Managing Hyperprogressive Disease in the Era of Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Blockade: A Case Discussion and Review of the Literature.

A breakthrough in oncology over the last 5 years, immunotherapy has proved its salutary effects in a wide range of solid tumors. The targeting of the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway can restore a competent antitumor T-cell response by addressing key tumor immune evasion mechanisms. This novel mechanism of action is associated with new patterns of responses that were not observed with conventional treatments such as chemotherapy or targeted therapies. Thus, hyperprogressive disease (HPD), an unexpected acceleration of cancer evolution after starting immunotherapy, has been reported by several groups with a PD-1/PD-L1 blockade. This tumor flare-up phenomenon is associated with a poorer outcome and is suspected to be an immune-related adverse event. Despite been highly debated, the issue of HPD is currently a real challenge for oncologists' practice in terms of patients' information, diagnosis, and management. Herein, we describe the case of a 57-year-old man diagnosed with metastatic urothelial carcinoma who developed a rapid tumor growth after an anti-PD-L1+ IO combination. This case illustrates how current practice should evolve to address the HPD reality in the anticheckpoint era. KEY POINTS: Hyperprogressive disease (HPD) is an unexpected acceleration of cancer growth after starting immunotherapy that is associated with a poor outcome. Definition of HPD is based on comparing kinetics of tumor growth before and after starting immunotherapy. No predictive biomarker has been homogenously identified in the reported studies. Suspected pathophysiology includes expansion of programmed cell death protein 1 (PD-1) + regulatory T cells, exhaustion of compensatory T cells, modulation of pro-tumorigenic immune cell subsets, activation of aberrant inflammation, or activation of oncogenic signaling. HPD is one of the most controversial immune-related adverse events, as the liability of immunotherapy in this tumor deleterious flare-up phenomenon has not been proved yet. The reported incidence of HPD in retrospective studies varies across different solid tumor types from 6% to 29%. This phenomenon has been mainly suspected in non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and in urothelial carcinomas, where several randomized phase III trials have shown early crossing over of survival curves. In the context of anti-PD-1/programmed death-ligand 1 therapy, in particular for NSCLC, HNSCC, or urothelial carcinoma, the authors recommend performing an early computed tomography (CT) assessment at week 3-4. In the case of an early progression, tumor molecular characterization by tumor biopsy or circulating tumor DNA could be urged. Immunotherapy discontinuation should be discussed. Performing a confirmatory CT scan 4 weeks later to exclude pseudoprogression should not be the rule. Early switch to cytotoxic therapy may counteract the deleterious flare-up. Patients should be informed of the risk of developing HPD. Health authorities and trial sponsors could monitor and report the rates of tumor flares in trials in order to help oncologists to properly inform their patients about the expected rates of HPD.

Clinical outcomes by infusion timing of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

BACKGROUND: We aimed to determine whether immune checkpoint inhibitors (ICI) time-of-day infusion might influence the survival of patients with advanced non-small cell lung cancer (NSCLC). METHODS: We retrospectively analysed patients who received single-agent anti-PD-(L)1 therapy in any line between 2016 and 2021. We calculated by Cox regression models the association between the proportion of ICI infusions received after 16:30h and overall survival (OS) and progression-free survival (PFS). RESULTS: 180 patients were included, 77% received ICI as second- or further-line (median of 12 infusions/patient). The median age was 65 years (IQR 57-70), 112 patients (62%) were male, 165 (92%) were current or former tobacco smokers, 140 (78%) had performance status (PS) 0 or 1, 26 (14%) were on steroid therapy at ICI initiation. Histology was non-squamous for 139 (77%), the median number of metastatic sites was 3, and 33% had brain metastases. Patients who received at least 20% of ICI infusions after 16:30h (65 out of 180, 36%) had a statistically significant shorter median PFS as compared with patients receiving less than 20% of infusions in the evening (4.9 vs 9.4 months, log-rank p = 0.020), while numerical but not statistical shorter OS was observed (14.0 vs 26.2 months, log-rank p = 0.090). In the multivariate analysis, receiving at least 20% of evening infusions did not significantly increase the risk of death, while PS and line of treatment were significantly correlated with the OS. On the contrary, a proportion of ICI administration after 16:30h ≥20% conferred an HR for the PFS of 1.44 (95% CI: 1.01-2.05, p = 0.043), but this prognostic effect was not found when including in the model the total number of ICI infusions received (HR 1.20, 95% CI: 0.83-1.75, p = 0.329). CONCLUSION: Time-of-day infusion of ICI may impact the survival of patients with advanced NSCLC. Underlying prognostic characteristics and the number of infusions received could represent conceivable confounding factors, linked to increased variance related to ICI infusion timing. Nonetheless, further studies may unravel chronobiological mechanisms modulating ICI efficacy.

Safety and Efficacy of Bevacizumab in Cancer Patients with Inflammatory Bowel Disease.

BACKGROUND: The safety of bevacizumab in combination with chemotherapy in patients with inflammatory bowel disease (IBD) and digestive and nondigestive cancers is poorly documented. METHODS: We retrospectively evaluated patient records of all adult cancer patients with IBD at our institution from April 2007 to May 2016 with an update in November 2019. RESULTS: Twenty-seven patients with a history of IBD (Crohn's disease, n = 22; ulcerative colitis, n = 5) who were treated with bevacizumab and chemotherapy for metastatic solid tumors were identified. At the time of advanced cancer diagnosis, 18 patients had quiescent IBD, whereas 9 patients had moderately active IBD. Among those with moderately active IBD, five had received corticosteroids less than six months prior to cancer diagnosis and one had received infliximab. The treated cancers were colorectal cancer (n = 13), small bowel cancer (n = 4), non-small cell lung cancer (n = 3), breast cancer (n = 3), and other cancers (n = 4). Patients received bevacizumab in combination with chemotherapy and/or as maintenance for a median of 6.7 months. Grade 2 or higher bevacizumab-related complications were proteinuria in two patients and hypertension, diarrhea, rectal bleeding, and intestinal perforation in one patient each. No clinical IBD flares were observed during bevacizumab treatment. CONCLUSION: Bevacizumab combined with chemotherapy is safe in cancer patients with moderately active or quiescent IBD.

Potential Biomarkers for the Efficacy of PD-1-PD-L Blockade in Cancer.

A decade ago, immune checkpoint blockade emerged as a major breakthrough in oncology, proposing a novel approach by which immune brakes could be released to enhance antitumor responses. Despite apparently modest improvement of the median duration of response, a spectacular doubling of long-term responses as compared to the available standard of care was seen, for instance, in metastatic melanoma. It soon became obvious that the percentage of patients responding to these novel approaches is relatively small, and the importance of an accurate prediction of responders became more and more clear. Strong predictive markers would allow for the administration of immune checkpoint blocker therapy to the patients most likely to benefit from it, and sparing the potential non-responders of a treatment which is far from innocuous, being associated with significant side-effects and, not least, an important price tag. A number of potential response predictors have already been investigated and partly validated, but they do not cover the major unmet need encountered in the current clinical setting. Here, we review biomarkers for immune checkpoint blockade efficacy, either clinically validated and currently in use, or which have been proposed as candidates and are currently under investigation.