Pembrolizumab for advanced non-small cell lung cancer (NSCLC): Impact of autoimmune comorbidity and outcomes following treatment completion.

INTRODUCTION: Pembrolizumab, an immune-checkpoint inhibitor, is approved for first-line treatment of metastatic NSCLC in patients with tumours expressing programmed death-ligand 1 (PD-L1) with tumour proportion score (TPS) of ≥50%. We aimed to clarify some uncertainties regarding use of immunotherapy in patients with previous autoimmune (AI) disorders and assess real-world outcomes following treatment completion. METHODS: We performed a retrospective case record review of 82 patients with tumours expressing PD-L1 at TPS ≥ 50% and receiving first-line Pembrolizumab. Survival was estimated using the Kaplan Meier method. RESULTS: After 36.93 months (IQR: 34.37-40.20) median follow-up, median OS was 13.6 months (95% CI 8.9-19.3). There were 10 patients (12%) with AI co-morbidities and there was a trend toward improved median OS for this group versus those without AI comorbidity, 42 months (14.87-NR) versus 10.7 months (7.3-17.8), p = 0.073. Sixteen patients (20%) with nonprogressive disease at 2 years had significantly better median OS compared to those who did not complete 2 years of treatment, NR (42- NR) and 8.7 (5.8-14.1), p < 0.001.Immune related adverse events (irAE) of any grade occurred in 90% of the AI cohort compared with 70.8% of patients without AI comorbidity. Low grade adrenal insufficiency was the only irAE which occurred at a significantly higher rate in the AI group, p = 0.02. CONCLUSION: Patients with previous AI diseases tolerate treatment well, and there is a non-significant trend for improved outcomes in this group. Patients who complete the course of pembrolizumab have significantly better survival outcomes than those who do not.

Long term survival in patients with human papillomavirus-positive oropharyngeal cancer and equivocal response on 12-week PET-CT is not compromised by the omission of neck dissection.

BACKGROUND AND AIM: The aim of this study was to evaluate the long-term safety of the omission of immediate neck dissections (IND) in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) achieving a less than complete nodal response on 12-week FDG PET-CT. MATERIAL AND METHODS: Patients with HPV-positive, node-positive HNSCC that were treated with radical (chemo) radiotherapy (RT) between January 2013 and September 2019 were identified. PET-CT responses were classified as complete (CR), incomplete (ICR) or equivocal (EQR) nodal responses. Clinical outcomes were obtained. RESULTS: 347 patients were identified. Median follow-up was 43.9 (IQR, 30.8-61.2) months. 62.8% (218/347) achieved a CR, 23.4% (81/347) EQR and 13.8% (48/347) ICR nodal response. 70 of 81 (86.4%) patients with an EQR and 25 of 48 (52.1%) with an ICR had no residual disease during follow up (a pathologically negative ND if surgery undertaken or no subsequent neck or distant relapse clinically/radiologically). Median survival of the EQR and CR groups were not reached, and despite the omission of IND in 95% of the EQR group there was no statistically significant differences in overall survival (OS) between the groups, p = 1.0. Median survival of ICR was not reached. However, OS for ICR group was significantly worse than that of CR, and EQR, both p < 0.001. CONCLUSION: The omission of IND in those achieving an EQR nodal response does not compromise long-term survival. This supports the safety of extended surveillance in patients with HPV-positive disease and an EQR on 12-week FDG PET-CT.

An International Expert Survey on the Indications and Practice of Radical Thoracic Reirradiation for Non-Small Cell Lung Cancer.

PURPOSE: Thoracic reirradiation for non-small cell lung cancer with curative intent is potentially associated with severe toxicity. There are limited prospective data on the best method to deliver this treatment. We sought to develop expert consensus guidance on the safe practice of treating non-small cell lung cancer with radiation therapy in the setting of prior thoracic irradiation. METHODS AND MATERIALS: Twenty-one thoracic radiation oncologists were invited to participate in an international Delphi consensus process. Guideline statements were developed and refined during 4 rounds on the definition of reirradiation, selection of appropriate patients, pretreatment assessments, planning of radiation therapy, and cumulative dose constraints. Consensus was achieved once ≥75% of respondents agreed with a statement. Statements that did not reach consensus in the initial survey rounds were revised based on respondents' comments and re-presented in subsequent rounds. RESULTS: Fifteen radiation oncologists participated in the 4 surveys between September 2019 and March 2020. The first 3 rounds had a 100% response rate, and the final round was completed by 93% of participants. Thirty-three out of 77 statements across all rounds achieved consensus. Key recommendations are as follows: (1) appropriate patients should have a good performance status and can have locally relapsed disease or second primary cancers, and there are no absolute lung function values that preclude reirradiation; (2) a full diagnostic workup should be performed in patients with suspected local recurrence and; (3) any reirradiation should be delivered using optimal image guidance and highly conformal techniques. In addition, consensus cumulative dose for the organs at risk in the thorax are described. CONCLUSIONS: These consensus statements provide practical guidance on appropriate patient selection for reirradiation, appropriate radiation therapy techniques, and cumulative dose constraints.

Phase 1/2a trial of intravenous BAL101553, a novel controller of the spindle assembly checkpoint, in advanced solid tumours.

BACKGROUND: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). RESULTS: Seventy-three patients received BAL101553 at doses of 15-80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. CONCLUSIONS: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties. CLINICAL TRIAL REGISTRATION: EudraCT: 2010-024237-23.

12 week PET-CT has low positive predictive value for nodal residual disease in human papillomavirus-positive oropharyngeal cancers.

OBJECTIVES: Surveillance PET-CT scans at 12 weeks post-radiotherapy for head and neck cancer can be used to omit neck dissections with no detriment in overall survival. Human Papillomavirus (HPV) driven tumours behave differently on conventional imaging after radiotherapy but it is unknown if this effect is seen on PET-CT and if HPV status affects the accuracy of PET-CT. We aimed to determine the negative and positive predictive values (NPV and PPV) of 12 week surveillance PET-CT in HPV positive and negative tumours, and investigate predictors of relapse in equivocal responders. MATERIALS AND METHODS: A retrospective cohort study in a UK tertiary level oncology hospital, between 2013 and 2016 included adults with oropharyngeal squamous cell carcinoma, or HPV positive head and neck squamous cell cancers of unknown primary, treated with radiotherapy. RESULTS: The PPVs of 12 week PET-CT in HPV positive and negative disease are 30% and 81.8% respectively (p < 0.01). The NPVs of 12 week PET-CT in HPV positive and negative disease are 92.9% and 55.6% respectively (p < 0.01). 67% of HPV positive patients with equivocal responses on 12 week PET-CT achieved complete response by 24 weeks. Equivocal responses in HPV positive disease had statistically similar survival to patients with complete responses. Comparing disease and imaging characteristics, there were no predictors of residual tumour. CONCLUSIONS: HPV positive tumours have a poor PPV of 30% on 12 week surveillance PET-CTs and take longer to achieve complete response. A period of further surveillance can be considered instead of an immediate neck dissection in this group of patients.

Real-world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer.

OBJECTIVES: To investigate the uptake, safety and efficacy of docetaxel chemotherapy in hormone-naïve metastatic prostate cancer (mPC) in the first year of use outside of a clinical trial. PATIENTS AND METHODS: Patients in the West of Scotland Cancer Network with newly diagnosed mPC were identified from the regional multidisciplinary team meetings and their treatment details were collected from electronic patient records. The rate of febrile neutropenia, hospitalisations, time to progression, and overall survival were compared between those patients who received docetaxel and androgen-deprivation therapy (ADT), or ADT alone using survival analysis. RESULTS: Of the 270 eligible patients, 103 received docetaxel (38.1%). 35 patients (34%) were hospitalised and there were 17 episodes of febrile neutropenia (16.5%). Two patients (1.9%) died within 30 days of chemotherapy. Patients who received ADT alone had an increased risk of progression (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.27-3.25; log-rank test, P = 0.002) and had an increased risk of death (HR 5.88, 95% CI: 2.52-13.72; log-rank test, P = 0.001) compared to the docetaxel group. The risk of febrile neutropenia was nine-times greater if chemotherapy was started within 3 weeks of ADT initiation (95% CI: 1.22-77.72; P = 0.032). CONCLUSION: Docetaxel chemotherapy in hormone-naïve mPC has significant toxicities, but has a similar effect on time to progression and overall survival as seen in randomised trials. Chemotherapy should be started at ≥3 weeks after ADT.

Current Advances in Checkpoint Inhibitors: Lessons from Non-Central Nervous System Cancers and Potential for Glioblastoma.

The adaptive immune system depends on the sequence of antigen presentation, activation, and then inhibition to mount a proportionate response to a threat. Tumors evade the immune response partly by suppressing T-cell activity using immune checkpoints. The use of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) antibodies counteract this suppression, thereby enhancing the antitumor activity of the immune system. This approach has proven efficacy in melanoma, renal cancer, and lung cancer. There is growing evidence that the central nervous system is accessible to the immune system in the diseased state. Moreover, glioblastomas (GBMs) attract CTLA-4-expressing T-cells and express PD-L1, which inhibit activation and continuation of a cytotoxic T-cell response, respectively. This may contribute to the evasion of the host immune response by GBM. Trials are in progress to determine if checkpoint inhibitors will be of benefit in GBM. Radiotherapy could also be helpful in promoting inflammation, enhancing the immunogenicity of tumors, disrupting the blood-brain barrier and creating greater antigen release. The combination of radiotherapy and checkpoint inhibitors has been promising in preclinical trials but is yet to show efficacy in humans. In this review, we summarize the mechanism and current evidence for checkpoint inhibitors in gliomas and other solid tumors, examine the rationale of combining radiotherapy with checkpoint inhibitors, and discuss the potential benefits and pitfalls of this approach.