Immunotherapy has emerged as a new standard of care, showing survival benefit for solid tumours in multiple disease sites and indications. The survival improvements seen in diseases that were highly resistant to traditional therapies, with a poor prognosis, are unprecedented. Although the benefits observed in clinical trials are undeniable, not all patients derive those benefits, leading to emerging combination strategies and an ongoing quest for biomarker selection. Here, we summarize the current evidence for immunotherapy in the treatment of solid tumours, and we discuss emerging strategies at the forefront of research. We discuss future challenges that will be encountered as experience and knowledge continue to expand in this rapidly emerging field.
As cancer strikes, individuals vary not only in terms of factors that contribute to its occurrence and development, but as importantly, in their capacity to respond to treatment. While exciting new therapeutic options that mobilize the immune system against cancer have led to breakthroughs for a variety of malignancies, success is limited to a subset of patients. Pre-existing immunological features of both the host and the tumor may contribute to how patients will eventually fare with immunotherapy. A broad understanding of baseline immunity, both in the periphery and in the tumor microenvironment, is needed in order to fully realize the potential of cancer immunotherapy. Such interrogation of the tumor, blood, and host immune parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. To approach these opportunities for progress, the Society for Immunotherapy of Cancer (SITC) reconvened the Immune Biomarkers Task Force. Comprised of an international multidisciplinary panel of experts, Working Group 4 sought to make recommendations that focus on the complexity of the tumor microenvironment, with its diversity of immune genes, proteins, cells, and pathways naturally present at baseline and in circulation, and novel tools to aid in such broad analyses.
<p>This includes Supplementary Table 1 with all adverse events by arm. Supplementary Figure 1 shows best overall response in patients with restaging imaging. Supplementary Figure 2 shows all somatic mutations, including those identified in an exploratory fashion.</p>
9557 Background: Melanoma has a high probability of central nervous system (CNS) spread. Although first line nivolumab and ipilimumab resulted in 56% response rate and 29.2 months median overall survival (OS) in patients with melanoma brain metastases (MBM), there is paucity of data for patients who develop MBM after prior systemic therapy. As this subgroup is often underrepresented in clinical trials, we aimed to evaluate the OS of non-treatment naïve patients who develop MBM and identify factors related to survival. Methods: In this single-center, retrospective study, consecutive melanoma patients with > 90 days from exposure to either immune checkpoint inhibitor (ICI), targeted therapy (TT), or chemotherapy, to CNS relapse were included. OS was defined as the time between CNS relapse and death by any cause. The Log-Rank method was used to calculate OS. Cox regression analysis was used to identify differences between subgroups. Variables with a p value < 0.1 were included in a multivariate model. A p value < 0.05 was considered statistically significant. Results: Between 2012 and 2018, 135 patients were identified. Median age was 57 (29-92) years, 92 (68%) were male, and median number of prior systemic therapies was 2 (1-6). One-hundred and nine (81%) patients had cutaneous melanoma; acral lentiginous melanoma (ALM) comprised 11 (8%) patients. Molecular studies were available for 123 patients, of whom 61 (50%) were BRAF V600 mutant. Eighty-nine (66%) patients had prior ICI, of whom 33 (37%) had prior exposure to both anti-PD1 and anti-CTLA-4, either as monotherapy or combination. Amongst the BRAF V600 mutant population, 48 (79%) had prior TT. Radiotherapy was given to 112 patients, of whom 55 (49%) had SRS. Median follow-up was 41 (95% CI 30-51) months. Median OS was 6.4 (95% CI 5.3-7.5) months. Patients with ALM, > 3 MBM, ECOG 2-4 and active treatment at CNS relapse (< 30 days from last dose of treatment to MBM diagnosis) were at increased risk of death, whilst subsequent treatment with ICI was related to better survival (Table). On multivariate analyses, age ( p = 0.007), subtype ( p = 0.04), number of MBM ( p = 0.01), active treatment at CNS relapse ( p < 0.001) and subsequent ICI ( p = 0.002) remained statistically significant. Exploratory analyses suggested subsequent treatment with anti-PD1 + anti-CTLA-4 (n = 42) compared favourably to subsequent anti-CTLA-4 only (n = 21) (13 x 7 months, p = 0.004), and was independent of prior ICI. Conclusions: Previously treated melanoma patients who develop MBM have a poor prognosis, but subsequent ICI therapy seems to be associated with better OS. Further clinical investigation to identify optimal anti-PD1-based therapies is warranted for non-treatment naïve patients who develop MBM.[Table: see text]
3003 Background: Inhibition of the MAPK pathway with dabrafenib (D) and trametinib (T) is efficacious in BRAF-mutant melanoma. MEK inhibitors have also shown activity in BRAF WT melanoma, particularly in NRAS-mutant tumors. However, most patients (pts) develop resistance to D and T. MEDI4736 (M), a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity, has shown clinical activity with durable responses and an acceptable safety profile in multiple tumor types. Combined therapy with these agents may lead to enhanced durable tumor responses. Methods: A phase I, multicenter, open-label study (NCT02027961) evaluating the safety and efficacy of M at 3 or 10 mg/kg IV every 2 weeks (q2w) in combination with D 150 mg twice daily + T 2 mg daily, or T alone in pts with stage IIIc/IV melanoma. Pts enroll by BRAF status into dose escalation cohorts (3+3 design), followed by dose expansion: BRAF mutant in Cohort A (M+D+T); BRAF WT in Cohort B (M+T) or Cohort C (sequential T→M). Prior BRAF/MEK inhibitors were prohibited; prior immunotherapy was allowed, including anti-PD-1/anti-PD-L1 therapy. Results: As of December 5, 2014, 50 pts were treated. DLTs were observed in 1 pt in Cohort A1 (reversible grade [G] 3 thrombocytopenia) and 1 pt in Cohort B (reversible G3 choroidal effusion). No MTD was identified; M 10 mg/kg q2w was selected for expansion in all cohorts. The most frequent drug-related adverse events (AEs) by cohort were: pyrexia (63%) and fatigue (54%) (Cohort A); diarrhea (30%) and rash (25%) (Cohort B); and vomiting (67%) (Cohort C). 2 pts discontinued due to drug-related AEs (DLTs above). Clinical activity to date is shown below. Most responses are ongoing (range of duration: 0.1+ - 32+ wk). Conclusions: M can be combined with T ± D at full doses with a manageable safety profile, and evidence of clinical activity in BRAF-mutant and WT melanoma. Clinical trial information: NCT02027961. Cohort n Any AE (%) Related AE (%) Related G ≥ 3 AE (%) CR/PR (n/n)a SD (n/n)a A1 (3 mg/kg M + D + T) 6 100 100 17 6/6 0/6 A2 (10 mg/kg M + D + T) 18 94 94 39 10/15 5/15 B (10 mg/kg M + T) 20 90 85 40 3/14 6/14 C (sequential T + 10 mg/kg M) 6 100 100 17 3/6 1/6 aIncludes pts with ≥ 1 follow up scan or discontinuation due to PD or death prior to first scan (confirmed and unconfirmed CR/PR).
11607 Background: Validated biomarkers of response to immune checkpoint inhibitors are needed. Methods: INSPIRE (NCT02644369) is a biomarker-driven study to comprehensively evaluate changes in genomic and immune landscapes in tumors and blood of patients (pts) treated with pembro at 200 mg IV Q3W. It consists of 5 histological cohorts of 20 evaluable pts each: head and neck squamous cell cancer (SCCHN), triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC), melanoma (MM) and mixed solid tumors (MST). All pts undergo pre- and on-treatment (week 6-9) fresh tumor biopsies (bx), and at progression for responders. The first core bx is for immunohistochemistry and subsequent cores are pooled to create single cell suspension for 5 prioritized biomarker assay groups: (1) whole exome/RNA-/TCR-sequencing; (2) T/B/NK, APCs, and/or Treg phenotyping; (3) patient-derived xenografts; (4) RNA-seq on viably sorted immune populations; (5) TIL expansion and characterization. Serial blood samples for immunophenotyping, chemokines/cytokines and ctDNA are collected. Results: 53 pts were enrolled from March 21, 2016-January 16, 2017 (5 SCCHN, 8 TNBC, 17 HGSOC, 7 MM, 16 MST). 84 tumor bx (53 pre-, 30 on-treatment, 1 progression) and 244 blood-based biomarker samples have been collected. The most common sites of tumor bx were: lymph nodes (27%), liver (22%) and skin (14%) (see table). For the 5 cohorts, the % of tumor bx with sufficient cellularity for biomarker assay groups 1 and 2 are: SCCHN (33%), TNBC (9%), HGSOC (52%), MM (55%), MST (55%). Conclusions: This report provides robust technical feasibility data to plan immune and molecular characterization of tumor and blood-based biomarkers in pts receiving ICI. Clinical trial information: NCT02644369. [Table: see text]
<div>Abstract<p>Purpose: In the phase III CheckMate 238 study, adjuvant nivolumab (NIVO) significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab (IPI) in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. Patients and Methods: Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline PD-L1 expression and received NIVO 3 mg/kg every 2 weeks or IPI 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. Results: At a minimum follow-up of 62 months, RFS with NIVO remained superior to IPI (HR 0.72; 95% CI, 0.60–0.86; 5-year rates of 50% versus 39%). 5-year DMFS rates were 58% with NIVO versus 51% with IPI. Five-year OS rates were 76% with NIVO and 72% with IPI (75% data maturity: 228 of 302 planned events). Higher levels of TMB, tumor PD-L1, intratumoral CD8+ T cells and interferon-gamma–associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both NIVO and IPI, albeit with limited clinically meaningful predictive value. Conclusion: NIVO is a proven adjuvant treatment for resected melanoma at high-risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with IPI and high OS rates. Identification of additional biomarkers are needed to better predict treatment outcome.</p></div>
Abstract Background: The molecular mechanisms underlying primary versus acquired resistance to anti-PD-1/L1 antibodies have not been comprehensively evaluated across different tumor types. Methods: The Immune Resistance Interrogation Study (IRIS; NCT04243720) is a prospective, investigator-initiated study at the Princess Margaret Cancer Centre, aimed to perform extensive multi-omic characterization of solid tumors with primary resistance (disease progression on first imaging; or stable disease <6 months) versus acquired resistance (partial or complete response; or stable disease ≥6 months) to antiPD-1/L1 agents. A one-time fresh tumor biopsy is collected from patients (pts) who have progressed on anti-PD1/L1 antibody-based treatment as their most recent line of therapy; liquid biopsy or archived FFPE tissue is allowed as alternates when fresh biopsy is insufficient. NGS was performed using Foundation One (324 genes) or Foundation Liquid (309 genes) panels. Frequencies of disrupted genes and variants were compared in pts with primary versus acquired resistance using Fisher’s exact test. The planned samples size of IRIS is 100 pts. Results: Among the first 35 pts enrolled, 22 (63%) had primary resistance and 13 (37%) had acquired resistance. The most common diagnosis was melanoma (17 pts; 49%); followed by head and neck squamous cell carcinoma (13 pts; 37%); endometrial cancer (2 pts; 6%); pleural mesothelioma, gastroesophageal junction and colorectal cancer (1 pt each; 3%). Foundation One was performed in 23 pts (66%), 22 of them (63%) had biopsies with sufficient quality for NGS, and 1 (3%) had the analysis performed using archival FFPE tissue. The remaining 12 pts (34%) had Foundation Liquid testing done using liquid biopsy. Thirty-three pts (94%) had at least one oncogenic alteration. Genes most frequently altered included: TP53 in 16 patients (46%), TERT promoter in 12 pts (34%), CDKN2A in 9 pts (26%), PIK3CA in 6 pts (17%), and PTEN in 5 pts (14%). At the variant level, the most frequent alterations were: TERT promoter -146C>T mutation in 6 patients (17%), followed by TERT promoter -124C>T mutation in 5 patients (14%), FGF19/FGF4/FGF3 and CCND1 amplifications in 4 pts each (11%), and MDM2 amplification, CDK4 amplification and CDKN2A loss, detected in 3 pts each (9%). Pts with acquired resistance had a higher frequency of TP53 mutations (9/13 = 69%) compared to primary resistance pts (7/22 = 32%), p=0.04; however this was not significant when corrected for multiple testing. Interestingly, amplifications in CDK4, CCND1, FGF 19/FGF 3/FGF 4, MDM2 and mutations in NF1 were only identified in pts with primary resistant tumors. Conclusions: No significant differences in disrupted genes and variants were observed in the current analysis. However, this can be due to the small number of pts analyzed thus far. Accrual to this study is ongoing. A comparison of alterations in oncogenic pathways is planned to further define the genomic landscape of pts with primary versus acquired resistance to anti-PD1/PDL1 blockade. Citation Format: Sofia Genta, Farnoosh Abbas Aghababazadeh, Ming S Tsao, Aaron R Hansen, Marcus O Butler, Albiruni R Razak, Philippe L Bedard, Ben X Wang, Pugh J Trevor, Sevan Hakgor, Jeffrey Woo, Benjamin Haibe-Kains, Lillian L Siu, Anna Spreafico. Immune resistance interrogation study (IRIS): Initial report of next generation sequencing (NGS) results in patients with primary versus acquired resistance to anti-PD1/L1 antibodies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA021.
