This month's featured editor is Dr. James Gulley, JITC Deputy Editor-in-Chief. “PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer” by Andrea Cercek et al
Mismatch repair deficient (dMMR) colorectal cancer is responsive to anti-PD-1-based immune checkpoint inhibition (ICI) in the metastatic setting, and Andrea Cercek and colleagues hypothesized that treatment with the anti-PD-1 monoclonal antibody dostarlimab may benefit patients with locally advanced rectal cancer as well. In this single-arm, prospective phase II study, patients with stage II or III rectal adenocarcinoma were given dostarlimab 500mg once every 3 weeks for 6 months, with subsequent chemoradiotherapy and resection planned in the absence of a clinical complete response (CR). The primary endpoints were sustained clinical CR or pathologic CR after completion of dostarlimab therapy and overall response to dostarlimab therapy. Patients with autoimmune disease, receiving immunosuppression, or who had received prior treatment for rectal cancer were excluded. Responses were assessed with serial imaging (MRI, PET, and CT), digital rectal exams, and endoscopies with biopsy. In this report, describing outcomes among the first 12 patients who completed dostarlimab therapy, the efficacy criteria for the overall response primary endpoint have been met. After a median follow of 12 months, 12 of 12 consecutive patients achieved clinical CR to neoadjuvant dostarlimab (100% [95% CI 74 to 100]). Four patients achieved 12 months of sustained clinical CR following completion of dostarlimab, however, a total of 13 patients are needed to meet the prespecified criteria for the durability primary endpoint. While 75% of patients experienced an adverse event, none were grade 3 or higher. At the time of publication, there were no reports of progression or recurrence (follow-up range, 6 to 25 months) and no patients had received chemoradiotherapy or surgery.
Why this matters: This study demonstrated remarkable response rates to ICI monotherapy in locally advanced, dMMR rectal cancer in a small number of patients with short term follow-up. Longer follow-up will provide important information on the durability of response and survival outcomes in this setting, potentially supporting neoadjuvant ICI as a strategy to spare patients from highly-morbid chemoradiotherapy and/or surgery.
“PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine" by Ramin Sedaghat Herati et al
Nature Immunology (2022)
PD-1 is expressed on many types of immune cells including follicular helper CD4+ T (Tfh) cells, yet the effects of PD-1/PD-L1 signaling blockade on cancer-unrelated immune responses, such as vaccine-induced humoral immunity, is largely unknown. Ramin Sedghat Herati and colleagues investigated the effects of anti-PD-1 therapy on immune responses to seasonal influenza vaccine. One week after vaccination, patients with urothelial carcinoma, renal cell carcinoma, and melanoma receiving anti-PD-1 therapy had higher numbers of circulating Tfh cells compared to patients not receiving anti-PD-1 as well as healthy adults. A subset of anti-PD-1 treated patients had robust induction of plasmablasts, which correlated with circulating ICOS+CD38+ Tfh cells. Gene expression analyses confirmed robust proliferation signatures in cTfh and plasmablasts from anti-PD-1-treated patients. Moreover, neutralizing antibody titers had twofold higher changes from baseline in the anti-PD-1-treated group. Interestingly, in patients receiving anti-PD-1 therapy, anti-H1 antibodies had reduced galactosylation, sialylation, and binding affinity, indicating they may have altered functionality. Humoral immunity is implicated in some irAEs, and gene expression profiles consistent with pre-vaccination activation of ICOS+CD38+ cTfh cells were enriched in patients that experience irAEs. Furthermore, a more robust ICOS+CD38+ cTfh response after vaccination was associated with irAE development.
Why this matters: This study highlights the importance of further investigation into the broader immunologic effects of anti-PD-1 therapy beyond the anti-tumor immune response. Additionally, pre- and post-vaccination activated circulating T follicular helper cells may be a biomarker for increased risk for irAEs with anti-PD-1.
“Phase II Randomized Study of Ramucirumab and Pembrolizumab versus Standard of Care in Advanced Non–Small-Cell Lung Cancer Previously Treated with Immunotherapy—Lung-MAP S1800A” by Karen L. Reckamp et al
Regimens based on anti-PD-(L)1 immune checkpoint inhibitors (ICIs) have become standard of care for first-line treatment of metastatic non-small cell lung cancer (NSCLC), offering some patients prolonged disease control. Limited treatment options are available, however, for patients who experience disease progression after treatment with anti-PD-(L)1. The Lung-MAP study is investigating molecularly matched targeted therapies in combination with ICIs for patients with stage IV or recurrent NSCLC previously treated with an anti-PD-(L)1. In this report, Karen L Reckamp and colleagues provide results from the nonmatched substudy of Lung-MAP, where patients who were not eligible for the biomarker-driven substudies were randomized to receive pembrolizumab plus ramuciramab, a VEGFR2 targeted therapy, or investigator’s choice of docetaxel plus ramucirumab, docetaxel, gemcitabine, or pemetrexed. The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and toxicity. The pembrolizumab plus ramuciramab combination (n = 69) was associated with a higher median OS than the comparator (n = 67), at 14.5 months versus 11.6 months (hazard ratio 0.69). Similar disease control rates were seen in both treatment arms, and the responses were more durable for patients receiving pembrolizumab plus ramuciramab (DOR 12.9 months versus 9.6 months). There were 3 treatment related deaths in the pembrolizumab plus ramuciramab group and 4 in the investigator’s choice group. Overall, the adverse events were consistent with the known toxicity profiles of the agents used, and fewer patients in the pembrolizumab plus ramuciramab arm required treatment discontinuation due to adverse events.
Why this matters: This study suggests that the addition of VEGF inhibition may help overcome resistance to anti-PD-1 in advanced NSCLC and is the first to demonstrate OS benefit over standard of care second-line options with a chemotherapy-free regimen. Further evaluation of this approach is warranted in subsequent trials with larger sample sizes.
“Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial” by Tomoko Yamazaki et al
In preclinical models, short course TGF-beta inhibition prior to chemotherapy and radiotherapy improves survival, primarily through enhanced CD8+ T cell tumor infiltration, cytotoxicity, and activation. Tomoko Yamazaki and colleagues hypothesized that the addition of the TGF-beta type 1 receptor kinase galunisertib to neoadjuvant chemoradiotherapy may improve response rates for patients with locally advanced rectal cancer. In a single-arm, phase II trial, 38 patients with untreated stage IIA─IIIC or IV rectal adenocarcinoma received two 14-day courses of oral galunisertib (150mg twice daily) before and during fluorouracil- or capecitabine-based chemoradiotherapy. Patients with less than a complete response (CR) underwent surgical resection while those who achieved a clinical CR could elect to proceed with (non-operative) systemic chemotherapy (modified FOLFOX6 or CAPEOX). Of the 35 patients who completed neoadjuvant therapy and underwent subsequent evaluation, 25 (71%) proceeded to total mesorectal excision, and 5 (20%) of these surgically-managed patients achieved a pathological CR. Three of the remaining 10 patients who were initially managed non-operatively with FOLFOX or CAPEOX ultimately elected to proceed with total mesorectal excision despite having achieved a clinical CR, and two of these three patients were subsequently found to have a pathological CR. Five of the seven patients who were managed strictly non-operatively maintained a clinical CR at 1 year following completion of systemic chemotherapy. After a median follow-up of 27 months, the primary endpoint was met with 12 patients (32%, one-sided 95% CI ≥19%) achieving pathological or clinical CR. There were no treatment-related deaths, and none of the three grade 4 adverse events were attributed to galunisertib.
Why this matters: Blockade of TGF-beta increased the pathological or clinical CR rate to chemoradiotherapy compared to historically-reported pathological CR rates for patients with locally advanced rectal adenocarcinoma. Modulation of immunosuppressive cytokines may represent a strategy to improve long-term survival and organ preservation for patients with biomarker-unselected rectal cancer.
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