Neoadjuvant Treatment In Patients Research Articles

Abstract LBA035: Canakinumab or Pembrolizumab as Monotherapy or in Combination as Neoadjuvant Therapy in Patients With Resectable Non-Small Cell Lung Cancer: CANOPY-N Trial

Abstract Background: Complete surgical resection is the standard treatment for patients with stage I-IIIA non-small cell lung cancer (NSCLC). Five-year survival rates in this population range from 19% to 50%, with most patients dying from distant recurrence. As neoadjuvant/adjuvant chemotherapy yields a modest 5% absolute overall survival benefit for these patients with NSCLC, new treatment options are needed. Preliminary data with PD-1 or PD-L1 inhibitors as neoadjuvant therapy have shown major pathologic responses (MPRs) or pathologic complete responses in patients with resectable NSCLC. In the CANTOS study, reduced incidence of NSCLC and decreased lung cancer–related mortality were observed in a dose-dependent manner in patients with atherosclerosis who received canakinumab (interleukin 1β inhibitor) versus those who received placebo. In preclinical NSCLC humanized models, treatment with canakinumab ± anti–PD-1 inhibitor has shown promising activity, and a synergistic effect was observed with this combination, which may enhance the efficacy of PD-1 inhibition by modulating pro-tumor inflammation in the tumor microenvironment. In this context, the CANOPY-N study was designed to evaluate the effect of canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant treatment for patients with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a Phase II, randomized, open-label study evaluating the effect of canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant treatment in patients with resectable NSCLC. Patients with histologically confirmed stage IB-IIIA NSCLC (excluding N2 and T4 tumors), no prior systemic therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and eligibility for surgery with a planned resection in approximately 4-6 weeks after first dose of study treatment are eligible to participate. An archival (if obtained up to 6 months before first day of treatment) or new biopsy is required. Approximately 110 patients will be randomized in a 2:2:1 ratio (stratified by histology [squamous/nonsquamous]) to receive a total of 2 doses (200 mg every 3 weeks) of canakinumab alone (n=44) or in combination with pembrolizumab (n=44) or pembrolizumab alone (n=22), with safety follow-up up to 130 days from last study-drug dose. The primary endpoint is MPR rate (≤10% of residual viable tumor cells at time of surgery), and secondary endpoints include overall response rate per RECIST 1.1, MPR rate based on local assessment, surgical feasibility rates, safety, incidence of antidrug antibodies, pharmacokinetic parameters, and assessment of the relationship between blood- or tissue-based biomarkers and MPR. As of May 27, 2021, there are 44 active study locations. Citation Format: Jay M. Lee, Jean-Louis Pujol, Pilar Garrido, Edward S. Kim, Masahiro Tsuboi, Rafael Caparica Bitton, Jiawei Duan, Cecile Blin, Alexander Savchenko, Tony Mok. Canakinumab or Pembrolizumab as Monotherapy or in Combination as Neoadjuvant Therapy in Patients With Resectable Non-Small Cell Lung Cancer: CANOPY-N Trial [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 LBA035.

The Role of Radiotherapy in Neoadjuvant Treatment of Patients with Operable Pancreatic Head Cancer

The Role of Radiotherapy in Neoadjuvant Treatment of Patients with Operable Pancreatic Head Cancer

Long-Term Outcomes of Watch & Wait (W&W) after Neoadjuvant Treatment in Patients With Rectal Cancer

To compare the outcomes of W&W strategy in patients with locally advanced rectal cancer who achieve complete clinical response (cCR) after neoadjuvant therapy, with those pathological complete response (pCR) after total mesorectal excision (TME).This is a retrospective cohort analysis study. 1014 Patients of histologically proven with locally advanced rectal adenocarcinoma who had received neoadjuvant chemotherapy were eligible between January 2014 and December 2019. In whom we included patients who had cCR offered management with W&W strategy after completing long-course concurrent chemoradiotherapy or short-course sequential chemoradiotherapy, no distant metastases within 6 months after treatment, follow-up ≥1 year, and patients who did not have cCR but pCR after TME. The primary endpoints were 3-year and 5-year overall survival (OS), colostomy-free survival (CFS), disease-free survival (DFS), non-local regrowth disease-free survival (non- regrowth DFS), and organ preservation rate. For comparative analysis, we also derived one-to-one paired cohorts of W&W versus pCR using propensity-score matching (PSM).118 patients were enrolled, 49 of whom had cCR and managed by W&W, 69 had pCR, with a median follow-up period of 49.5 months (IQR 12.1-79.9). No difference in 3-year OS (97.1% vs 96.7%) and 5-year OS (93.8% vs 90.9%, P = 0.696) between W&W and pCR, but patients managed by W&W had significantly better 3-year and 5-year CFS (89.1% vs 43.5%, P < 0.0001). Six patients had local regrowth managed by W&W, while no local recurrence in the pCR group, which had better 3-year DFS (83.6% vs 97%) and 5-year DFS (83.6% vs 91.2%, P = 0.047). However, after salvage surgery, no significantly difference in 3-year non-regrowth DFS (95.9% vs 97%) and 5-year non-regrowth DFS (92.8% vs 97%, P = 0.407) between these two groups. In the PSM analysis (34 patients in each group), absolutely better CFS (90.1% vs 26.5%, P < 0.0001) were noted in the W&W group, but no differences in other survival between groups. A median interval of 17.5 weeks was observed for achieving cCR, while only 23.9% of patients achieved cCR within 5 to 12 weeks from radiation completion. Patients with short-course sequential chemoradiotherapy achieved cCR significantly later when compared with those with long-course concurrent chemoradiotherapy (19 vs 9.8 wk, P < 0.0001).The long-term outcomes of W&W strategy in patients with locally advanced rectal cancer were not inferior to that of those with pCR. 87.7% of patients had successful rectum preservation in W&W group, although patients may require a longer interval for efficacy assessment.

Neoadjuvant treatment: A window of opportunity for nutritional prehabilitation in patients with pancreatic ductal adenocarcinoma.

Patients affected by pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced disease at the time of diagnosis, limiting an upfront surgical approach. Neoadjuvant treatment (NAT) has become the standard of care to downstage non-metastatic locally advanced PDAC. However, this treatment increases the risk of a nutritional status decline, which in turn, may impact therapeutic tolerance, postoperative outcomes, or even prevent the possibility of surgery. Literature on prehabilitation programs on surgical PDAC patients show a reduction of postoperative complications, length of hospital stay, and readmission rate, while data on prehabilitation in NAT patients are scarce and randomized controlled trials are still missing. Particularly, appropriate nutritional management represents an important therapeutic strategy to promote tissue healing and to enhance patient recovery after surgical trauma. In this regard, NAT may represent a new interesting window of opportunity to implement a nutritional prehabilitation program, aiming to increase the PDAC patient’s capacity to complete the planned therapy and potentially improve clinical and survival outcomes. Given these perspectives, this review attempts to provide an in-depth view of the nutritional derangements during NAT and nutritional prehabilitation program as well as their impact on PDAC patient outcomes.

P-289 Gastric and esophageal signet ring cell adenocarcinoma: A retrospective analysis of outcomes at Mayo Clinic

Adenocarcinoma of the esophagus, gastroesophageal junction (GEJ), or stomach with signet ring cell (SRC) features pertains a worse prognosis. Therefore, clinicians tend to have lower threshold for initiating systemic therapy in such patients given the aggressive behavior. Neoadjuvant treatment (NAT) with chemotherapy or chemoradiation (CRT) is considered the standard of care in locoregional disease. However, the benefit of NAT in patients with SRC is unclear. In this study we investigated the clinical characteristics and outcomes of patients with locoregional SRC of esophagus/stomach along with the effect of NAT on outcomes.

Abstract CT237: Canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant therapy in patients with surgically resected non-small cell lung cancer: CANOPY-N trial

Abstract Background: Complete surgical resection is the standard treatment for patients with stage I-IIIA non-small cell lung cancer (NSCLC). Five-year survival rates range from 19% to 50%, with most patients dying from distant recurrence. Neoadjuvant or adjuvant chemotherapy improves overall survival (OS) by only 5% in patients with NSCLC, and new treatment options are needed. Preliminary data for PD1 or PD-L1 inhibitors as neoadjuvant therapy have shown major pathologic responses (MPRs) or pathologic complete responses (pCRs) in patients with early-stage NSCLC. The CANTOS study demonstrated reduced incidence of NSCLC and decreased lung cancer-related mortality with canakinumab (interleukin 1β inhibitor) versus placebo, in a dose-dependent manner for patients with atherosclerosis. In preclinical NSCLC humanized models, treatment with canakinumab ± anti-PD-1 inhibitor could lead to antitumor activity. Combination of canakinumab and pembrolizumab is expected to enhance the efficacy of PD-1 inhibition by inhibiting dysregulated inflammation in the tumor microenvironment. Based on available evidence, the CANOPY-N study was designed to evaluate the effect of canakinumab and pembrolizumab as monotherapy or in combination as neoadjuvant treatment for patients with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a Phase II, randomized, open-label study evaluating the effect of canakinumab and pembrolizumab as monotherapy or in combination as neoadjuvant treatment in patients with resectable NSCLC. Patients with histologically confirmed stage IB-IIIA NSCLC (excluding N2 and T4 tumors), no prior systemic therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and eligibility for surgery and with a planned surgical resection in approximately 4-6 weeks (after first dose of study treatment) are eligible to participate. An archival (if obtained up to 6 months before first day of treatment) or new biopsy is required. Approximately 110 patients will be randomized in a 2:2:1 ratio (stratified by histology [squamous/nonsquamous]) to one of the treatment arms to receive a total of 2 doses (200 mg every 3 weeks) of canakinumab alone (n=44) or in combination with pembrolizumab (n=44) or pembrolizumab alone (n=22), with safety follow-up up to 130 days from last study drug dose. The primary endpoint is MPR rate (≤10% of residual viable tumor cells at time of surgery), and secondary endpoints include determination of overall response rate, MPR rate based on local review, surgical feasibility rates, incidence of antidrug antibodies, and pharmacokinetic parameters. As of October 19, 2020, there are 36 active study locations. Citation Format: Jay M. Lee, Tony Mok, Pilar Garrido, Edward S. Kim, Çağatay Arslan, Masahiro Tsuboi, Tuochuan Dong, Cecile Blin, Vanessa Rodrik-Outmezguine, Bijoyesh Mookerjee, Vanessa Passos, Jean-Louis Pujol. Canakinumab or pembrolizumab as monotherapy or in combination as neoadjuvant therapy in patients with surgically resected non-small cell lung cancer: CANOPY-N trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT237.

Temporal determinants of tumour response to neoadjuvant rectal radiotherapy.

IntroductionIn locally advanced rectal cancer, longer delay to surgery after neoadjuvant radiotherapy increases the likelihood of histopathological tumour response. Chronomodulated radiotherapy in rectal cancer has recently been reported as a factor increasing tumour response to neoadjuvant treatment in patients having earlier surgery, with patients receiving a larger proportion of afternoon treatments showing improved response. This paper aims to replicate this work by exploring the impact of these two temporal factors, independently and in combination, on histopathological tumour response in rectal cancer patients.MethodsA retrospective review of all patients with rectal adenocarcinoma who received long course (≥24 fractions) neoadjuvant radiotherapy with or without chemotherapy at a tertiary referral centre was conducted. Delay to surgery and radiotherapy treatment time were correlated to clinicopathologic characteristics with a particular focus on tumour regression grade. A review of the literature and meta-analysis were also conducted to ascertain the impact of time to surgery from preoperative radiotherapy on tumour regression.ResultsFrom a cohort of 367 patients, 197 patients met the inclusion criteria. Complete pathologic response (AJCC regression grade 0) was seen in 46 (23%) patients with a further 44 patients (22%) having at most small groups of residual cells (AJCC regression grade 1). Median time to surgery was 63 days, and no statistically significant difference was seen in tumour regression between patients having early or late surgery. There was a non-significant trend towards a larger proportion of morning treatments in patients with grade 0 or 1 regression (p = 0.077). There was no difference in tumour regression when composite groups of the two temporal variables were analysed. Visualisation of data from 39 reviewed papers (describing 27379 patients) demonstrated a plateau of response to neoadjuvant radiotherapy after approximately 60 days, and a meta-analysis found improved complete pathologic response in patients having later surgery.ConclusionsThere was no observed benefit of chronomodulated radiotherapy in our cohort of rectal cancer patients. Review of the literature and meta-analysis confirms the benefit of delayed surgery, with a plateau in complete response rates at approximately 60-days between completion of radiotherapy and surgery. In our cohort, time to surgery for the majority of our patients lay along this plateau and this may be a more dominant factor in determining response to neoadjuvant therapy, obscuring any effects of chronomodulation on tumour response. We would recommend surgery be performed between 8 and 11 weeks after completion of neoadjuvant radiotherapy in patients with locally advanced rectal cancer.

The comparison of short-term postoperative outcomes between upfront surgery and surgery following neoadjuvant treatment in pancreatic ductal adenocarcinoma

In cases that neoadjuvant treatment (NAT) was performed before surgery, research on short-term postoperative outcomes seems to have been insufficient. We aimed to compare short-term outcomes between patients who received upfront surgery and those who received surgery following NAT for pancreatic ductal adenocarcinoma (PDAC). We retrospectively reviewed 1,244 cases of PDAC that had pancreatectomy at Samsung Medical Center from January 2010 to March 2020. The resectability status was evaluated according to NCCN guidelines 2017, and cases with distant metastasis were excluded. All cases were classified into two groups of resectable group (R group) and borderline resectable group (BR group). In each group, factors were compared between the cases that upfront surgery was performed (UpS cases) and the cases that surgery was performed after NAT (NAT cases). In R group (n = 981), the clinical, operative, pathologic features did not show distinct differences between UpS cases (n = 973) and NAT cases (n = 8). In BR group (n = 248), patients were younger, preoperative/pre-NAT tumor size was larger, and less cases were accompanied by vascular resection in NAT cases (n = 85) compared with UpS cases (n = 163). There were many oncologic benefits in BR group compared with R group. The short-term postoperative outcomes had no significant differences between UpS cases and NAT cases in both R group and BR group. In cases of NAT, there were no significant differences from upfront surgery in terms of short-term outcomes including postoperative complication. Therefore, we think it is reasonable to perform aggressive surgery for NAT patients.

Direct comparison of F-18 FDG PET/CT and MRI to predict pathologic response to neoadjuvant treatment in locally advanced rectal cancer: a meta-analysis.

The purpose of the current study was to compare the diagnostic accuracies of F-18 FDG PET/CT and MRI for prediction of pathologic responses to neoadjuvant treatment (NAT) in locally advanced rectal cancer (LARC) patients based on a systematic review and meta-analyses. The PubMed, Cochrane, and Embase databases were searched to identify studies that conducted direct comparisons of the diagnostic performance of F-18 FDG PET/CT and MRI for the prediction of pathologic response to NAT in patients with LARC from the earliest available date of indexing up to July 31, 2020. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR + and LR-), and we constructed summary receiver operating characteristic curves. In nine studies (427 patients), the pooled sensitivity of F-18 FDG PET/CT was 0.79 (95% CI 0.71-0.86) and the pooled specificity was 0.74 (95% CI 0.60-0.84). LR syntheses yielded an overall LR + of 3.1 (95% CI 1.9-5.0) and an LR- of 0.28 (95% CI 0.18-0.43). The pooled diagnostic odds ratio (DOR) was 11 (95% CI 5-26). The pooled sensitivity of MRI was 0.89 (95% CI 0.77-0.95) and the pooled specificity was 0.66 (95% CI 0.55-0.76). LR syntheses yielded an overall LR + of 2.6 (95% CI 1.9-3.6) and an LR- of 0.17 (95% CI 0.08-0.37). The pooled DOR was 15 (95% CI 6-42). In meta-regression analysis, no variable was identified as the source of the study heterogeneity. F-18 FDG PET/CT and MRI showed similar diagnostic performances for the prediction of pathologic responses to NAT in patients with LARC. However, each modality can be a complement to other rather than being used singly.

Efficacy and safety of camrelizumab combined with FLOT versus FLOT alone as neoadjuvant therapy in patients with resectable locally advanced gastric and gastroesophageal junction adenocarcinoma who received D2 radical gastrectomy.

e16020 Background: Docetaxel-based neoadjuvant chemotherapy has been suggested to be beneficial in patients with locally advanced gastric and gastro-oesophageal junction cancer (GC/GEJC). And immunotherapy also show promising treatment efficacy for advanced GC/GEJC. Here we compared the safety and efficacy of camrelizumab combined with chemotherapy versus chemotherapy alone as the neoadjuvant therapy for patients with resectable locally advanced GC/GEJC. Methods: Eligible patients diagnosed as resectable locally advanced GC/GEJC were randomized to receive neoadjuvant treatment, in arm A, the patients received FLOT alone (docetaxel 50 mg/m²; oxaliplatin 85 mg/m²; leucovorin 200 mg/m²; 5-FU 2600 mg/m², every 2 weeks), in arm B, the patients received FLOT combined with camrelizumab(camrelizumab 200mg intravenously every 3 weeks). Eligible patients underwent gastrectomy with D2 lymph node dissection. The primary end point of this trial was pCR rate and R0 resection rate, and the secondary end points were ORR,PFS, OS and safety profile. Results: From January 15 2020 to January 15 2021, 24 patients were recruited (11 patients in arm A and 13 patients in arm B). 19 patients had completed planned neoadjuvant treatment for 4 cycles (9 pts in the arm A, 10 ptsin the arm B). Two patients in the arm A were waiting for gastrectomy. This analysis was based on the 17 pts. In the arm A, the median age was 61 years (47-72 years) and a total of 5 males and 4 females, ECOG PS 0 (n = 1), ECOG PS 1 (n = 8). In the arm B, the median age was 63 years (57-71 years) and a total of 9 males and 1 females, all patients with ECOG PS 1. The R0 resection rate was high in arm B compared with arm A (10/10,100% vs. 5/7, 71.4%). No pCR were observed in the two arms. Tumour regression grade were as follows:TRG1 [arm A 0% (0/7), arm B 10% (1/10)], TRG2 [arm A 43% (3/7), arm B 60% (6/10)], TRG3 [arm A 29% (2/7), arm B 30% (3/10)].There was a significantly higher proportion of patients achieved a postoperative ypN0 in the arm B than arm A(60% vs 0%), which had preoperative clinical stage cT3-4N+M0. Postoperative pathologic staging was as follows: ypT1 [arm A 14% (1/7); armB 30% (3/10)]. ypT2 [armA 0% (0/7); armB 30% (3/10)]. ypT3 [arm A 29% (2/7); arm B 20% (2/10)]. ypT4 [armA 29% (2/7); armB 20% (2/10)]. Neither serious intraoperative complications nor immune-related adverse events were observed during perioperation. Treatment-related AEs neutropenia and leukopenia were manageable and there was no treatment-related death. Conclusions: Camrelizumab combined with FLOT showed promising efficacy as neoadjuvant treatment for patients with locally advanced gastric or GEJ adenocarcinoma, with low complications and acceptable toxicity. Clinical trial information: ChiCTR2000030610.

Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC).

8503 Background: CheckMate 816 (NCT02998528) is a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC. The study met its first primary endpoint, demonstrating significantly improved pathological complete response (pCR) with neoadjuvant NIVO + chemo. Here we report key surgical outcomes from the study. Methods: Adults with stage IB (≥ 4 cm)–IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK alterations were randomized to NIVO 360 mg + platinum-doublet chemo Q3W or chemo Q3W for 3 cycles (n = 179 each). Definitive surgery was to be performed within 6 weeks of treatment. Primary endpoints are pCR (defined as 0% viable tumor cells in lung and lymph nodes) and event-free survival; both are evaluated by blinded independent review. Feasibility of surgery and surgery-related adverse events (AEs) are exploratory endpoints. Results: Baseline characteristics were comparable between arms; 64% of patients (pts) were stage IIIA. Definitive surgery rates were 83% with NIVO + chemo (n = 149) vs 75% with chemo (n = 135). Reasons for cancelled surgery were disease progression (12 and 17 pts, respectively), AEs (2 pts/arm), or other scenarios (14 and 19 pts, respectively; including pt refusal, unresectability, poor lung function). Minimally invasive surgery rates were 30% and 22%, and conversion from minimally invasive to open surgery rates were 11% and 16% for NIVO + chemo and chemo, respectively. Lobectomy was performed in 77% vs 61% of pts, and pneumonectomy in 17% and 25% for NIVO + chemo vs chemo, respectively. AEs were responsible for delays of surgery in 6 pts in the NIVO + chemo arm and 9 pts in the chemo arm. An R0 resection was achieved in 83% vs 78% of pts and median residual viable tumor (RVT) cells in the primary tumor bed were 10% vs 74% for NIVO + chemo vs chemo. There was no increase in median (Q1, Q3) duration of surgery and length of hospitalization between NIVO + chemo vs chemo (184 [130, 252] vs 217 [150, 283] min; and 10.0 [7, 14] vs 10.0 [7, 14] days, respectively). Any-grade and grade 3–4 surgery-related AEs were reported in 41% vs 47% and 11% vs 15% of the NIVO + chemo vs chemo arms, respectively. Grade 5 surgery-related AEs were reported in 2 vs 0 pts in the NIVO + chemo vs chemo arms; 0 vs 3 pts died due to treatment-related AEs, respectively. Conclusions: In CheckMate 816, neoadjuvant NIVO + chemo did not impede the feasibility and timing of surgery, nor the extent or completeness of resection vs chemo alone; treatment was tolerable and did not increase surgical complications. NIVO + chemo led to increased depth of pathological response. The surgical outcome data from CheckMate 816 along with significant improvement in pCR support NIVO + chemo as a potential neoadjuvant option for patients with stage IB to IIIA resectable NSCLC. Clinical trial information: NCT02998528.

63O Letrozole and palbociclib versus third generation chemotherapy as neoadjuvant treatment in luminal breast cancer: Survival results of the UNICANCER-NeoPAL study

The NeoPAL trial compared letrozole-palbociclib (LETPAL) combination to standard chemotherapy (CT) as neoadjuvant treatment in patients with high-risk LBC. Both LETPAL and CT were associated with poor pathological response, and equivalent clinical responses, while LETPAL let to encouraging biomarker responses in Prosigna®-defined high-risk LBC. We now evaluate the survival outcomes of both groups.

Coming of Age of Immunotherapy of Urothelial Cancer.

Following platinum-based regimens becoming the reference standard of care, it has taken almost four decades to find a systemic treatment that improved overall survival in metastatic urothelial tumors. Single-agent immune checkpoint inhibitors have not only improved overall survival but also the quality of life of patients with metastatic urothelial tumors after failure of platinum-based regimens and as a maintenance therapy after four to six cycles of standard first-line chemotherapy. In addition, very promising data are emerging when single-agent immunotherapy is offered as adjuvant or neoadjuvant treatment for patients with muscle-invasive disease and also in the non-muscle-invasive setting. There is an extensive debate about the role of PD-L1 expression as a reliable biomarker to predict the activity of immune-based regimens. Furthermore, the lack of consensus concerning its utility means that there is a need for more and better tools to identify patients who are likely to benefit from these novel approaches. The field of urothelial tumors now additionally exploits novel antibody-drug conjugates and fibroblast growth factor-receptor inhibitors that are being tested in combination with immunotherapy. This added complexity contributes to an enormous increase in the challenges that will be faced shortly.

Neoadjuvant immunotherapy for non-small cell lung cancer: State of the art.

Lung cancer mortality has decreased over the past decade and can be partly attributed to advances in targeted therapy and immunotherapy. Immune checkpoint inhibitors (ICIs) have rapidly evolved from investigational drugs to standard of care for the treatment of metastatic non‐small cell lung cancer (NSCLC). In particular, antibodies that block inhibitory immune checkpoints, such as programmed cell death protein 1 (PD‐1) and programmed cell death 1 ligand 1 (PD‐L1), have revolutionized the treatment of advanced NSCLC, when administered alone or in combination with chemotherapy. Immunotherapy is associated with higher response rates, improved overall survival (OS), and increased tolerability compared with conventional cytotoxic chemotherapy. These benefits may increase the utility of immunotherapy and its combinational use with chemotherapy in the neoadjuvant treatment of patients with NSCLC. Early findings from various ongoing clinical trials suggest that neoadjuvant ICIs alone or combined with chemotherapy may significantly reduce systemic recurrence and improve long‐term OS or cure rates in resectable NSCLC. Here we further summarize the safety and efficacy of various neoadjuvant treatment regimens including immunotherapy from ongoing clinical trials and elaborate the role of neoadjuvant immunotherapy in patients with resectable NSCLC. In addition, we discuss several unresolved challenges, including the evaluations to assess neoadjuvant immunotherapy response, the role of adjuvant treatment after neoadjuvant immunotherapy, the efficacy of treatment for oncogenic‐addicted tumors, and predictive biomarkers. We also provide our perspective on ways to overcome current obstacles and establish neoadjuvant immunotherapy as a standard of care.

Abstract PS8-36: Why is neoadjuvant treatment for patients with triple negative breast cancer of T1cN0 required ?

Abstract Background) Patients with early stage triple negative breast cancer(TNBC) are typically treated with surgery and chemotherapy, and sometimes radiotherapy. Despite effective neoadjuvant and adjuvant chemotherapies, the relapse rate is high and up to 50% of patients will experience disease recurrence including 10% of patients with stage I disease, and pCR is useful surrogate marker for patients with neoadjuvant treatment. Currently Neoadjuvant treatment is recommended for patients with TNBC of 2cm or larger at diagnosis. However, patients with T1 disease at diagnosis are mostly recommended with upfront surgery because uncertain clinical meaning of pCR and potential escalation of treatment for patients with non-pCR in this group. The aim of this study is to see whether patients with T1c of TNBC has different prognosis from T1a /b of same or different subtype and the potential benefit of neoadjuvant treatment exist or not. Material and methods) From 2000 to 2015, female patients treated with upfront surgery for stage I-III breast cancer were included. Patients of estrogen receptor positive disease and TNBC were further stratified according to the tumor size. The primary objective of this study was to see the different incidence of disease recurrence, for which chi-square test or Fisher’s exact tests were used. The secondary objective was recurrence free survival and distant disease free survival, for which Kaplan-Meier(K-M) graphs were generated and compared with log-rank test. Results) None of the TNBC patients experienced disease recurrence when they have T1a/b disease. However, patients with T1c disease showed similar incidence of disease recurrence with patients with T2 or T3 stage (89% vs. 86%), suggesting conventional T staging might not reflect real characteristics of TNBC. On the other hands, patients with ER positive disease less affected by tumor size, showing incidence of recurrent disease of T1a/b, T1c and T2 or over as 96.7%, 93.1% and 91.5% respectively. K-M graphs were generated and log-rank test showed worse survival of patients with T1c of TNBC than T1a/b and rather similar prognosis with patients with T2 or over. Conclusion) Effective adjuvant treatment, such as capecitabine had been proposed for patients with non-pCR. However, mixed results are reported, suggesting appropriate selection of patients is critical. While we need to define TNBC better, patients also need appropriate biomarker to decide whether they need escalated treatment after completion of neoadjuvant treatment. Given the dismal prognosis of T1c of TNBC, we propose this group of patients might benefit from preoperative systemic treatment with using pathologic result as surrogate marker. Citation Format: Hyang Suk Choi, In-Jeong Cho, Hany Noh, Kwang-Min Kim, Kyoung Tae Nam, Airi Han. Why is neoadjuvant treatment for patients with triple negative breast cancer of T1cN0 required ? [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-36.

Abstract PS12-03: Letrozole and palbociclib versus 3rd generation chemotherapy as neoadjuvant treatment in luminal breast cancer: Survival results of the UNICANCER-NeoPAL study

Abstract Background Palbociclib is a CDK4/6 inhibitor with demonstrated survival benefits in combination with endocrine therapy in advanced luminal breast cancer (LBC). Its potential role in early breast cancer is currently explored. The NeoPAL trial compared letrozole-palbociclib (LETPAL) combination to standard chemotherapy (CT) as neoadjuvant treatment in patients with high-risk LBC. Both LETPAL and CT were associated with poor pathological response, and equivalent clinical responses, while LETPAL let to encouraging biomarker responses in Prosigna®-defined high-risk LBC. We now evaluate the survival outcomes of both groups. Patients and Methods NeoPAL (UCBG10/4, NCT02400567) is a randomized, parallel, non-comparative phase II study. Postmenopausal women with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II-III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks (LETPAL), or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2) x3 21-day courses followed by docetaxel 100 mg/m2 x3 21-day courses (CT). Secondary endpoints included progression-free survival (PFS) and invasive-disease free survival (iDFS), all measured from the date of randomization. Exploratory objectives aimed at evaluating the impact of PEPI score and residual cancer burden (RCB) on survival outcomes in both arms. Results 53 pts were randomized in each arm (both with 11% Luminal A N+ and 89% Luminal B). 23 of the 53 pts in the LETPAL arm received postoperative adjuvant chemotherapy. Median follow-up is 40.4 months [0-56.6]. 11 progressions have been observed (10 metastatic events, 1 regional progression), of which 3 were in the LETPAL and 8 in the control arm. Two additional iDFS events were observed in the LETPAL arm (secondary malignancies). PFS (HR = 1.01; 95%CI [0.36; 2.90], p=0.98) and iDFS (HR= 0.83; 95%CI [0.31; 2.23], p=0.71) did not differ between both arms. 40 months PFS rate is 86.7% (78.0-96.4) and 87.2% (78.1-97.4) in LETPAL and CT arms respectively. PEPI (PEPI II/II vs I: HR 0.80, 95%CI 0.18-3.67) and RCB scores (RCB II/III vs 0/I: HR 1.36; 95%CI 0.17-10.6) did not appear as independent predictors of PFS or iDFS. Conclusions Despite its small size, NeoPAL suggests that a neoadjuvant LETPAL strategy, together with selected postoperative administration of chemotherapy, may spare chemotherapy in some pts with luminal breast cancer while allowing very good long-term outcomes. Citation Format: Suzette Delaloge, Sylvain Dureau, Véronique D'Hondt, Isabelle Desmoulins, Pierre-Etienne Heudel, François Duhoux, Christelle Levy, Florence Lerebours, Marie Ange Mouret-Reynier, Florence Dalenc, Jean-Sébastien Frenel, Christelle Jouannaud, Laurence Venat-Bouvet, Suzanne Nguyen, Cécile Callens, David Gentien, Jerome Lemonnier, Anne Vincent-Salomon, Hélène Manduzio, Paul-Henri Cottu. Letrozole and palbociclib versus 3rd generation chemotherapy as neoadjuvant treatment in luminal breast cancer: Survival results of the UNICANCER-NeoPAL study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-03.

Effect of Additional Trastuzumab in Neoadjuvant and Adjuvant Treatment for Patients with Resectable HER2-Positive Gastric Cancer.

Recent studies have reported a beneficial role of trastuzumab in neoadjuvant treatment (NAT) among resectable gastric cancer (GC) patients; however, the effect of adjuvant treatment (AT) combined with trastuzumab is understudied. We performed a retrospective cohort study to compare chemotherapies with or without trastuzumab among human epidermal growth factor receptor 2-positive (HER2 +) locally advanced GC patients in the AT and NAT settings, respectively. We enrolled 208 HER2 + resected GC patients who underwent perioperative/postoperative treatment in 2010-2019 in a single-centered hospital, including 135 AT patients and 73 NAT patients. We used inverse probability of treatment weighting (IPTW) to balance potential confounding factors between the treatment groups, and estimated the treatment effect of trastuzumab. Pathological and survival outcomes were evaluated. The number of trastuzumab-exposed patients in the AT and NAT cohorts was 31 (23.0%) and 34 (46.6%), respectively. After IPTW adjustment, AT combined with trastuzumab showed a better overall survival (OS) over chemotherapy alone (p = 0.023). In IPTW-adjusted NAT analysis, trastuzumab-exposed patients had an improvement in tumor pathological regression and downstaging, with lower tumor regression grade scores (p = 0.002), ypTNM stages (p < 0.001), ypN stages (p = 0.035), and ypT stages (p < 0.001). Loss of HER2 positivity following trastuzumab treatment was observed in NAT patients; however, we did not observe any significant effect of trastuzumab on OS (p = 0.126). Given the improvement in tumor regression and downstaging among NAT patients, and the OS benefit in AT patients, trastuzumab could be considered a promising treatment for locally advanced HER2 + GC patients. In particular, re-evaluation of HER2 status should be considered following NAT combined with trastuzumab.

Weight gain during neoadjuvant therapy is associated with improved recurrence-free survival for patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma

Presenter: Jonathan Hue MD | Case Western Reserve University School of Medicine Background: Weight loss commonly precedes the diagnosis of pancreatic ductal adenocarcinoma (PDAC). There is growing emphasis on neoadjuvant treatment for patients with localized disease. The severity and impact of weight loss during neoadjuvant therapy is not well studied. We hypothesized that weight loss during neoadjuvant chemotherapy would be associated with poor short- and long-term outcomes. Methods: We performed a single institution retrospective cohort study of patients with histologically confirmed PDAC who received neoadjuvant chemotherapy (with or without radiotherapy) and underwent a pancreatectomy between 2009-2021. We abstracted patient weights within 1 year preceding diagnosis, as well as at diagnosis, chemotherapy start, and before pancreatectomy. Patients were categorized based on weight change from start of chemotherapy to surgery: weight gain (≥5%), stable ( < 5% gain to < 5% loss), and weight loss (≥5%). The association between weight change and pathologic, perioperative, and long-term outcomes was analyzed. Results: A total of 127 patients received neoadjuvant therapy followed by pancreatectomy during the study period, of whom 95 had raw weights recorded at the specified time points and were included in the analysis. The median weight loss prior to diagnosis was 7.9% (range: 0.5% gain to 24.1% loss). Thirty patients (31.6%) lost weight during neoadjuvant chemotherapy, 56 (59.0%) had stable weight, and nine (9.5%) gained weight. Patients who lost weight were more likely to have locally advanced disease compared to patients with stable weight or weight gain (26.7% vs 8.9% vs 11.1%, p=0.12). CA19-9 levels were similar at the time of diagnosis and prior to pancreatectomy across groups. There was no difference between the three groups in the number of chemotherapy cycles administered, chemotherapeutic regimens, rate of neoadjuvant radiotherapy, or the time from initiation of chemotherapy to surgery. There was no difference in pathologic (tumor size, lymph node positivity, margin positivity, pathologic response to therapy) or perioperative (in-hospital complication rate, length of stay, discharge disposition) outcomes based on degree of weight loss during therapy. Utilization of adjuvant chemotherapy and adjuvant radiotherapy was also similar between groups. Median overall survival of patients who gained weight during neoadjuvant therapy was longer than that of patients with stable weight or weight loss (38.4 vs 25.8 vs 26.7 months, p=0.58), but this did not reach statistical significance. Median recurrence-free survival of patients who gained weight during neoadjuvant therapy was longer than that of patients with stable weight or weight loss (29.5 vs 9.6 vs 14.0 months, p=0.07, Figure). After controlling for clinical and treatment factors as well anatomic stage, weight gain was associated with improved recurrence-free survival benefit compared to weight loss (HR=0.15, 95% CI 0.03-0.81). A similar association was not identified when analyzing overall survival (HR=1.17, 95% CI 0.28-4.80). Conclusion: Weight trends during neoadjuvant therapy are variable, but the majority of patients maintain weight or lose weight. Patients who gain weight during neoadjuvant therapy may have improved recurrence-free survival. The association between weight and overall survival is less clear. Future studies may validate weight as a predictor of survival among patients receiving neoadjuvant therapy for localized PDAC.

Difference between carbohydrate antigen 19-9 and fluorine-18 fluorodeoxyglucose positron emission tomography in evaluating the treatment efficacy of neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma: Results of a dual-center study.

BackgroundAn accurate evaluation of neoadjuvant treatment is important to maximize the prognostic benefit of this strategy in each individual patient. The main aim of the present study is to investigate the difference between carbohydrate antigen 19‐9 and fluorine‐18 fluorodeoxyglucose positron emission tomography (FDG‐PET) in evaluating the response to neoadjuvant treatment for resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC) patients.MethodsPancreatic ductal adenocarcinoma patients with positive standard uptake values (SUV) on FDG‐PET before neoadjuvant chemoradiotherapy (NACRT) were enrolled (n = 141). In all patients, CA19‐9 and FDG‐PET were evaluated before the initiation of and after the completion of NACRT. The statuses of CA19‐9 and FDG uptake alterations during NACRT were assessed in association with survival and tumor recurrence profiles.ResultsA favorable response in each CA19‐9 and FDG‐PET was significantly related to better survival, respectively, than the unfavorable response (44.3% vs 19.5%, P < .001 and 45.8% vs 24.6%, P < .001). The status of CA19‐9 was significantly associated with the incidence of distant recurrence whereas the status of FDG‐PET was significantly associated with the incidence of local recurrence, and only patients with a favorable response in both CA19‐9 and PET statuses showed a significantly better survival than the others (5‐year survival: 56% vs 24%, P < .001), and those with unfavorable response in either of CA19‐9 or PET status showed similar poor survival to those with unfavorable in both (P = .164).ConclusionCA19‐9 and PET evaluation provided oncologically different risk assessments in terms of tumor recurrence profile, and favorable response in both CA19‐9 and FDG‐PET were necessary to achieve prognostic benefit from NACRT.

Current trend of breast cancer neoadjuvant treatment in China: a cross-sectional study

Objective: To investigate the current trend of breast cancer neoadjuvant therapy and provide reference for the improvement of breast cancer clinical guideline in the future. Methods: Questionnaires of cross-sectional survey were sent to 110 hospitals (breast cancer surgery quantity surpassing 200) between July 2018 and September 2018. The stages and subtypes, therapeutic regimen, treatment assession, operation choice and preforming of patients underwent neoadjuvant therapy were recorded. Results: Neoadjuvant treatment has been performed in all of the 110 hospitals. The total number of breast patients underwent neoadjuvant therapy was about 14 550 (17.0% in surgical patients) in 2017. For all of the neoadjuvant patients, the proportion of stageⅡ patients was less than 30% in 81 hospitals, and the proportion of stage Ⅲ was more than 50% in 84 hospitals. The numbers of estrogen receptor (ER) (+ )/human epidermal growth factor receptor-2 (HER-2) (-), ER (-)/HER-2 (+ ) and triple negative subtype breast cancer patients were 3 550 (24.4%), 6 024 (41.4%) and 4 991 (34.3%), respectively. Patient's scruples of relatively delayed operation and weak will of breast conservation after neoadjuvant therapy were the majority reasons for neoadjuvant therapy restriction. Anthracycline followed by taxane was the most usual neoadjuvant therapeutic regimens in 53.6% hospitals, and anthracycline plus taxane was the first choice in 42.7% hospitals. Chemotherapy with targeting therapy was recommended to HER-2 positive neoadjuvant patients in 80.9% hospitals. To assess treatment outcome of neoadjuvant treatment, 42.7% hospitals used MRI in more than 50% patients while the usage rate of MRI was less than 20% in 37.3% hospitals. The proportions of hospital using repeat-marking, tattoo and metal clip as the first method to identify the primary tumor region and lymph nodes were 60.0%, 29.1% and 10.9%, respectively. Breast-conservation rate after neoadjuvant therapy was less than 20% in 87.3% hospitals. Conclusions: Neoadjuvant therapy for breast cancer is widely performed in most hospitals in China, while the proportion of neoadjuvant treatment in patients with operable breast cancer is still low. Meanwhile, the idea of achieving de-escalation operation through neoadjuvant treatment is not promoted and the therapeutic evaluation method of neoadjuvant treatment needs further studies to improve.