Complete Metabolic Response to Combined Immune Checkpoint Inhibition after Progression of Metastatic Colorectal Cancer on Pembrolizumab: A Case Report.

DNA mismatch repair deficient (dMMR) and microsatellite instable (MSI) metastatic colorectal cancer (mCRC) can be successfully treated with FDA- and EMA-approved immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab (as single agents targeting the anti-programmed cell death protein-1 (PD-1)) or combinations of a PD-1 inhibitor with ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-targeting antibody. The best treatment strategy beyond progression on single-agent ICI therapy remains unclear. Here, we present the case of a 63-year-old male with Lynch-syndrome-associated, microsatellite instability-high (MSI-H) mCRC who achieved a rapid normalization of his tumor markers and a complete metabolic remission (CMR), currently lasting for ten months, on sequential ICI treatment with the combination of nivolumab and ipilimumab followed by nivolumab maintenance therapy after progression on single-agent anti-PD-1 ICI therapy. The therapy was well-tolerated, and no immune-related adverse events occurred. To the best of our knowledge, this is the first case of a sustained metabolic complete remission in an MSI-H mCRC patient initially progressing on single-agent anti-PD-1 therapy. Thus, dMMR mCRC patients might benefit from sequential immune checkpoint regimens even with long-term responses. However, further sophistication of clinical algorithms for treatment beyond progression on single-agent ICI therapy in MSI-mCRC is urgently needed.

Initial Results of 68Ga-FAPI-46 PET/MRI to Assess Response to Neoadjuvant Chemotherapy in Breast Cancer.

Improving imaging-based response after neoadjuvant chemotherapy (NAC) in breast cancer assessment could obviate histologic confirmation of pathologic complete response (pCR) and facilitate deescalation of chemotherapy or surgery. Fibroblast activation protein inhibitor (FAPI) PET/MRI is a promising novel molecular imaging agent for the tumor microenvironment with intense uptake in breast cancer. We assessed the diagnostic performance of follow-up breast 68Ga-FAPI-46 (68Ga-FAPI) PET/MRI in classifying the response status of local breast cancer and lymph node metastases after completion of NAC and validated this approach immunohistochemically. Methods: In women who completed NAC for invasive breast cancer, follow-up 68Ga-FAPI PET/MRI and corresponding fibroblast activation protein (FAP) immunostainings were retrospectively analyzed. Metrics of 68Ga-FAPI uptake and FAP immunoreactivity in women with or without pCR were compared using the Mann-Whitney U test. Diagnostic performance to detect remnant invasive cancer was calculated for tracer uptake metrics using receiver-operating-characteristic curves and for masked readers' visual assessment categories of PET/MRI and MRI alone. Results: Thirteen women (mean age ± SD, 47 ± 9 y) were evaluated. Seven of the 13 achieved pCR in the breast and 6 in the axilla. FAP immunoreactivity was significantly associated with response status. The 68Ga-FAPI PET/MRI mean breast tumor-to-background ratio was 0.9 (range, 0.6-1.2) for pCR and 2.1 (range, 1.4-3.1) for no pCR (P = 0.001). Integrated PET/MRI could classify breast response correctly in all 13 women based on readers' visual assessment or tumor-to-background ratio. Evaluation of MRI alone resulted in at least 2 false-positives. For lymph nodes, PET/MRI readers had at least 2 false-negative classifications, whereas MRI alone resulted in 2 false-negatives and 1 false-positive. Conclusion: To our knowledge, this was the first analysis of 68Ga-FAPI PET/MRI for response assessment after NAC for breast cancer. The diagnostic performance of PET/MRI in a small study sample trended toward a gain over MRI alone, clearly supporting future prospective studies.

Predictors of Anxiety and Depression in Differentiated Thyroid Cancer Survivors: Results of a Cross-Sectional Study.

Background: Despite an excellent survival rate, impairments are recognized in the quality of life and emotional well-being of differentiated thyroid cancer (DTC) survivors. Predictors for anxiety and depression in DTC patients are not well characterized. Objective: To identify predictors for anxiety and depression in DTC survivors. Methods: In this cross-sectional study, all DTC survivors presenting for follow-up between 2014 and 2019 in a tertiary referral hospital were asked to complete the "Hospital Anxiety and Depression Scale" (HADS). Depression (HADS-D) and anxiety (HADS-A) subscores were dichotomized for analysis. Univariate and multivariable logistic regression analyses were performed to identify predictors of anxiety and depression. Inverse probability weighting was applied to correct for bias due to nonresponse. Results: Six hundred forty patients meeting study inclusion criteria completed the HADS questionnaire (73% female, mean age 50 years). Of these, 37.6% and 15.7% of patients demonstrated HADS-A and HADS-D scores ≥8. Female sex, elevated body mass index (BMI), permanent recurrent laryngeal nerve damage (RLND), permanent hypoparathyroidism (PH), comorbidities classified in chapter XIX of the International Classification of Diseases, 10th Revision (ICD-10; external causes of morbidity and mortality), and comorbidities in chapter XXI of ICD-10 (factors influencing health status and contact with health services) were independent predictors for elevated anxiety scores with adjusted odds ratios of 1.9 ([CI 1.2-3.2], p < 0.01), 1.0 ([CI 1.0-1.1], p = 0.02), 2.6 ([CI 1.0-6.3], p = 0.04), 2.0 ([CI 1.1-3.5], p = 0.02), 5.5 ([CI 1.0-29.6], p < 0.05), and 1.7 ([CI 1.1-2.6], p = 0.03). PH, elevated anti-Tg titer, comorbidities of the digestive system (chapter XI of ICD-10), and comorbidities of the genitourinary system (chapter XIV of ICD-10) were independent predictors for depression with adjusted odds ratios of 2.2 ([CI 1.2-4.2], p = 0.01), 1.0 ([CI 1.0-1.0], p = 0.04), 3.0 ([CI 1.5-6.1], p < 0.01), and 2.4 ([CI 1.0-5.7], p = 0.04). Conclusions: Female sex, elevated BMI, RLND, PH, and comorbidities classified in chapter XIX and chapter XXI of ICD-10 are predictors for anxiety in DTC patients. PH, elevated anti-Tg titer, comorbidities of the digestive system, and comorbidities of the genitourinary system are predictors for depression in DTC patients. Physicians involved in the follow-up of DTC patients should devote particular attention to the emotional well-being in DTC patients with PH or permanent RLND.

Fibroblast Activation Protein Triggers Release of Drug Payload from Non-internalizing Small Molecule Drug Conjugates in Solid Tumors.

PURPOSE: Small molecule drug conjugates (SMDC) are modular anticancer prodrugs that include a tumor-targeting small organic ligand, a cleavable linker, and a potent cytotoxic agent. Most of the SMDC products that have been developed for clinical applications target internalizing tumor-associated antigens on the surface of tumor cells. We have recently described a novel non-internalizing small organic ligand (named OncoFAP) of fibroblast activation protein (FAP), a tumor-associated antigen highly expressed in the stroma of most solid human malignancies. EXPERIMENTAL DESIGN: In this article, we describe a new series of OncoFAP-Drug derivatives based on monomethyl auristatin E (MMAE; a potent cytotoxic tubulin poison) and dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment. RESULTS: The tumor-targeting potential of OncoFAP was confirmed in patients with cancer using nuclear medicine procedures. We used mass spectrometry methodologies to quantify the amount of prodrug delivered to tumors and normal organs, as well as the efficiency of the drug release process. Linkers previously exploited for anticancer drug conjugates were used as benchmark. We identified OncoFAP-Gly-Pro-MMAE as the best performing SMDC, which has now been prioritized for further clinical development. OncoFAP-Gly-Pro-MMAE selectively delivered more than 10% injected dose per gram of MMAE to FAP-positive tumors, with a tumor-to-kidney ratio of 16:1 at 24 hours post-injection. CONCLUSIONS: The FAP-specific drug conjugates described in this article promise to be efficacious for the targeting of human malignancies. The extracellular release of potent anticancer payloads mediates durable complete remission in difficult-to-treat animal models of cancer.