Adjuvant Trials Research Articles

A standing platform for cancer drug development using ctDNA-based evidence of recurrence.

The time required to conduct clinical trials limits the rate at which we can evaluate and deliver new treatment options to patients with cancer. New approaches to increase trial efficiency while maintaining rigor would benefit patients, especially in oncology, in which adjuvant trials hold promise for intercepting metastatic disease, but typically require large numbers of patients and many years to complete. We envision a standing platform - an infrastructure to support ongoing identification and trial enrolment of patients with cancer with early molecular evidence of disease (MED) after curative-intent therapy for early-stage cancer, based on the presence of circulating tumour DNA. MED strongly predicts subsequent recurrence, with the vast majority of patients showing radiographic evidence of disease within 18 months. Such a platform would allow efficient testing of many treatments, from small exploratory studies to larger pivotal trials. Trials enrolling patients with MED but without radiographic evidence of disease have the potential to advance drug evaluation because they can be smaller (given high probability of recurrence) and faster (given short time to recurrence) than conventional adjuvant trials. Circulating tumour DNA may also provide a valuable early biomarker of treatment effect, which would allow small signal-finding trials. In this Perspective, we discuss how such a platform could be established.

Inadequate staging and excessive surveillance imaging: Evaluating the magnitude of benefit of targeted therapies in lung cancer

Several phase III trials have altered the management of oncogenic driven non-small cell lung cancer (NSCLC) including those harboring EGFR and ALK mutations. However, several of these pivotal trials deviated from standard-of-care practices for either baseline imaging or surveillance imaging. This occurred despite sponsor acknowledgement in a clinical trial protocol that historical trials utilized imaging modalities that potentially under-staged patients. Inadequate baseline imaging for adjuvant trials instead of PET/CT may not identify individuals with metastatic disease, and thereby subject such individuals with metastatic disease to inferior treatment if randomized to the control arm. Similarly, more frequent surveillance imaging than what is considered standard-of-care may identify disease progression earlier than what is expected in real-world clinical practice and therefore embellish the magnitude of benefit between a targeted therapy and the control arm. While targeted therapies have provided clinical benefit for individuals with oncogenic driven NSCLC, physicians and patients must be cognizant that clinical trial deviations from standard-of-care imaging practices may have embellished the magnitude of benefit for several of these therapies.

Standardized Definitions for Efficacy End Points for Adjuvant Trials—The Updated STEEP Criteria

This Viewpoint discusses how the inclusion or exclusion of certain events in the standardization of clinical trial end points can affect the interpretation of results.

Adjuvant treatment for renal cell carcinoma: current status and future

Purpose of review Renal cell carcinoma (RCC) is resistant to chemotherapy. Adjuvant interferon and tyrosine kinase inhibitors were ineffective. Immune checkpoint inhibitors (ICIs), however, have shed new hope in this setting. In the current review, updated evidence of adjuvant therapy in RCC is summarized. Recent findings KEYNOTE-564 demonstrated survival benefits of adjuvant Pembrolizumab in RCC. EAU guidelines now recommend adjuvant pembrolizumab to ccRCC patients at an increased risk of recurrence, as defined in the study. At a median follow-up of 24 months, the disease-free survival (DFS) was significantly longer for the Pembrolizumab group than placebo group [DFS 77.3 vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval (95% CI), 0.53–0.87; P = 0.002]. From its updated analysis, at median follow up of 57.2 months, overall survival (OS) benefit of Pembrolizumab was demonstrated (hazard ratio for death, 0.62; 95% CI, 0.44–0.87; P = 0.005). A number of other adjuvant ICI trials have though been negative. Summary Pembrolizumab is currently the only adjuvant therapy for RCC showing survival benefits, amid a number of negative trials on adjuvant immunotherapy. Currently, there is no role for adjuvant tyrosine-kinase inhibitors and radiotherapy for RCC. Meanwhile, a multidisciplinary approach and shared decision-making should be adopted.

Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC)

BackgroundCancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC. MethodsIn vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome. ResultsIn vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts. DiscussionAlthough in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.

New treatment strategy for early hormone receptor-positive HER2-negative breast cancer: updated results of adjuvant abemaciclib trial in operable and locally advanced breast cancer

Abemaciclib is an oral inhibitor 4 and 6 (CDK4/6). Abemaciclib differs from other drugs in this group in suppression spectrum of cyclin-dependent kinases and is proven to improve survival rates in different treatment lines of metastatic breast cancer. In randomized clinical trials 3rd phase in patients with early hormone-dependent HR+ HER2 negative breast cancer high risk of progression abemaciclib in conjunction with hormone therapy significantly improves invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS). Long- term outcome studies monarchE with 5 – year follow – up of patients showed that abemaciclib adding to ET increases 5-year IDFS from 76 to 83.6% (HR0.680; 95% CI 0.599 to 0.772; p <0.001) and 5-year DRFS from 79.2% to 86.0% (HR0.675; 95% CI 0.588 to 0.774; p <0.001). Adverse events of 3rd degree and higher are registrated in 45.5% of patients in abemaciclib group and in 12,7% in control group and mainly presented by neutropenia (18.6 and 0.7%) and diarrhea (7,6 and 0.1%). Toxicity profile was expected and controlled. The reasonable dose reduction of abemaciclib did not lead to deterioration of long-term treatment result.

Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.

ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.

Long-term outcomes by lobular versus ductal histology in four NSABP adjuvant breast cancer trials.

We evaluated differences in long-term outcomes of invasive lobular carcinoma (ILC) vs breast cancers of no special type (NST) treated with anthracycline-based adjuvant chemotherapy using 4 National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized phase III trials (B-22, B-25, B-28, B-30). Our cohort included 11,251 patients with NST and 1,231 with ILC. Patients with ILC were older, had larger and more often estrogen receptor-positive tumors, and more positive lymph nodes. During early follow-up (0-5 years), patients with ILC had fewer recurrences (HR: 0.797; 95% confidence interval [CI] 0.685-0.929) and deaths (HR: 0.756; 95% CI 0.623-0.917). After 5 years patients with ILC had more recurrences (HR: 1.30; 95% CI 1.085-1.558) and deaths (HR: 1.044; 95% CI 0.898-1.214). Conditional probability analysis showed significant interactions between time-period and histologic type for recurrences (p < .001) and deaths (p < .001). Patients with ILC have elevated risk of late recurrence and death compared to patients with NST.

Evaluation of American Urological Association Renal Cell Carcinoma Risk Groups for Chromophobe Renal Cell Carcinoma

ObjectivesTo develop and compare various models for risk stratification in chromophobe renal cell carcinoma (chrRCC). Models have been developed to predict progression-free (PFS) and cancer-specific survival (CSS) following surgery for localized renal cell carcinoma (RCC). Notably, chromophobe RCC (chrRCC) is not included in American Urological Association (AUA) risk stratification, as nuclear grading is not recommended. MethodsWe queried our institutional registry to identify patients managed surgically for unilateral, sporadic, M0, chrRCC from 1970-2012. AUA risk groups were defined using reported criteria, excluding grade, and were compared to the Mayo system incorporating nodal involvement, perinephric/renal sinus fat invasion, and sarcomatoid differentiation. PFS and CSS were estimated using the Kaplan-Meier method. Predictive ability was summarized using c-indexes from Cox proportional hazard regression models. ResultsA total of 257 patients were identified. Thirty-nine patients experienced disease progression at a median 30 months (IQR 5.0-84) and 25 died from chrRCC at a median 34 months (IQR 15-79) following surgery. PFS and CSS rates at 10 years after surgery were 84% and 90%, respectively. C-indexes for modified AUA and Mayo risk groups were similar at 0.76 and 0.75, respectively, for PFS, and 0.77 and 0.76, respectively for CSS. ConclusionsThe modified AUA and Mayo risk stratification systems have similarly robust c-indexes for PFS and CSS in chrRCC. These models can be used to counsel patients based on pathologic features, inform clinicians on appropriate follow-up pathways, and identify patients at risk of disease progression for enrollment in adjuvant systemic therapy trials.

15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1).

Validated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier. This study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS). 15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter. In the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Prognostic impact of selection criteria of current adjuvant endocrine therapy trials NATALEE and monarchE in postmenopausal HRpos/HER2neg breast cancer patients treated with upfront letrozole

BackgroundThe monarchE and NATALEE trials demonstrated the benefit of CDK4/6 inhibitor (CDK4/6i) therapy in adjuvant breast cancer (BC) treatment. Patient selection, based on clinical characteristics, delineated those at high (monarchE) and high/intermediate recurrence risk (NATALEE). This study employed a historical patient cohort to describe the proportion and prognosis of patients eligible for adjuvant CDK4/6i trials. MethodsBetween 2009 and 2011, 3529 patients were enrolled in the adjuvant PreFace clinical trial (NCT01908556). Eligibility criteria included postmenopausal patients with hormone receptor-positive (HRpos) BC for whom a five-year upfront therapy with letrozole was indicated. Patients were categorized into prognostic groups according to monarchE and NATALEE inclusion criteria, and their invasive disease-free survival (iDFS) and overall survival (OS) were assessed. ResultsAmong 2891 HRpos patients, 384 (13.3 %) met the primary monarchE inclusion criteria. The majority (n = 261) qualified due to having ≥ 4 positive lymph nodes. For NATALEE, 915 out of 2886 patients (31.7 %) met the eligibility criteria, with 126 patients (13.7 %) being node-negative. Patients from monarchE with ≥ 4 positive lymph nodes and NATALEE with stage III BC exhibited the poorest prognosis (3-year iDFS rate 0.87). Patients ineligible for the trials demonstrated prognoses similar to the most favorable patient groups within the eligibility criteria. ConclusionPatient populations eligible for monarchE and NATALEE trials differed. Nearly a third of the postmenopausal HRpos population, previously under upfront letrozole treatment, met the NATALEE prognostic eligibility criteria. As certain eligible groups had a prognosis similar to non-eligible patients, it might be interesting to explore additional patient groups for CDK4/6i therapy.

A novel risk classification model integrating CEA, ctDNA, and pTN stage for stage 3 colon cancer: a post hoc analysis of the IDEA-France trial.

We assessed the added value of incorporating carcinoembryonic antigen (CEA) to circulating tumor DNA (ctDNA) and pathological TN (pTN) stage for risk classification in stage 3 colon cancer (CC). We retrospectively analyzed postoperative CEA values in patients with CC from the IDEA-France phase 3 trial. The relation between disease-free survival (DFS) and CEA was modeled through restricted cubic splines. Prognostic value of CEA, ctDNA, and pTN was assessed with the Kaplan-Meier method. Multivariate analysis was used to identify prognostic and predictive factors for DFS. Among 696 patients (35%), CEA values were retrievable, and for 405 (20%) both CEA and ctDNA were available. An optimized CEA threshold of 2 ng/mL was identified, the 3-year DFS was 66.4% for patients above the threshold and 80.9% for those below (HR, 1.74; 95% CI, 1.33-2.28, P < .001). In multivariate analysis, CEA ≥ 2 ng/mL contributed significantly to model variability, becoming an independent prognostic factor for DFS (HR, 1.82; 95% CI,1.27-2.59), alongside ctDNA (HR, 1.88; 95% CI, 1.16-3.03) and pTN (HR, 1.78; 95% CI, 1.24-2.54). A novel integrated risk classification combining CEA, ctDNA, and pTN stage reclassified 19.8% of pT4/N2 patients as low risk and 2.5% of pT3/N1 patients as high risk. This new classification demonstrated the 3-year DFS of 80.8% for low-risk patients and 55.4% for high-risk patients (HR, 2.66, 95% CI, 1.84-3.86, P < .001). Postoperative CEA value is a prognostic factor for DFS in stage 3 CC, independently of ctDNA and pTN. It advocates for systematic reporting in future adjuvant trials. Integrating both biomarkers with pTN could refine risk classification in stage 3 CC.

Recurrence patterns following nephrectomy for renal cell carcinoma in a Danish nationwide cohort.

This study aimed to characterize the demographic and clinical features of patients with renal cell carcinoma (RCC) post-surgery for localized or locally advanced disease in a national Danish cohort, with a specific focus on describing recurrence patterns in a subgroup aligned with the adjuvant KEYNOTE-564 trial classification. This was a retrospective analysis of the Danish Renal Cancer (DaRenCa) database. Eligible subjects were individuals with an RCC diagnosis between January 2014 and December 2017 who subsequently underwent radical or partial nephrectomy. Variables of interest were demographic and clinical characteristics, rates and sites of recurrence. Recurrence rates were also assessed in a subpopulation stratified using the risk classifications of the KEYNOTE-564 trial. A total of 2164 RCC patients were identified. Most patients (84.8%) had non-metastatic RCC (stage M0). A recurrence was observed in 250 of the M0 patients (13.6%). Patients with a recurrence were older, male, had a higher tumour stage, had undergone radical nephrectomy and had a higher Leibovich score. The majority (74.8%) of M0 patients had recurrence at distant metastatic sites. A total of 392 patients were stratified by the KEYNOTE-564 risk classification: 335 intermediate-high risk, 17 high risk and 40 M1 NED (metastatic with no evidence of disease). Recurrence was observed in 37.0%, 88.2% and 27.5% of these risk groups, respectively. This study elucidates the rates and determinants of post-surgical RCC recurrence in Denmark, underscoring the potential of adjuvant immunotherapy in refining therapeutic strategies, identifying suitable beneficiaries and minimizing overtreatment risks in RCC care.

Clinical validation of a prognostic 7-marker IHC assay (7-IHC) in 382 patients (pts) with stage IB/IIA cutaneous melanoma (CM; MELARISK-001).

9572 Background: For pts with resected CM, adjuvant anti-PD1 is approved for AJCC v8 stage IIB–IV and BRAFi/MEKi for stage III–IV disease. Nonetheless, there remains a subgroup of pts within stages IB/IIA, which is at high risk of relapse and death, accounts for a considerable share of overall CM mortality (1), and lacks access to such therapy. Thus, adjuvant clinical trials in this “early”-stage setting may be merited. However, this subgroup is not detectable via AJCC staging alone. A prognostic 7-IHC assay that was developed (2), and analytically (3) and prospectively clinically validated (4) to identify stage IB/IIA pts at high risk of relapse and death, may be useful in selecting pts for adjuvant trials (2,4). Here, we report results from the MELARISK-001 multicenter study of that assay. Methods: MELARISK-001 enrolled consecutive pts diagnosed with stage IB/IIA CM from 2000–16, with available formalin-fixed paraffin-embedded primary melanoma. Specimens were analyzed by 7-IHC and pts classified as either high-risk or low-risk. Kaplan-Meier survival analysis and multivariate Cox regression analysis (MVA) against Breslow thickness, ulceration, age, and sex were performed. Results: MELARISK-001 included 382 pts; 247 (65%) pts in stage IB, 135 (35%) in stage IIA, all sentinel node-negative. Median Breslow thickness was 1.6 mm, median age 60Y. 212 pts (55%) were classified as 7-IHC high-risk, 170 pts (45%) as 7-IHC low-risk. Median follow-up for recurrence-free survival (RFS) was 90 mos, for melanoma-specific survival (MSS) 98 mos. Comparing 7-IHC high-risk vs low-risk pts, 5Y RFS was 79% vs 100%, 10Y RFS, 72% vs 99%, 5Y MSS, 92% vs 100%, and 10Y MSS 82% vs 100% (Table; logrank p&lt;0.001). In MVA, 7-IHC risk class (hazard ratio [HR] 22.3; 95% CI 7.0–70.9), Breslow thickness (1.5; 1.1–1.9), and age (1.61; 1.0–2.5) were significant independent prognosticators of RFS. 7-IHC HR for MSS could not be computed due to 7-IHC's 100% sensitivity. Prognostic performance variables (95% CI) for RFS were: sensitivity 98% (91%–100%), positive predictive value 26% (20%–33%), negative predictive value 99% (97%–100%). Conclusions: 7-IHC risk categorization identified 98% of relapses and 100% of CM-related deaths in stage IB/IIA pts. In MVA, 7-IHC risk class was the strongest independent prognosticator of survival endpoints. 7-IHC high-risk pts have a relapse rate comparable to that of later-stage pts for whom adjuvant therapy is approved. MELARISK-001 provides further evidence supporting use of 7-IHC to identify early-stage pts at high risk of relapse and death who may benefit from adjuvant therapy trials. 1. Whiteman et al J Invest Dermatol 2015. 2. Meyer et al PloS ONE 2012. 3. Ziemer et al Diagnostics2023. 4. Meyer et al Eur J Cancer 2023. [Table: see text]

Correlation of eTILs with recurrence free survival (RFS) in stage IIB-IIIA melanoma and use as biomarker for stratification for clinical trials.

9567 Background: Immunotherapy is approved for resected stage IIB-IIIC, but treatment of all patients, particularly those with IIB-IIIA disease, incurs unneeded expense and toxicity. Biomarkers are urgently needed for patient stratification. Time constraints in clinical trial design have led to the adoption of recurrence free survival (RFS) as a primary endpoint in adjuvant melanoma trials. Tumor infiltrating lymphocytes (TILs) are a well-established biomarker in primary melanoma, but quantification is subjective. Electronic TILs (eTILs) are a previously published automated digital pathology tool to quantify TILs. Methods: A retrospective cohort of 194 patients with Stage II-III melanoma from Roswell Park Comprehensive Cancer Center (RPCCC, n=133) and Geisinger Medical Center (GMC, n=61) were evaluated for eTILS by blinded investigators. Patients were included based on a search of dermatopathology databases and tissue availability. Digital images of diagnostic slides were analyzed using quPath, a publicly available software. Briefly, tumor areas were selected to include infiltrating lymphocytes with minimal adjacent stroma. Color variations in H&amp;E images were standardized, and cell types quantified utilizing a machine learning algorithm. A previously published threshold of 16.6% eTILs, calculated as lymphocytes/tumor cells x 100, was used. Patients were staged using American Joint Committee on Cancer (AJCC) guidelines, version 8. Survival was assessed using Kaplan-Meier Curves and correlation of clinic-pathologic features with survival was tested using Cox Proportional Hazards Models. Results: Of 194 patients, 56 were stage IIA, 85 were IIB-IIIA, and 53 were IIIB-D. Median follow up was 47.5 months. 103 patients had eTILs &gt;16.6% of whom 13 (12.6%) died and 84 had eTILS &lt;16.6% of whom 23 (27.4%) died during follow-up. HR for death from melanoma within 5 years for the high eTIL group was 0.53 (CI 0.21-0.90, p=0.024). DSS was significantly longer in the high eTIL group than the low eTIL group (p=0.0095). Among 85 stage IIB-IIIA patients, local and distant recurrence data was available for the RPCCC cohort of 68 patients. 46 of these patients had high eTILs of whom 9(19.6%) recurred and 22 had low eTILS of whom 10 (45.95%) recurred. HR for recurrence within 5 years for the high eTIL group was 0.44 (CI0.23-0.83, p=0.012). RFS was significantly longer in the high TIL group (p=0.016) as was distant metastatic recurrent survival (p= 0.0063). eTIL score correlated with RFS in a univariable Cox model (p=0.033) and added to stage and depth in a multivariable Cox model (p=0.018). Conclusions: eTILs, readily evaluable at low cost using diagnostic slides, correlate with clinical outcome in a retrospective cohort of 194 patients. eTILS should be prospectively evaluated as a biomarker to stratify early-stage melanoma patients for adjuvant clinical trials.

24P Standardizing data collection in adjuvant colon cancer trials: A consensus project from the IDEA and ACCENT international consortia and national experts

24P Standardizing data collection in adjuvant colon cancer trials: A consensus project from the IDEA and ACCENT international consortia and national experts

A window-of-opportunity (WOO) trial of giredestrant +/- LHRHa vs anastrozole+LHRHa in premenopausal women with ER+/HER2- early breast cancer (EBC; IBCSG 67-22; PREcoopERA).

TPS628 Background: Adjuvant endocrine therapy (ET) for premenopausal women with ER+/HER2- EBC often includes ovarian function suppression (OFS) via a GnRH or LHRH agonist (LHRHa) plus an aromatase inhibitor (AI) or tamoxifen. Younger age is associated with lower rates of ET adherence indicating side effects are less acceptable to these women. The development of drug regimens without OFS are clearly an unmet medical need in this setting. New oral selective ER degraders (SERDs) are emerging as potentially useful ETs in the (neo)adjuvant settings. Giredestrant is an efficient and potent SERD and a full antagonist, which translates into better anti-proliferation activity than known SERDs. PREcoopERA is a WOO trial aiming to determine, among premenopausal women with ER+/HER2- EBC: if giredestrant+LHRHa provides greater anti-proliferative activity than anastrozole+LHRHa; and if giredestrant without LHRHa provides similar (non-inferior) anti-proliferative activity to giredestrant+LHRHa. Results would provide rationale for subsequent (neo)adjuvant clinical trials. Methods: PREcoopERA (NCT05896566) is a randomized, open-label, 3-arm, WOO trial evaluating the anti-proliferative activity and safety of the oral SERD giredestrant +/- LHRHa triptorelin, as compared to the AI anastrozole + triptorelin. Eligible are premenopausal women with untreated ER+/HER2- operable stage I-III (excl. T4) EBC, with Ki-67 ≥10%. 220 women will be randomized in 2:2:1 ratio to giredestrant (30 mg/d po for 4 weeks until rebiopsy) + triptorelin (3.75 mg IM on D1); giredestrant alone; or anastrozole (1 mg/d po) + triptorelin. Rebiopsy is planned for D29, either during primary surgery or standalone procedures. The primary endpoint is change in Ki-67 labeling index between pre-treatment diagnostic tumor biopsy and post-treatment rebiopsy, as assessed by the IBCSG Pathology Office. Sample size of 80:80:40 randomized women are planned to test superiority of 4 weeks giredestrant+triptorelin vs anastrozole+triptorelin to reduce Ki-67 (hypothesized percentage changes -80% vs -65%) and to test non-inferiority of 4 weeks giredestrant vs giredesrant+triptorelin (within 10% as non-inferiority margin). The trial was activated on 9 October 2023. The first woman was enrolled on 25 January 2024. Clinical trial information: NCT05896566 .

Quality Assurance in Radiotherapy (RT)-Specific Trials: Indian Scenario

AimsThere is evidence that proper radiotherapy trial quality assurance (RTTQA) translates into improved outcomes for patients. However, the practice of RTTQA is heterogeneous and implemented in a diverse manner across trials. In this paper, we review the RTTQA report for randomised trials (RCT) conducted in India and present our experience with RTTQA for various clinical trials and highlight the key achievements and challenges. Materials and methodsSearch was performed using the keywords and the variations thereof for “radiotherapy” and author affiliations from India, its states and major metropolitan cities. Pubmed search filters were used to restrict results to RCT published in the past 5 years (2019–2024). Reporting of RTTQA procedures from publications and protocols was documented along with the protocol-specified dosimetric goals. We also evaluated a few clinical trials performed in the Department of Radiation Oncology at Tata Medical Center. The different RTTQA procedures and results for four representative clinical trials have been described. ResultsA formal RTTQA process was reported by only one out of 24 randomised controlled trials and formal dosimetric goals were pre-specified by 9 of 13 trials where IMRT was used as treatment. RTTQA requirements were tailored for each clinical trial at Tata Medical Center. For the HYPORT trial, the RTTQA process focused on ensuring the matchline doses were homogenous. HYPORT B trial commissioned the use of a simultaneous integrated boost technique which emphasised conformal avoidance of dose spillage to contralateral breast and lung. HYPORT Adjuvant and PROPARA trials are multicentre clinical trials. While HYPORT Adjuvant focussed on ensuring that the dose delivery met the predefined constraints, segmentation of the target volume was important for the PROPARA trial. ConclusionWe demonstrate different RTTQA procedures required for representative clinical trials and highlight key challenges encountered.

Molecular residual disease (MRD) analysis from the ADAURA trial of adjuvant (adj) osimertinib in patients (pts) with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).

8005 Background: Osimertinib (osi) is a third-generation, central nervous system-active EGFR-TKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. Adj osi (3 years [yrs]) is recommended for resected EGFRm stage IB–IIIA NSCLC, based on significant improvements in disease-free survival (DFS) and overall survival (OS) in the Phase III ADAURA study (NCT02511106). A trend towards an increased DFS event rate beyond 3 yrs suggests some pts may benefit from longer adj osi treatment (tx). We explored if plasma ctDNA-based, tumor-informed MRD could predict disease recurrence. Methods: Eligible pts (≥18 yrs [≥20 in Japan/Taiwan], WHO PS 0/1 with completely resected EGFRm [Ex19del/L858R] stage IB, II or IIIA [AJCC 7th edition] NSCLC) were randomized 1:1 to osi 80 mg once daily or placebo (pbo) until disease recurrence, tx completion (up to 3 yrs), or a discontinuation criterion was met. Personalized MRD panels (RaDaR, NeoGenomics) were used, comprised of ≤50 tumor-specific variants, based on whole exome sequencing of resected tumor tissue (variants identified in germline DNA removed). Plasma sample collection: baseline (BL; at randomization surgery and adj Ctx, if received), on tx (every 12 weeks [wks]), tx discontinuation, and post-tx completion (wk 12, wk 24, then every 24 wks until 5 yrs). Plasma samples were analyzed for detection of ctDNA (MRD+). Molecular recurrence or DFS (MRD/DFS) was defined as time from randomization to post-BL MRD+, disease recurrence, or death and was compared across arms. DFS was investigator-assessed. Results: Of 682 pts randomized, 245 (36%) had samples required to produce MRD panels, which were evaluable for 220 (32%) pts across both arms. In the osi vs pbo arms, 5/112 (4%) vs 13/108 (12%) pts were MRD+ at BL; 4/5 pts became MRD– during osi tx vs 0/13 pts on pbo. On tx, MRD detection had clinical sensitivity of 65% (62 MRD+/96 DFS+), specificity of 95% (118 MRD–/124 DFS–) and preceded a DFS event by a median (95% CI) of 4.7 (2.2, 5.6) months (mos) across both arms. Median follow-up time from randomization was 44.2 (95% CI 42.4, 49.1) and 19.1 (95% CI 11.1, 28.3) mos for osi and pbo arms, respectively. Overall, 86% (95% CI 78, 92) vs 36% (95% CI 27, 45) pts in the osi vs pbo arms were MRD/DFS event free at 36 mos (HR: 0.23; 95% CI 0.15, 0.36). MRD/DFS events in the osi arm were detected at any time post-BL in 28 (25%) pts, of whom 19/28 (68%) had events post-adj osi. Most (11/19 [58%]) MRD/DFS events detected occurred within 12 mos of osi tx completion. Conclusions: MRD+ preceded DFS events in most pts with a median lead time of 4.7 mos across both arms. MRD– was maintained for most pts during adj osi tx with the majority of MRD/DFS events occurring after osi tx completion. MRD detection could potentially identify a subset of pts likely to benefit from longer adj osi. Clinical trial information: NCT02511106 .

Dose-dense adjuvant chemotherapy in patients with HER2-low early breast cancer: An exploratory analysis of the GIM2 trial.

532 Background: Dose-dense (DD) adjuvant chemotherapy represents the standard treatment for patients with node-positive early-stage HER2-negative breast cancer, but its role in HER2-low disease is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated efficacy of DD chemotherapy among patients affected by HER2-negative breast cancer according to HER2 immunohistochemistry (IHC) score (low vs. zero). Methods: Patients with node-positive early breast cancer were randomly assigned to receive either DD or standard schedule anthracycline- and taxane-based chemotherapy. HER2 status was assessed locally. Tumours with HER2 score 0 were classified as HER2-zero, while those with a HER2 score 1+ or 2+ without fluorescence in situ hybridization (FISH) amplification were defined as HER2-low. Some tumours were classified as HER2-negative with unknown IHC score. Survival outcomes were compared between patients with HER2-zero vs HER2-low tumours. Results: Among 2003 patients enrolled in the GIM2 trial, 1243 subjects were eligible for this analysis. Median age was 52 years (interquartile range [IQR] 44-59) and 604 patients (48.6%) were pre-menopausal. Hormone receptor status was positive in 87.9% of cancers. 475 tumours were classified as HER2-zero (38.2%), 446 (35.9%) were defined HER2-low and 322 (25.9%) were HER2-negative with unknown IHC score. No significant differences were found in terms of baseline characteristics between these three subgroups. At a median follow-up of 14.9 years (IQR 8.4-16.2), no significant interaction was observed between treatment effect and HER2 status in invasive disease-free survival (iDFS) (p for interaction=0.46) nor in overall survival (OS) (p for interaction=0.43). Comparing patients with HER2-zero breast cancer with those affected by HER2-low tumours, no significant differences in iDFS were observed (15yr iDFS were 61% vs. 54%, respectively, p=0.25), nor OS differences (15yr OS were 75% vs. 72%, respectively, p=0.19). When investigating DD schedule efficacy among patients with HER2-zero tumours, hazard ratio (HR) for iDFS was 0.64 (95% confidence interval [CI] 0.46-0.87) and HR for OS was 0.57 (95%CI 0.38-0.88). Similarly, within patients affected by HER2-low breast cancer, HR was 0.83 (95%CI 0.62-1.11) for iDFS and 0.83 (95%CI 0.57-1.22) for OS. These results were consistent with the findings of efficacy of DD chemotherapy in the overall population included in this analysis (HR for iDFS 0.73 [95%CI 0.61-0.89]; HR for OS 0.69 [95%CI 0.54-0.88]). Conclusions: In this exploratory analysis of a large phase III adjuvant trial, HER2 status (i.e. HER2-zero vs HER2low) did not show prognostic value. In patients with high-risk early breast cancer, the benefit of DD chemotherapy was observed irrespective of HER2 status. Clinical trial information: NCT00433420 .