at diagnosis, squamous histology and lack of tumor PD-L1 expression were independent predictors of shorter PFS and OS in multivariable analysis (HR 1.6-3.9 for PFS and OS, all P < .05). CONCLUSION: Chemoimmunotherapy increases the rate of adverse events and hospitalization without prolonging PFS or OS in newly diagnosed NSCLC patients aged 70 years or older compared to pembrolizumab monotherapy. ECOG PS 2, presence of brain metastases at diagnosis, squamous histology and PD-L1 negativity are associated with poor outcome.

Upfront and Repeated Stereotactic Radiosurgery in Patients With Brain Metastases From NSCLC.

INTRODUCTION: Approximately 40% of non-small-cell lung cancer (NSCLC) patients develop brain metastases (BM). Stereotactic radiosurgery (SRS) instead of whole-brain radiotherapy (WBRT) is increasingly administered as an upfront treatment to patients with a limited number of BM. We present outcomes and validation of prognostic scores for these patients treated with upfront SRS. METHODS: We retrospectively analyzed 199 patients with a total of 268 SRS courses for 539 brain metastases. Median patient age was 63 years. For larger BM, dose reduction to 18 Gy or hypofractionated SRS in 6 fractions was applied. We analyzed the BMV-, the RPA-, the GPA- and the lung-mol GPA score. Cox proportional hazards models with univariate and multivariate analyses were fitted for overall survival (OS) and intracranial progression-free survival (icPFS). RESULTS: Sixty-four patients died, 7 of them of neurological causes. Thirty eight patients (19,3%) required a salvage WBRT. Median OS was 38, 8 months (IQR: 6-NA). In univariate analysis as well as multivariate analysis, the Karnofsky performance scale index (KPI) ≥90% (P = 0, 012 and P = 0, 041) remained as independent prognostic factor for longer OS. All 4 prognostic scoring indices could be validated for OS assessment (BMV P = 0, 007; RPA P = 0, 026; GPA P = 0, 003; lung-mol GPA P = 0, 05). CONCLUSION: In this large cohort of NSCLC patients with BM treated with upfront and repeated SRS, OS was markedly favourable, in comparison to literature. Upfront SRS is an effective treatment approach in those patients and can decidedly reduce the impact of BM on overall prognosis. Furthermore, the analysed scores are useful prognostic tools for OS prediction.

Comorbidity in limited disease small-cell lung cancer: Age-adjusted Charlson comorbidity index and its association with overall survival following chemoradiotherapy.

Background: Combined, platinum-based thoracic chemoradiotherapy (TCR) is the current state-of-the-art treatment for patients with limited disease (LD) small-cell lung cancer (SCLC). There is only limited data available regarding the effect of comorbidities on survival following TRC. The purpose of this study is to assess the age-adjusted Charlson comorbidity index (ACCI) as a predictor of overall survival in LD-SCLC patients undergoing TCR. Patients and methods: We retrospectively analyzed 367 SCLC patients diagnosed with LD-SCLC who received TCR between 2003 and 2017. We evaluated the ACCI (n = 348) as a predictor of overall survival (OS). In this cohort, 322 patients (88%) received platinum-based TCR (either cisplatin or carboplatin), and 37 (10%) patients received vincristine based TCR. Median radiation dose was 60 Gy (range 24-66 Gy). Additionally, 83% of patients (n = 303) received prophylactic cranial irradiation (PCI, 30 Gy in 2 Gy fractions). Kaplan-Meier survival analysis was performed for OS. For comparison of survival curves, Log-rank (Mantel-Cox) test was used. Univariate and multivariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS. Results: Patients with an ACCI > 6 had a significantly shorter OS compared with patients with an ACCI ≤ 6 (median 11 vs. 20 months; p = 0.005). Univariate analysis for OS revealed a statistically significant effect for ACCI > 6 (HR 1.7; 95% CI 1.2-2.4; p = 0.003), PCI (HR 0.5; 95% CI 0.3-0.7; p < 0.001), and Karnofsky performance status ≤ 70% (KPS) (HR 1.4; 95% CI 1.1-1.90; p = 0.015). In multivariate analysis, OS was significantly associated with PCI (HR 0.6; 95% CI 0.4-0.9; p = 0.022) and ACCI > 6 (HR 1.5; 95% CI 1.0-2.1; p = 0.049). Conclusion: Comorbidity is significantly associated with survival in patients with LD-SCLC undergoing TCR. The ACCI may be a valuable tool to identify patients with a shorter survival and thus might be used for risk stratification and oncological decision making.

High-risk patients with locally advanced non-small cell lung cancer treated with stereotactic body radiation therapy to the peripheral primary combined with conventionally fractionated volumetric arc therapy to the mediastinal lymph nodes.

Introduction: A very narrow therapeutic window exists when delivering curative chemoradiotherapy for inoperable locally advanced non-small cell lung cancer (NSCLC), particularly when large distances exist between areas of gross disease in the thorax. In the present study, we hypothesize that a novel technique of stereotactic body radiation therapy (SBRT) to the primary tumor in combination with volumetric arc therapy (VMAT) to the mediastinal lymph nodes (MLN) is a suitable approach for high-risk patients with large volume geographically distant locally advanced NSCLC. Patients and methods: In this single institutional review, we identified high-risk patients treated between 2014 and 2017 with SBRT to the parenchymal lung primary as well as VMAT to the involved MLN using conventional fractionation. Dosimetrically, comparative plans utilizing VMAT conventionally fractionated delivered to both the primary and MLN were analyzed. Clinically, toxicity (CTCAE version 5.0) and oncologic outcomes were analyzed in detail. Results: A total of 21 patients were identified, 86% (n=18) of which received chemotherapy as a portion of their treatment. As treatment phase was between 2014 and 2017, none of the patients received consolidation immunotherapy. Target volume (PTV) dose coverage (99 vs. 87%) and CTV volume (307 vs. 441 ml) were significantly improved with SBRT+MLN vs. for VMAT alone (p<0.0001). Moreover, low-dose lung (median V5Gy [%]: 71 vs. 77, p<0.0001), heart (median V5Gy [%]: 41 vs. 49, p<0.0001) and esophagus (median V30Gy [%]: 54 vs. 55, p=0.03) dose exposure were all significantly reduced with SBRT+MLN. In contrast, there was no difference observed in high-dose exposure of lungs, heart, and spinal cord. Following SBRT+MLN treatment, we identified only one case of high-grade pneumonitis. As expected, we observed a higher rate of esophagitis with a total of seven patients experience grade 2+ toxicity. Overall, there were no grade 4+ toxicities identified. After a median 3 years follow up, disease progression was observed in 70% of patients irradiated using SBRT+MLN, but never in the spared 'bridging' tissue between pulmonary SBRT and mediastinal VMAT. Conclusion: For high risk patients, SBRT+MLN is dosimetrically feasible and can provide an alternative to dose reductions necessitated by otherwise very large target volumes.

The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions.

BACKGROUND: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce. PATIENTS AND METHODS: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases. RESULTS: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8+ and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants. CONCLUSIONS: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival.