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Alberto Cruz-Bermudez
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ES06 - Perioperative Therapy for Early Stage NSCLC (ID 221)
- Event: WCLC 2020
- Type: Educational Session
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 14:15 - 15:15, Scientific Program Auditorium
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ES06.01 - Neoadjuvant IO Monotherapy vs. Chemo-IO (ID 4046)
14:15 - 15:15 | Author(s): Alberto Cruz-Bermudez
- Abstract
- Presentation
Abstract
Anti-PD1/PD-L1 (anti-PD(L)1) antibodies activity is based on the blockade of PD-1 protein in lymphocytes or PD-L1 in tumor cells, preventing lymphocytes inactivation and promoting tumor elimination. A great part of the knowledge of its mechanism is due to neoadjuvant immunotherapy studies. In the situation with the intact tumor, on one side, anti-PD(L)1 rejuvenates the tumor-specific cytotoxic T cells from the tumor microenvironment, causing them to activate, proliferate and mobilize to eliminate distant micrometastasis. Additionally, anti-PD(L)1 increases tumor antigen presentation by dendritic cells in the tumor-draining lymph nodes activating new tumor-specific T cells that then migrate to tumor sites. Both processes trigger a powerful systemic anti-tumor immune response and the generation of memory T-cells that may provide long-term protection. Conversely, the neoantigen repertoire is reduced when the primary tumor is resected, limiting this anti-tumor immune response in the adjuvant setting and representing a strong argument for the neoadjuvant approach. Moreover, several immunological pathways are disrupted by surgical stress. While essential for wound healing, surgical stress leads to the expansion of Tregs, MDSC, and M2 macrophages, resulting in an overall state of immunosuppression with PD-1/CTLA-4 increase and T-cell exhaustion. Immune checkpoint inhibitors in neoadjuvant settings might be advantageous in activating tumor-infiltrating T-cells prior to surgery, and avoiding PD-1 expression on immune cells in the postoperative period.
Patients with NSCLC treated with neoadjuvant chemotherapy exhibited higher levels of PD-L1+ malignant cells and TILs than patients who underwent upfront tumor resection without neoadjuvant treatment. In patients who underwent neoadjuvant treatment, those with higher abundance of helper T cells and TAMs survived longer, suggesting that these cells may be important in chemotherapy response.
The neoadjuvant treatment has theoretical advantages like assessment of response to chemotherapy in vivo and this, in turn, helps identify patients who will potentially benefit from this therapy; perhaps the better locoregional drug delivery because of intact vessels presurgery; better tolerability; early treatment of micrometastatic disease; downstaging with improved resectability and offers the possibility for the identification of surrogate clinical and biological markers that may correlate with response to therapy and a potential long-term outcome. However neoadjuvant therapy has potential disadvantages: delay in local therapy due to toxicity, risk progression in chemoresistant patients, and pre-operative complications.
The prolonged duration of clinical trials for resectable stages I and III NSCLC, in which OS has been used as the primary endpoint, has resulted in slow progress and high expenses. There is a need for surrogate markers of efficacy outcome, aside from the traditional endpoints of OS or PFS, to accelerate the development of new therapies in early-stage NSCLC. Complete surgical resection, tumor downstaging, and complete and major pathologic responses after neoadjuvant chemotherapy have been associated with improved survival in resectable NSCLC.
Multiple checkpoint inhibitors have been evaluated as neoadjuvant treatment, but their use in this setting remains investigational.
Forde, et al. evaluated the feasibility of two doses of neoadjuvant PD-1 blockade in a recent pilot study in 21 patients with early-stage (I–IIIA) NSCLC (NCT02259621). Two preoperative doses of the anti-PD-1 inhibitor nivolumab (3mg/kg) were administered intravenously every two weeks, with surgery planned about 4 weeks after starting the neoadjuvant therapy. While only 10% of patients had objective responses on post-treatment CT-scans, MPR occurred in 45% of patients who went to surgery and 13% of patients had pathologic complete responses. Furthermore, MPR occurred in PD-L1-positive and PD-L1-negative tumors, and TMB was predictive of pathologic response to anti-PD-1 therapy.
LCMC3 trial (NCT02927301) is a phase II single-arm study of neoadjuvant atezolizumab monotherapy in patients with resectable early-stage NSCLC. The initial safety analysis of the first 54 of 180 planned patients who received two cycles of atezolizumab (PD-L1 inhibitor) monotherapy every three weeks in patients with stages IB to selected IIIB (T3N2) resectable NSCLC prior to surgical resection. By RECIST, 6/82 patients had a partial response, 72 had stable disease and 4 had progressive disease. The MPR rate was 18% (95% CI: 11-28%) 15/82, 4 patients had CPR (5%).
NEOSTAR study (NCT03158129) is a phase II study of induction checkpoint blockade for untreated patients with stage I-IIIA (single N2) NSCLC. The patients received three doses of nivolumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q2w followed by surgery. Five of the 31 patients initially scheduled for surgery did not proceed to resection (one with hypoxemia grade 3, two with high surgical risk and two were no longer resectable). In the 26 resected patients, MPR rate was 28% with nivolumab and 31% with the combination. In ASCO 2019 updated data were presented, 39 of 44 underwent surgery, 89% resectability. The MPR rate was 24% overall, 17% with nivolumab, and 33% with the combination therapy. Secondary adverse events were 4%, including 2 bronchopleural fistulas and 8 air leaks.
As for combined ICI and chemotherapy, there are also different studies.
NADIM trial (NCT03081689) is a prospective, open-label, single-arm phase 2 trial, that evaluated the safety and efficacy of neoadjuvant chemotherapy paclitaxel + carboplatin plus nivolumab followed by adjuvant nivolumab in 46 patients with resectable stage IIIA (N2 or T4) NSCLC. The primary endpoint was progression‑free survival (PFS) at 24 months. Forty-one of 46 patients had undergone surgery and all tumors were resectable with R0 resection. At 24 months, progression-free survival was 77%. Intention to treat analysis shows 34 patients (83%) achieved MPR of which 26 (63%) had complete pathologic response (CPR). Downstaging was seen in 37 (90%) of cases. This is the first multi-center study to explore chemotherapy and immunotherapy in the neoadjuvant setting in stage IIIA.
In Shu C trial (NCT02716038), from Columbia University, patients received neoadjuvant treatment with atezolizumab, nab-paclitaxel, and carboplatin. Results show that 17/30 patients (57%) achieved MPR of which 10 (33%) had CPR.
Immunotherapy has revolutionized the treatment of advanced stages of lung cancer, becoming early stages of its next challenge.
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FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP12.09 - Molecular Insight into NADIM Clinical Trial: Potential Immune Biomarkers of Pathological Response for NSCLC Patients. (ID 3552)
00:00 - 00:00 | Author(s): Alberto Cruz-Bermudez
- Abstract
- Presentation
Introduction
Many studies have demonstrated that chemo-immunotherapy is a promising approach for NSCLC patients but still exists a lack of prediction biomarkers of survival. We have recently showed that pathological response is a surrogate of progression free survival (PFS) including infiltrating immune cells as potential biomarker of pathological response in NADIM clinical trial (Provencio et al., 2020. Lancet Oncology, in press).
New biomarkers in peripheral blood are being described, focused on the immune system response. Preliminary data was presented at WCLC 2019 however additional results are included in this report. Here we describe the effect of chemo-immune neoadjuvant treatment on resectable NSCLC stage III patients’ immune system and describe blood biomarkers that could help to identify responders to this combination therapy.
Methods
Peripheral mononuclear cells (PBMCs) and plasma from NADIM clinical trial patients before and after chemo-immune neoadjuvant treatment were used. Phenotyping and activation levels of immune cell populations were analyzed by flow cytometry, focused on CD4 T cells, CD8 T cells, T cells NK like and NK cells. Moreover, characterization of the immune response was evaluated by a cytokine array.
Clinical evaluation of pathological response, classified patients in 3 groups, complete (CPR, 0% tumor cells), major (MPR, <10% viable tumor) and incomplete (IPR, >10% viable tumor). Wilcoxon and Kruskall-Wallis statistic tests were used.
Results
Even though we have previously described a decrease of T lymphocytes on tissue after treatment, we do not see these changes on blood. Thus, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neoadjuvant treatment. However, lower levels of activated CD4 T cells and NK cells were observed. Interestingly, this decrease was exclusively statistically significant for patients who achieved a CPR, but no differences were observed for MPR or IPR. As expected, detection of PD1+ cells after neoadjuvant Nivolumab (anti-PD1) treatment was almost completely abrogated, however, a trend for higher PD1+ cell proportions was observed in patients achieving CPR at diagnosis.
Furthermore, many cytokines involved in immune response and described as putative biomarkers for immunotherapy in NSCLC as IL-2, IL-15, IL-6, IL-13 or IFN-gamma, among others, were decreased after neoadjuvant treatment. Notably, stratifying by pathological responses, this decrease was statistically significant only for non-complete responses.
Conclusion
The analysis of immune cell markers on blood samples could be a source for potential surrogate markers of pathological response to neoadjuvant treatment on NSCLC patients.
Similarly, to what occurs in tissue, CPRs showed differences compared to MPR or IPR in some blood markers, both at the cellular and cytokine level. Thus, after treatment, patients achieving CPRs do not seem to reduce their levels of cytokines such as IL-2, IL-15, IL-6, IL-13 or IFN-g associated with anti-tumor response, but they do reduce their levels of activated CD4 and NK cells
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P60 - Tumor Biology and Systems Biology - Basic and Translational Science - Immune Bio (ID 198)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P60.07 - TMB and Selected Mutations in Resectable Stage IIIA NSCLC Patients Receiving Neo-Adjuvant Chemo-Immunotherapy from NADIM Trial (ID 2142)
00:00 - 00:00 | Presenting Author(s): Alberto Cruz-Bermudez
- Abstract
Introduction
Tumor Mutational Burden (TMB) assessment and identification of specific mutations associated to anti-PD1 blockade therapy resistance have become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, the clinical relevance of these parameters in terms of pathological response and PFS in neo-adjuvant chemo-immunotherapy has not been established. To answer this question we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab.
Methods
Pretreatment TMB, defined as the number of nonsynonymous variants (missense and nonsense single nucleotide variants (SNVs)), plus insertion and deletion variants (INDELs) detected per megabase (Mb) of exonic sequence, was estimated from 27 patients that had enough diagnostic material for next generation sequencing using the Oncomine Tumor mutation Load assay (ThermoFisher) following manufacturer’s instructions. The panel covers 1.7 Mb of 409 genes with known cancer associations. Regarding pathological responses, patients were classified into 3 groups: pathologic complete response (pCR) (0% viable tumour at any localization tested), major pathologic response (MPR, <10% viable tumour) and pathologic incomplete response (pIR) (>10% of viable tumour). At data analysis, median follow-up time was 22.7 months.
Results
Median TMB was 5.89 (range 1.68 – 73.95). No differences in TMB value between histologies (adenocarcinoma vs squamous cell), smoking status (former vs current), age or sex were observed. Somatic mutations were identified in lung cancer driver genes such as TP53, KRAS, EGFR, CDKN2A, NOTCH1, BRAF and in specific genes associated with resistance to immunotherapy such as STK11, KEAP1, and RB1. No genomic alterations in ALK, ROS1, PTEN or ERBB2 were found.
Based on literature, a poor prognosis mutation signature (presence of EGFR, STK11, KEAP1 or RB1 mutations) was generated. A third of the sequenced patients (9/27) harboured at least one mutation in one of these genes.
Pathological response data was available from 23 out of 27 patients sequenced. Both the TMB value and the presence of these resistance mutations were not associated with the degree of pathological response.
Regarding PFS, TMB alone was not predictive of disease progression using different thresholds. However, the presence of these resistance mutations was associated with shorter PFS (log-rank p-value=0.032). The median PFS for mutated patients was 21.4 months (95% CI 16-26 months) while median PFS was not reached in non-mutated patients.
Additionally, the combination of this mutational signature with TMB (absence of resistance mutations and TMB-Higher than median) was able to distinguish patients that strongly benefit from this therapy. Although the median PFS was not reached in both groups yet, statistically significant differences were observed (log-rank p-value=0.046). PFS at 18 and 24 months was 100% (95% CI not estimable) for Non-mutated patients with TMB-High vs 70% (95% CI 50-89%) and 58% (95% CI 35-81%) for the rest of patients (mutated patients plus Non-mutated patients with TMB-Low).
Conclusion
TMB did not predict benefit from chemo-immunotherapy induction in our cohort. However, the presence of EGFR/STK11/KEAP1/RB1 mutations alone, or in combination with TMB, may help identify patients that unlikely benefit from neo-adjuvant chemo-immunotherapy
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P60.11 - TCR Repertoire Predicts Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemoimmunotherapy from NADIM Trial (ID 3417)
00:00 - 00:00 | Author(s): Alberto Cruz-Bermudez
- Abstract
Introduction
Characterization of the T-cell receptor (TCR) repertoire has become a novel approach to monitor immunotherapy responses, however there is lack of knowledge about its clinical relevance as predictive biomarker of pathological response in neoadjuvant chemoimmunotherapy. For this purpose, we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant Paclitaxel + Carboplatin + Nivolumab for 3 cycles, achieving a 63% of complete pathologic responses (CPR). PD-L1 TPS and TMB as CPR biomarkers showed AUC ROC of 0.77 and 0.55, respectively, reinforcing the need for new biomarkers (Provencio, M. et al. 2020).
Methods
TCR repertoires from primary tumours or lymph nodes of 19 NSCLC patients were obtained, at both time points: diagnosis and after neoadjuvant treatment. TCR repertoire was analysed in terms of convergence, diversity, evenness and clonal space, defined as the summed frequency of clones belonging to a frecuency group (top 1%, top 1% to 2%, 2% to 5%, and >5%) relative to the total T-cell repertoire. The results were correlated with pathological response groups and ROC curve analysis was performed to test if TCR repertoire-derived parameters could identify patients with CPR.
Results
There were no statistically significant differences observed in TCR repertoire in biopsy samples in terms of diversity (p = 0,797) or convergence (p = 0,202) between the three pathological response groups or between biopsy and surgery samples. However, we observed differences in terms of evenness in biopsy samples between the pathologic response groups (p=0.037), which were lower in those patients who achieved CPR. The AUC for evenness was 0.844 (IC: 0.667-1.000), p=0,011. An evenness value of <0.8639 showed a sensitivity of 50% and specificity of 100% identifying patients with CPR.
Moreover, the clonal space of the TOP 1% clones in diagnostic samples was higher in patients that achieved CPR (p=0.002). The AUC of this novel biomarker was 0.9667 (IC: 0.897-1.036) (p=0.0006). A TOP 1% clonal space higher than 0.1607 showed a sensitivity of 90% and specificity of 88.9% identifying patients with CPR.
Conclusion
Our results support the association between the uneven distribution of T-lymphocytes clones proportions present in the tissue at diagnosis and response to chemoimmunotherapy. Specifically, higher clonal space occupied by the TOP 1% clones seems to outperform PD-L1 and TMB as predictive biomarker of CPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy.
