FROM JUNE 5, 2022
Can immune checkpoint blockade replace surgery for mismatch repair-deficient rectal cancer?
LBA5. Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer.
Andrea Cercek (Memorial Sloan Kettering Cancer Center) presented results from a phase 2 study investigating the use of PD-1 blockade monotherapy (dostarlimab) to treat mismatch repair-deficient (dMMR) rectal cancer. The current standard of care for rectal cancer is chemotherapy and radiation followed by surgery. Other dMMR cancers respond to immune checkpoint blockade (ICB), and this study investigates whether ICB could replace chemotherapy, radiation and/or surgery. 18 patients participated in the study, all patients had stage 2 or stage 3 rectal cancer, 94% of the patient tumors were node-positive, and the mean tumor mutational burden (TMB) was 67, ranging from 36 to 106. Patients received dostarlimab monotherapy every three weeks for six months. Of the 14 patients that completed the course of treatment, 100% exhibited a clinical complete response (cCR). The median follow-up is 6.8 months, and all patients have remained disease free for up to 2 years after treatment. Of the four remaining patients currently undergoing the 6-month course of treatment, one patient achieved cCR in month 3 of treatment, and the remaining three patients exhibited partial responses 3 to 4 months into treatment. The median follow-up for this study is 6.8 months, and longer follow-up is required to establish durability of the response. This trial establishes a framework for immuno-ablative therapy and underscores the impact of biomarker-driven therapy for treating early-stage disease.
Perioperative combination therapy with atezolizumab and FLOT chemotherapy promotes pathological regression of esophagogastric adenocarcinoma
- Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: Interim results from DANTE, a randomized, multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK.
Salah-Eddin Al-Batran (Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest, Frankfurt) presented interim results from the DANTE study to compare the safety and efficacy of perioperative PD-L1 blockade (atezolizumab) combined with docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) chemotherapy compared to FLOT alone in resectable esophageal adenocarcinoma. Perioperative FLOT is the standard of care for patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma, and recent studies have shown how PD(L)-1 blockade prolongs survival in patients with advanced gastric or GEJ adenocarcinoma. Patients in Arm B (n=146) received 4 cycles of FLOT prior to surgery and 4 cycles of FLOT post-surgery, and patients in Arm A (n=148) received 4 cycles FLOT treatments with atezolizumab before and after surgery. Patients in Arm A received 8 additional cycles of atezolizumab monotherapy after post-surgery FLOT + atezolizumab treatment. 80% of patients in the study had T3-T4 tumors, and 80% were positive for nodal disease. 23 patients (8%) were MSI high, and 41% had PD-L1 CPS <1, 58% had PD-L1 CPS >=1, 27% PD-L1 CPS >= 5 and 18% PD-L1 CPS >= 10. 93% of patients completed pre-operative therapy, and 43% of patients completed post-operative therapy. Similar numbers of patients in each group experienced serious adverse events (99 in Group A and 98 in Group B), and morbidity was 3% for Group A and 2% for Group B. The rates of margin-free (R0) resection for groups A and B were 93% and 91%, respectively. Histopathology studies showed that 23% of patients in Arm A and 15% of patients in Arm B had no residual tumor (pT0), and 69% (Arm A) and 54% (Arm B) had no cancer in earby lymph nodes (pN0). 24% of patients in Arm A and 15% in Arm B achieved complete pathological regression (TRG1a). For Arm A, increased rates of pathological regression correlated with increased PD-L1 CPS scores and with MSI-high tumors. This phase II study indicates that perioperative treatment with FLOT and atezolizumab is tolerated and safe and promotes pathological regression. A phase III trial further investigating perioperative treatment with FLOT and atezolizumab is in progress.
High expression of LAG-3 in tumors correlates with high expression of other immune checkpoint proteins
- LAG-3 transcriptomic expression correlates with high levels of PD-1, PD-L1, PD-L2, and CTLA-4 checkpoints and with high tumor mutational burden across cancers.
Jacob J. Adashek (University of South Florida, H. Lee Moffitt Cancer Center & Research Institute) presented results from a study investigating the gene expression profile of Lymphocyte Activation Gene 3 (LAG-3) in different cancers. LAG-3 has been identified as an immune checkpoint protein, and recent evidence indicates that blockade of LAG-3 combined with PD-1 blockade provides greater clinical benefit than PD-1 blockade alone in patients with melanoma. The RNA expression levels of 397 genes in various types of solid tumors from 514 patients were analyzed. Transcript abundance was normalized and ranked to a reference population of 735 tumors representing 35 histologies. 116 (22.6%) tumors had high LAG-3 transcript levels. The cancers with the highest proportion of LAG-3 overexpression were neuroendocrine, uterine, sarcoma (33%), breast (31%), ovarian (30%), pancreatic (24%), lung (20%), stomach (16%) and colorectal (15%). High expression levels of LAG-3 also correlated with high expression of PD-L1, high PD-1, high PD-L2, high CTLA-4, and high tumor mutation burden. These data indicate that a variety of tumors exhibit high transcription levels of LAG-3 and that high expression of LAG-3 also correlates with high expression of targets of immune checkpoint inhibitors and with high TMB. Studies are ongoing to identify individualized gene expression profiles to identify patients who would most likely gain clinical benefits from treatment with immune checkpoint inhibitors.
PD-1 blockade for desmoplastic melanoma in the neoadjuvant setting
9502. Neoadjuvant PD-1 blockade in patients with resectable desmoplastic melanoma (SWOG 1512).
Kari Lynn Kendra (The Ohio State University Comprehensive Cancer Center) presented results from the SWOG 1512 study investigating the effects of neoadjuvant anti-PD-1 monotherapy on resectable desmoplastic melanoma (DM). 29 patients with resectable DM underwent 3 cycles of pembrolizumab monotherapy prior to surgery. 28 patients underwent resection of the tumor with or without sentinel lymph node biopsy or lymph node dissection. 16 patients (55%) achieved a pathological complete response after surgery, with no viable cancer cells detected. 13 patients achieved a non-pathological complete response, with one patient having 0.2 mm residual disease. At the 9-week follow-up, the overall response rate was 46% (n=12), with a complete response occurring in 15% (n=4) of patients. To date, no patients have relapsed. Median recurrence-free survival and median overall survival was not reached. Treatment related adverse events occurred in 72% (n=12) of patients with 2 patients experiencing an adverse event of grade 3 or higher. This study supports the use of immune checkpoint blockade at earlier stages of DM treatment and has the potential to change the course of therapy for patients with locally advanced DM.
Determining the optimal sequencing of therapies for melanoma in the neoadjuvant setting
- NeoTrio: Randomized trial of neoadjuvant (NAT) pembrolizumab (Pembro) alone, in sequence (SEQ) with, or concurrent (CON) with dabrafenib plus trametinib (D+T) in resectable BRAF-mutant stage III melanoma to determine optimal combination of therapy.
Georgina V. Long (Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals) reported results from the NeoTrio study to determine the optimal regimen for BRAF+MEK inhibitors (dabrafenib + trametinib; D + T) with a PD-1 inhibitor (pembrolizumab) for neoadjuvant therapy in stage III resectable nodal melanoma. Patients were randomized into three groups: Patients in the ALONE arm (n=20) received two cycles pembrolizumab monotherapy during the 6 weeks leading up to the therapeutic lymph node dissection (LND). Patients in the SEQuential arm (n=20) received D +T for one week followed by 2 cycles of pembrolizumab in the 6 weeks before LND. Patients in the CONcurrent arm (n=20) received 2 cycles of pembrolizumab and D + T concurrently during the 6 weeks before LND. All patients underwent 15 cycles of adjuvant pembrolizumab after LND. Median follow-up was 20.3 months. 55% (n=11), 50% (n=10), and 80% (n=16) of patients achieved a pathological response in the ALONE, SEQ, and CON arms, respectively. Pathological complete response (pCR) was achieved by 30% (n=6), 15% (n=3), and 50% (n=10) of patients in ALONE, SEQ, and CON, respectively. A complete response by RECIST criteria was achieved by 2 patients in ALONE, 0 patients in SEQ, and 7 patients in CON. 12-month event free survival (EFS) was 80% for all three arms, and 12-month recurrence free survival (RFS) was 89%, 80%, and 84% for ALONE, SEQ, and CON. 12-month overall survival (OS) was 95% for ALONE, 100% for SEQ, and 90% for CON. In SEQ and CON, late recurrences did occur in patients in the SEQ (n=1) and CON (n=1) arms who had previously achieved pCR. Adverse events >= grade 3 occurred in 5% of ALONE patients (n=1), 25% of SEQ patients (n=5) and 55% of CON patients (n=11). Adverse events leading to treatment interruption occurred in 19 patients (95%) in CON, and 8 patients (40%) in CON discontinued treatment due to adverse events. CONcurrent treatment with D + T + pembrolizumab provided the highest pathological response and complete response rates, but treatment toxicity was concerning. EFS and RFS were similar to patients receiving neoadjuvant pembrolizumab alone. Previous studies indicate early treatment with BRAF+MEK inhibitors induces intertumoral CD8 T cells. Because the SEQuential treatment with D + T + pembrolizumab did not provide a better pathological response rate than pembrolizumab monotherapy suggests that T cell induction by BRAF+MEK inhibitors does not enhance response to PD-1 inhibition. The NeoTrio trial is ongoing, and translational studies to identify factors that impact patient response to neoadjuvant immunotherapy will be presented in the future.
Analyses of key subgroups in the RELATIVITY-047 trial
- Nivolumab (NIVO) + relatlimab (RELA) versus NIVO in previously untreated metastatic or unresectable melanoma: OS and ORR by key subgroups from RELATIVITY-047.
Hussein A. Tawbi (The University of Texas MD Anderson Cancer Center) reported recent findings on subgroups from the RELATIVITY-047 trial comparing nivolumab (nivo; anti-PD-1) monotherapy to nivo + relatimab (rela; anti-LAG-3) combination therapy for previously untreated metastatic/unresectable melanoma. 714 patients participated in the phase 2/3 study. At the 19.3-month follow-up for RELATIVITY-047, treatment with nivo + rela showed gains in progression free survival (PFS), overall survival (OS), and overall response rate (ORR) compared to nivo monotherapy. When patients were stratified by PD-L1 expression and LAG-3 expression, nivo + rela produced similar gains compared to nivo monotherapy in OS, PFS, and ORR, regardless of PD-L1 and LAG-3 status. PFS, OS, and ORR also favored nivo + rela in patients older than 75 years, in patients with acral and mucosal melanoma, and in patients with BRAF mutant and BRAF wild-type. With regards to baseline prognostic factors, PFS, OS, and ORR favored nivo + rela regardless of LDH, tumor burden, and metastasis. Longer follow-up in the RELATIVITY-047 trial indicates that the PFS benefit from nivo + rela over nivo monotherapy has remained consistent. Additionally, PFS, OS, and ORR favor combination therapy with nivo + rela over nivo monotherapy across multiple subgroups regardless of biomarkers and baseline prognostic factors.