Progression-free Survival Data Research Articles

Sotorasib (Soto) plus panitumumab (Pmab) and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreaK 101 phase 1b safety and efficacy.

3513 Background: Soto, a KRASG12C inhibitor, had a 9.7% objective response rate (ORR) as monotherapy for chemorefractory patients (pts) with KRAS G12C-mutated mCRC. When combined with Pmab, a monoclonal anti-EGFR antibody, ORR increased to 30%, supporting the model that the doublet mitigates Soto-related feedback reactivation of the RAS-MAPK pathway and accumulation of activated EGFR. We hypothesize that Soto plus Pmab and FOLFIRI will further enhance Soto efficacy while maintaining a manageable safety profile. We report the first results for a KRASG12C inhibitor combined with an EGFR inhibitor and chemotherapy in pts with prior mCRC treatment. Methods: Pts included dose exploration and expansion cohorts from CodeBreaK 101 subprotocol H (NCT04185883) who received Soto (960 mg PO daily) plus Pmab (6 mg/kg IV Q2W) and standard-dose FOLFIRI (IV Q2W). Key eligibility criteria were KRAS G12C-mutated mCRC and ≥1 prior treatment for metastatic disease. Pts in dose expansion were KRASG12C inhibitor-naïve. The primary endpoint was safety. Secondary endpoints included efficacy and pharmacokinetics (PK). Results: As of November 30, 2022, 33 pts (median age: 53 years; 48% female) were treated (6 in dose exploration, 27 in dose expansion). Median prior lines of systemic therapy was 2 (range: 1-6), with 33% and 67% of pts receiving 1 or ≥ 2 prior lines, respectively; 97% had prior fluoropyrimidine and 73% had prior irinotecan. Two pts in dose exploration received prior Soto. None of the 6 pts in dose level 1 of dose exploration had dose limiting toxicities (DLTs) during DLT evaluation (first 28 days), and Soto (960 mg PO daily) plus Pmab (6 mg/kg IV Q2W) and FOLFIRI (IV Q2W) was the recommended phase 2 dose. Treatment-related adverse events (TRAEs) of any grade occurred in 32 (97.0%) pts; 1 pt discontinued the full regimen due to grade 3 ALT increase. Fifteen (45.5%) had grade ≥ 3 TRAEs (most commonly dermatologic; n = 5). There were no fatal TRAEs. Safety findings were consistent with known profiles of Soto, Pmab, and FOLFIRI. No clinically meaningful PK interaction was observed between Soto and irinotecan. Of 31 pts evaluable for response, confirmed ORR (all partial responses) was 58.1% (95% CI: 39.1, 75.5). The 2 pts with prior Soto achieved partial response (n = 1) and stable disease (n = 1). Disease control rate was 93.5% (95% CI: 78.6, 99.2). With median follow-up of 5.7 and 7.4 months, respectively, progression-free and overall survival data are not yet mature. Fully enrolled data will be presented. Conclusions: In the first ever data set for this novel combination, Soto plus Pmab and FOLFIRI showed promising safety and efficacy in pretreated KRAS G12C-mutated mCRC, with a confirmed ORR of 58.1%. Adverse events were manageable and consistent with the expected safety profile of the drugs used, and there was no clinically meaningful Soto and irinotecan PK interaction. Clinical trial information: NCT04185883 .

A multicenter study of central nervous system (CNS) metastasis in EGFR-mutated advanced non–small-cell lung cancer in Thailand: CNS progression-free survival analysis.

e14002 Background: Central Nervous System (CNS) metastasis is common in patients with advanced stage non-small cell lung cancer (NSCLC), which impacts their survival and quality of life. Nearly Half of NSCLCs in Thailand are EGFR (Epidermal Growth Factor Receptor) mutated NSCLCs. The aim of this study was to define the prevalence of CNS metastasis in EGFR mutated advanced NSCLC in Thai patients and their survival during the year 2013-2019.Now we reported CNS progression free survival data in subgroup with evidence of CNS progression. Methods: We retrospectively conducted a multicenter study of EGFR mutated advanced NSCLC from 9 government hospitals in Thailand from January 2013 to December2019. Demographic data and cancer treatments were recorded with previous reports of overall survival data in all cohorts. Brain imaging was performed upon neurologic signs and symptoms. Treatment of CNS metastasis, CNS progression date and overall survival data were collected. The analysis of CNS progression free survival and overall survival was performed and the effect of Osimertinib was defined. Results: There were 254 patients with advanced EGFR mutated NSCLCs. The prevalence of CNS metastasis was 32.28% (82 patients). There were 25.6% (21) of patients with definite evidence of CNS progression by imaging or clinical. In this group, Brain metastasis at first diagnosis was 61.9% (13 patients). EGFR TKIs was given as first line 42.9% (9 patients), second line 33.3% (7 patients), third line 19% (4 patients). Whereas one patient did not received EGFR TKIs. Most of EGFR TKIs treatment was first generation for 95% (19 patients). Osimertinib was given in 23.8% (5) of patients as second line, third line and fourth line for 2, 1 and 2 patients, respectively. The onset of CNS metastasis before EGFR TKIs was 76.2% when compared to 4.8%, 19% during EGFR TKIs and after EGFR TKIs, respectively. Treatment of brain metastasis was whole brain radiation for 85.7% (18 patients), followed by surgery with whole brain radiation for 14.3% (3 patients). The median CNS progression free survival was 14.00 (9.51,18.48) months. The median CNS progression free survival between no Osimertinib treatment and Osimertinib treatment was 13 (10.38,15.61) months and 21 (17.49,24.5) months, respectively. The median survival was 30.03 (19.6,40.45) months. The median survival between no Osimertinib treatment and Osimertinib treatment was 26.58 (18.96,34.20) months and NR (NR, NR), respectively. Conclusions: The prevalence of CNS progression was 25.6% in patients with EGFR mutated NSCLC in Thailand. Treatment with EGFR TKIs improved CNS progression free survival better than historical data.3rd generation EGFR TKIs Osimertinib in later line prolong clinical benefit of CNS Progression free survival and overall survival better than 1st generation EGFR TKIs alone.

Risk of further progression or death among durable progression-free survivors with melanoma in PD-1 blockade trials: Implications for imaging surveillance.

9529 Background: Durable progression-free survivors (dPFSors) over 2 years have been reported among melanoma patients treated with PD-1 blockade. However, non-negligible risk of further progression still exists and the optimal imaging surveillance interval is unknown. Methods: Individual patient data of progression-free survival (PFS) were extracted from PD-1 blockade clinical trials with follow-up of at least 5 years of PFS events. Co-treatment with anti-CTLA4 antibody was allowed. Patients with PFS of at least 2 years were considered as dPFSors. Conditional risk of progression or death with 95% CI was estimated based on a piece-wise exponential survival model, with the assumption that within each year from the beginning of the third year, the risk of progression/death (P/D) was constant. Conditional risks of P/D every 3, 4, 6, and 12 months in each subsequent year were calculated with 95% confidence interval (CI). We pre-specified three maximal risk levels – 10%, 15%, and 20% at each imaging scanning interval. An interval is considered as acceptable if the 95% CI upper bound of the risk at each scan is lower than a pre-specified risk level. Results: Of 1495 melanoma patients from 3 clinical trials, 474 (31.7%) were dPFSors. Among them, the PFS probability for additional 3 years was 76.4%. During the 3 years, no more than 5.0% of patients had P/D in any quarters. The yearly risk of P/D was 15.5% (95% CI 13.7% - 17.3%), 8.8% (6.8% - 10.8%), and 6.3% (3.8% - 8.8%) during the 3rd, 4th, and 5th year, respectively. Under risk at 10%, 15%, and 20%, melanoma dPFSors can be scanned every 6, 6, and 12 months during the 3rd year, every 6, 12, and 12 months during the 4th, and every 12, 12, and 12 months during the 5th, respectively. Conclusions: Based on their own risk tolerance level, our findings allow clinicians and dPFSors make data-driven decisions regarding imaging surveillance schedule beyond every 3 months. [Table: see text]

Individual patient-level data validation of surrogate and modified endpoints for immunotherapy in advanced hepatocellular carcinoma: Post-hoc analysis of IMbrave150 and real-world observations.

4090 Background: Immune checkpoint inhibitors (ICIs) have become the preferred treatment for advanced hepatocellular carcinoma (HCC). Surrogate endpoints including overall response rate (ORR) and progression-free survival (PFS) are preferred outcome measures in early-phase trials. However, ICIs can induce atypical patterns of response and progression, calling into question the validity of surrogate endpoints as predictive of overall survival (OS) benefit. We performed a post-hoc analysis of a large, randomized phase 3 clinical trial (IMbrave150) and cross-sectional analysis of a multi-institution real-world environment (RWE) to assess the OS surrogacy of ORR and PFS using Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), or immune-modified RECIST (imRECIST) in patients treated with ICIs. Methods: The IMbrave150 cohort in our analysis included 279 out of 336 patients treated with atezolizumab and bevacizumab in the intent-to-treat population. The RWE cohort included 328 patients with Child-Pugh A or B disease treated in the first or subsequent-line setting with anti-PD-1/L1 therapies. RECIST, mRECIST, and imRECIST ORR and PFS data for the IMbrave150 cohort was determined by investigators and central review, while RECIST ORR and PFS data for the RWE cohort was determined by treating providers or retrospective review. Results: In the IMbrave150 and RWE cohorts, Child-Pugh A patients treated in the first-line setting with CR/PR showed greater OS versus patients with SD/PD (IMbrave150: HR 0.16, 95% CI 0.10-0.26; RWE: HR 0.25, 95% CI 0.15-0.43). CR was associated with the greatest OS benefit, followed by PR, SD, and PD. Patients treated in the second-line setting or with Child-Pugh B disease showed that ORR was able to discriminate OS benefit but hazard ratios were closer to the null. In both cohorts, there was a positive rank correlation between RECIST PFS and OS (IMbrave150: Kendall's τ = 0.44, p < 0.001); RWE: Kendall's τ = 0.52, p < 0.001). However, only 31-46% of the variance in OS rankings was explained by PFS rankings. mRECIST PFS and imRECIST PFS showed a positive rank correlation with OS, with an explained variance of 30% and 38% for mRECIST and imRECIST, respectively. Conclusions: Our results suggest that RECIST ORR is a robust surrogate endpoint in HCC treated with ICIs. In contrast, the explained variance between RECIST PFS and OS in both the IMbrave and RWE cohorts was limited. This may reflect the impact of ICIs on response to subsequent therapies which may extend OS benefit. Although prior studies have proposed that modifications to RECIST may lead to more accurate surrogate markers, mRECIST and imRECIST ORR or PFS in HCC treated with ICIs were not associated with greater predictive performance compared to RECIST.

Validation of the PDACai signature in predicting relative benefit from frontline FOLFIRINOX (FFX) and gemcitabine/nab-paclitaxel (GA) for patients (pts) with metastatic pancreatic cancer (mPDAC).

4149 Background: Nearly 50% of pts with mPDAC never receive a 2nd line of therapy for metastatic disease following frontline FFX or GA. Genomic alterations in the DDR pathway (e.g. BRCA1/2) are associated with increased progression-free survival (PFS) on platinum-containing regimens (e.g. FFX), but other biomarker-treatment associations that predict benefit from GA and/or FFX in mPDAC remain unexplored. In this retrospective real-world evidence (RWE) study, we use a data-driven machine learning approach to gain new insights from the mutational landscape in mPDAC and validate the PDACai signature in predicting personalized benefit from both FFX and GA. Methods: We analyzed real-world outcomes from 711 pts with mPDAC who underwent genomic profiling via the Know Your Tumor program or were referred to Perthera by treating oncologists. Chart-abstracted PFS data on either 1st line FFX or GA were split (60:40) into independent training and validation cohorts for each regimen. All models integrate a shared set of clinical (age < 63, sex) and lab-agnostic molecular features derived from clinical NGS testing reports (DDR pathway alterations, specific KRAS variants, frequently mutated genes). Relative benefit scores predicted by FFX or GA models were evenly binned into three PDACai signature categories representing lower, middle, and upper tertiles for each independent cohort. Statistical differences in median PFS were evaluated using ordinal Cox regression. Results: Median PFS followed predicted trends as generated by PDACai for each therapy in training and validation cohorts. The predictive utility of PDACai was confirmed in the independent validation cohorts when comparing PFS on FFX (p = 0.03744; HR = 0.75 [95% CI: 0.58-0.98]) and GA (p = 0.00006861; HR = 0.65 [95% CI: 0.53-0.8]) across tertiles. Conclusions: Response to chemotherapy is heterogeneous and difficult to predict in pts with mPDAC. Using RWE, the PDACai signature successfully predicted relative differences in PFS on both FFX and GA in mPDAC. With prospective validation, personalized insights generated by PDACai from pts with similar biomarker profiles could be used to tailor treatment sequencing in pts with NGS testing results, particularly those without actionable genomic findings. [Table: see text]

The inflammatory prognostic index as a potential predictor of prognosis in metastatic gastric cancer

Clinical studies aimed at identifying effective and simple prognostic markers for gastric cancer are still being carried out. Inflammatory prognostic index (IPI) is being recognized as a promising prognostic marker in patients with Non-Small Cell Lung Cancer. To evaluate the prognostic utility of IPI in stage 4 gastric cancer. A total of 152 patients with stage 4 gastric cancer, whose laboratory parameters, progression-free survival (PFS) and overall survival (OS) data could be accessed, were evaluated. Kaplan Meier analysis was used for survival analyses. Hazard ratios were expressed with 95% CI values. All methods were performed in accordance with the relevant guidelines and regulations. Study was approved by the Manisa Celal Bayar University’s Non-Invasive Clinical Research Ethics Committee (approval No. E-85252386-050.04.04-49119, date: 22.03.2021). We confirm that all methods were performed in accordance with relevant named guidelines and regulations. Median age at diagnosis was 63 years (range: 32–88). The number of patients who received first-line chemotherapy was 129 (84.9%). Median PFS with first-line treatment was 5.3 months, while it was 3.3 months with second-line treatment. Median OS was 9.4 months. Median IPI score was 22.2. We evaluated IPI score for its value in detecting survival status with ROC analysis and identified an IPI cut-off score of 14.6. Low IPI score was significantly associated with longer PFS and OS compared to high IPI (PFS in high vs. low IPI, 3.6 vs. 7 months; p < 0.001) (OS in high vs. low IPI, 6.6 vs. 14.2 months; p < 0.001). IPI score can be an independent prognostic index that is inexpensive, easy to access and evaluate for patients with metastatic gastric cancer, and may be useful in predicting survival in daily practice.

Results of R-CHOP and R-CHOP + interleukin-2 regimens in first-line therapy in patients with diffuse B-cell lymphoma

The study was made to evaluate the effect of interleukin-2 (IL-2) as part of the R-CHOP regimen on the rate of a complete metabolic response (CMR) using the data of interim positron emission tomography (PET/CT) and progression-free survival compared to the standard regimen in patients with diffuse B-cell lymphoma (DCLC). The data of 152 patients with biopsy-proven DCLC who were treated in the period 2015–2020 were included. Among them, 59 patients were included in the prospective group (R-CHOP + IL-2 in a total course dose of 5,000,000 IU). The control group consisting of 93 patients received standard R-CHOP therapy. PET/CT was performed after 4 courses of therapy, metabolic response was assessed using the Deauville scale, and Deauville 1-2 was classified as CMR. The rate of CMR in the R-CHOP+IL-2 group was 67.8 %, while in the control group it was 50.5 % (pχ² = 0.044). The 5-year progression-free survival (PFS) in the R-CHOP+IL-2 and R-CHOP groups was 80.7 and 64.5 %, respectively (p = 0.04). In the favorable and intermediate prognosis groups (IPI 0–3), PFS was not statistically significantly different depending on treatment. At high risk (IPI 4–5), the 5-year PFS in the R-CHOP + IL-2 and R-CHOP groups was 71.4 and 25.0 %, respectively (p = 0.02). Including IL-2 in the R-CHOP regimen in the first-line treatment of patients with DCLC increases the incidence of CMR according to 18-FDG PET/CT after 4 courses of chemoimmunotherapy and PFS in the high-risk group.

Progression-free survival and safety at 3.5 years of follow-up: results from the randomised phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer

PurposeTo report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). MethodsPatients with newly diagnosed advanced ovarian cancer with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy regimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by investigator assessment (INV) are reported. ResultsIn 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5years. Median INV-PFS was 24.5 versus 11.2months (hazard ratio, 0.52; 95% confidence interval [CI], 0.40–0.68) in the HRd population and 13.8 versus 8.2months (hazard ratio, 0.66; 95% CI, 0.56–0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4months (hazard ratio, 0.65; 95% CI, 0.49–0.87), respectively. Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and placebo-treated patients. Overall survival remained immature. ConclusionsNiraparib maintained clinically significant improvements in PFS with 3.5years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of HRD status. No new safety signals were identified.

37P Enhanced tumor-immunity drives resistance to CDK4/6 inhibitors in advanced breast cancer

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have led to a paradigm shift in the treatment of hormone receptor-positive (HR+)/HER2- advanced breast cancer (ABC). Prior data has suggested a key role of tumor immunity in CDK4/6i success. We investigate immune-mediated resistance to CDK4/6i treatment. 63 samples from 55 patients with HR+HER2- ABC treated with CDK4/6i were recruited (34 primary, 21 metastatic (M1) and 8 paired biopsies). Gene expression (GE) was assessed using NanoString Breast Cancer 360™, including intrinsic subtype (IS). Patients were stratified in good/poor responders (GR/PR), considering hormone sensitivity and progression-free survival (PFS) data from pivotal studies (GR n=38, 66.5%). Multiple t-tests comparisons were used to identify GE differences and Kaplan Meier and Cox regression models for survival. GE comparisons between primary and M1 biopsies showed significantly higher expression of immune-related features and oestrogen receptor (ER)-signalling in primary biopsies (T.test; p-value<0.05). GE profiles between response groups were compared to identify mechanisms of resistance to CDK4/6i. Most tumors were luminal A or B (n=23, 36.5% each). The IS were not significantly associated with response (Chi-square p>0.05). High GE of tumor-immunity related signatures such as macrophages, PD-L2, inflammatory-chemokines, IDO1, and T-regs were associated with reduced efficacy of CDK4/6i (mean log2FC 0.5; p<0.05). Survival analysis in first-line CDK4/6i confirmed longer PFS within patients with luminal tumours (p=0.02). Type of M1 (visceral or non-visceral) and type of response (PR vs GR) were also associated with significantly shorter PFS and overall survival (OS) (p<0.05), remaining as independent predictors after adjustment by the standard clinico-pathological variables. High expression of macrophages signature (HR: 3.14; p=0.03) and other genes related to immunity/inflammation (CD68, CD163, CCR1 or CDC25B) were also associated with worse OS (HR 1.8-6.1; p-value<0.05). Immune function plays a key role in tumor evolution and CDK4/6i efficacy. Further investigation of immune-tumor crosstalk and the role of immunotherapy in this setting is needed to improve CDK4/6i efficacy.

Comparison of prognostic value of different metabolic response criteria determined by PET/CT in patients with metastatic breast cancer under CDK 4/6 inhibitor treatment

PurposeThis study evaluates the prognostic role of different [18F]FDG PET/CT metabolic response criteria in metastatic breast cancer (MBC) patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6). Materials and methodsWe retrospectively evaluated the data of MBC patients treated with CDK 4/6 inhibitors who underwent an [18F]FDG PET/CT scan before starting and during treatment. [18F]FDG PET/CT response was assessed with the European Organization for Research and Treatment of Cancer (EORTC), PET Response Criteria in Solid Tumors (PERCIST), and whole-body total lesion glycolysis (WBTLG) criteria. Fleiss kappa was computed to assess the agreement between metabolic response criteria. The endpoint of the study was progression-free survival (PFS). PFS data were analyzed by the Kaplan–Meier method and compared using the log-rank test. ResultsThe study included sixteen MBC patients who received CDK 4/6 inhibitors therapy. According to PERCIST, partial metabolic response (PMR) was found in seven patients, stable metabolic disease (SMD) in seven patients, and progressive metabolic disease (PMD) in two patients. According to EORTC, PMR was detected in eight patients, SMD in seven patients, and PMD in one patient. According to WBTLG, PMR was found in 10 patients, SMD in four patients, and PMD in two patients. There was a fair agreement between the three criteria. While progression was detected in seven of the patients during follow-up, no progression was detected in nine of them. Kaplan–Meier analysis revealed that the responders according to WBTLG showed significantly longer PFS than non-responders. ConclusionTreatment response according to WBTLG criteria during treatment appears to be associated with prolonged PFS in patients treated with CDK 4/6 inhibitors for MBC.

The Pattern of Progression to First-Line Treatment with Dabrafenib and Trametinib in Patients with Unresectable or Metastatic, BRAF-Mutated, Cutaneous Melanoma: Results of the Observational T-WIN Study.

In patients with B-RAF-mutated cutaneous melanoma, targeted therapies are the treatment of choice to achieve a rapid response. In this multicentric, prospective, observational study, patients with B-RAF-mutated cutaneous melanoma who were treated with dabrafenib and trametinib were categorized in two cohorts (cohort A: limited disease (n = 104) and cohort B: bulky disease (n = 97)) according to lactate dehydrogenase levels. The primary endpoint was the progression pattern; the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety data. From baseline to time of progression, there was a progression from nodal to other sites of disease in cohort A and from skin and nodal to other sites in cohort B. In both the cohorts, the number of involved organs and metastases at each location decreased. The median OS was 32.4 months (95% CI: 20.1 months (not estimable)) for cohort A, and 10.5 months (95% CI: 8.3-14.4 months) for cohort B; median PFS was 12.4 months (95% CI: 10.9-17.0 months) for cohort A, and 8.1 months (95% CI: 6.3-9.4 months) for cohort B. No new safety signals were reported. This study describes the patterns of first-line treatment progression with dabrafenib and trametinib in Italian clinical practice. The effectiveness and safety data were consistent with previous trials and extended to a real-world heterogeneous population.

Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma

BackgroundA phase 2/3 trial — A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma (RELATIVITY-047) — evaluated nivolumab + relatlimab as a fixed-dose combination and found a significant progression-free survival (PFS) benefit over nivolumab monotherapy in previously untreated unresectable or metastatic melanoma. We now report updated PFS and safety data and the first results for overall survival (OS) and objective response rate (ORR).MethodsPatients were randomly assigned 1:1 to receive nivolumab 480 mg and relatlimab 160 mg fixed-dose combination or nivolumab 480 mg alone, given intravenously every 4 weeks. PFS (primary end point) according to the Response Evaluation Criteria in Solid Tumors, version 1.1, was assessed by blinded independent central review (BICR). Secondary end points, tested hierarchically, were OS and then ORR per Response Evaluation Criteria in Solid Tumors, version 1.1, per BICR.ResultsAt a median follow-up of 19.3 months, median PFS according to BICR was 10.2 months (95% confidence interval [CI], 6.5 to 14.8) with nivolumab + relatlimab versus 4.6 months (95% CI, 3.5 to 6.4) with nivolumab (hazard ratio, 0.78; 95% CI, 0.64 to 0.94). Median OS was not reached (NR) (95% CI, 34.2 to NR) with nivolumab + relatlimab versus 34.1 months (95% CI, 25.2 to NR) with nivolumab (hazard ratio, 0.80; 95% CI, 0.64 to 1.01; P=0.059) (prespecified value for statistical significance, P≤0.043). ORRs per BICR were 43.1% (95% CI, 37.9 to 48.4) versus 32.6% (95% CI, 27.8 to 37.7), respectively. Grade 3/4 treatment-related adverse events were observed in 21.1% of patients treated with nivolumab + relatlimab versus 11.1% treated with nivolumab.ConclusionsThe fixed-dose combination of nivolumab + relatlimab showed consistent PFS benefit versus nivolumab with approximately 6 months of additional median follow-up. The combination treatment did not reach the preplanned statistical threshold for OS, with a 10.3 percentage-point difference in ORR. Grade 3/4 treatment-related adverse events were more frequent with nivolumab + relatlimab versus nivolumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov number, NCT03470922.)

Abstract P4-01-01: RIBANNA 5th interim analysis: Matched-pair analysis of progression-free survival (PFS) across treatment cohorts and comparison of frontline ribociclib + endocrine therapy PFS data from RIBANNA vs MONALEESA trials, in HR+, HER2– ABC

Abstract Background: Ribociclib (RIB) plus endocrine therapy (ET) has demonstrated a statistically significant survival benefit across the three phase 3 MONALEESA (ML) trials, irrespective of menopausal status, line of therapy, or combination partner. RIBANNA (CLEE011ADE03), a prospective, noninterventional study assessing the efficacy and safety of RIB + ET, or ET monotherapy or chemotherapy (CT) in first-line (1L) setting in pre-, peri- and postmenopausal patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) is ongoing in Germany since October 2017 to gain insights into real-world scenario. In the 5th interim analysis (IA) from RIBANNA, a matched-pair analysis of 1L PFS data from the three treatment cohorts and comparison of 1L PFS data on RIB + ET from RIBANNA versus (vs) ML trials will be performed. Methods: Pre-, peri- and postmenopausal women receiving RIB + ET, ET monotherapy, or CT as 1L treatments for HR+, HER2– ABC, in accordance with German treatment guidelines, were included. Propensity score matched (PSM) analysis of PFS data from the 3 treatment cohorts will be conducted to reduce the bias due to confounding variables. In addition to safety analyses, comparison of 1L PFS data on RIB + ET from RIBANNA vs ML trials will be performed. Results: By the cutoff date of the 4th IA (October 11, 2021), data were available for 2187 pts, including 1849 (83.0%), 193 (78.1%), and 145 (73.6%) pts from the RIB + ET, ET monotherapy, and CT cohorts in 1L setting, respectively (Table 1). Of these 2187 pts, 1111 postmenopausal pts received 1L RIB + letrozole; 357 postmenopausal pts received 1L RIB + fulvestrant, and 158 pre- and perimenopausal pts received 1L RIB + anastrazole/letrozole. The unadjusted Kaplan–Meïer estimate for median PFS was 31.7 months (95% confidence interval [CI], 28.5–36.2) in the RIB + ET cohort, 25.7 months (95% CI, 18.0–not reached) in the ET monotherapy cohort, and 15.3 months (95% CI, 9.5–17.5) in the CT cohort. The most frequent treatment-emergent adverse events (grade 3 or 4) in the RIB + ET and ET monotherapy cohorts were neutropenia (14.8% and 6.6%, respectively) while that in CT cohort was general physical health deterioration (9.1%). Conclusions: In RIBANNA, a diverse pt population is being analyzed in a real-world setting; treatment with RIB + ET has been observed to be well adopted. The 5th IA is planned in October 2022 and data will be presented in SABCS 2022, which will include PSM analysis to compare 1L PFS data across treatment cohorts as well as comparison of 1L PFS data on RIB + ET from RIBANNA vs ML trials. The safety profile of RIB was found to be similar to those observed in ML trials. Table 1. Patient demographics and baseline clinical characteristics from the 4th IA. Citation Format: Christian Jackisch, Cosima Brucker, Thomas Decker, Anne Engel, Peter A. Fasching, Thomas Göhler, Jan Janssen, Andreas Köhler, Kerstin Lüdtke-Heckenkamp, Diana Lüftner, Marion van Mackelenbergh, Frederik Marmé, Arnd Nusch, Beate Rautenberg, Toralf Reimer, Marcus Schmidt, Rudolf Weide, Pauline Wimberger, Christian Roos, Achim Wöckel. RIBANNA 5th interim analysis: Matched-pair analysis of progression-free survival (PFS) across treatment cohorts and comparison of frontline ribociclib + endocrine therapy PFS data from RIBANNA vs MONALEESA trials, in HR+, HER2– ABC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-01.

Abstract PD17-12: Primary efficacy and safety results from the AMALEE trial evaluating 600 mg vs 400 mg starting doses of first-line ribociclib in patients with HR+/HER2− advanced breast cancer

Abstract Background: In the Phase III MONALEESA (ML)-2, -3 and -7 trials, a 600 mg dose of ribociclib (RIB) demonstrated significant overall survival benefit in patients (pts) with HR+/HER2− advanced breast cancer (ABC) but was associated with QTcF (&amp;gt;480 ms, 3%-7%) and neutropenia (G3/4, 57%-64%) adverse events (AEs) which were managed by dose reductions. The Phase II AMALEE study was performed as a postmarketing commitment to assess whether reducing the starting dose of RIB from the recommended dose (3 wk on, 1 wk off) of 600 mg/day to 400 mg/day decreases QTcF prolongation without compromising the efficacy of first-line RIB in pts with HR+/HER2− ABC. Here, we present efficacy and safety results from the primary analysis of AMALEE. Methods: AMALEE is a randomized Phase II open-label study including pre- and postmenopausal pts with HR+/HER2− ABC with no prior therapy for ABC. Pts received RIB 400 mg + nonsteroidal aromatase inhibitor (NSAI) or RIB 600 mg + NSAI. The primary endpoint is to determine whether overall response rate (ORR) in the 400 mg arm is noninferior to the 600 mg arm. The key secondary endpoint is QTcF prolongation at cycle 1, day 15 (C1D15) 2 hours post dose. Additional endpoints included safety, progression-free survival (PFS), duration of response (DOR), time to response (TTR), and pharmacokinetics. Results: A total of 376 pts were randomized 1:1 to receive RIB at either 400 mg or 600 mg doses. Baseline (BL) characteristics and prior antineoplastic therapy were balanced across treatment (tx) arms. At the time of the data cutoff (June 11, 2021), median follow-up was 14.9 mo (min, 6.1; max, 23.8), and all pts had been treated for ≥6 months from randomization or had discontinued study tx. ORR for RIB was 41.5% (95% CI, 34.4-48.7) with 400 mg vs 45.3% (95% CI, 38.1-52.6) with 600 mg (ORR ratio for RIB 400 mg vs 600 mg, 0.921 [90% CI, 0.757-1.121]). The lower 90% CI boundary did not meet the prespecified noninferiority (NI) margin of 0.814. Results for ORR by subgroups were consistent with the overall analysis set. RIB plasma exposure was lower at 400 mg than 600 mg; the geometric mean Cmax and AUC0-24h at C1D15 were approximately 28% and 43% lower in the 400 mg than the 600 mg arm (Cmax 1080 vs 1500 ng/mL and AUC0-24h 16400 vs 28600 ng × h/mL). This study met the key secondary endpoint, change in QTcF at C1D15 in the RIB 400 mg group with a 90% CI upper boundary of &amp;lt; 20 ms. Mean change in QTcF from BL to C1D15 2 hours post dose was lower in the 400 mg (12.5 ms, 90% CI, 10.9-14.1) than the 600 mg arm (19.7 ms, 90% CI, 17.4-22.0). QTcF ≥501 ms occurred in 1.6% of pts in the 400 mg arm vs 0.5% in the 600 mg arm. Rates of G3/4 neutropenia were lower in the 400 mg (31.4%) than the 600 mg arm (46.3%). Other safety results were consistent with those previously reported for RIB in the ML trials. Median duration of exposure to RIB was 8.0 mo (min, 0.1; max, 23.7) in the 400 mg arm vs 8.8 mo (min, 0.5; max, 20.8) in the 600 mg arm. Dose reductions of RIB were more frequent in the 600 mg group with 30.5% vs 13.8% of pts requiring 1 dose reduction in the 600 mg and 400 mg groups, respectively. Dose reductions were primarily attributable to AEs, with neutropenia being the most frequently reported AE requiring a dose modification. Rates of discontinuation due to AEs were similar in the 400 mg vs 600 mg arms (8.5% vs 9.6%). PFS, DOR, and TTR data are currently immature. Conclusions: RIB at the 400 mg dose shows a better safety profile vs 600 mg in terms of key AEs that are RIB concentration dependent (neutropenia and QTcF prolongation). ORR was 3.8% lower with 400 mg than 600 mg. The lower 90% CI boundary of the ORR ratio did not meet the NI margin, thus this study was unable to demonstrate statistical NI of the 400 mg vs 600 mg dose of RIB using ORR as the endpoint. Updated results with additional follow-up and the clinically relevant endpoint PFS will be presented at the congress. Citation Format: Fatima Cardoso, William Jacot, Sherko Küemmel, Sudeep Gupta, Rama Balaraman, Liudmila Lebedeva, Yan Ji, Aparna Lakshmanan, Khalid Amin, Zheng Li, Joseph Sparano. Primary efficacy and safety results from the AMALEE trial evaluating 600 mg vs 400 mg starting doses of first-line ribociclib in patients with HR+/HER2− advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-12.

Generic Lenalidomide Rivelime Versus Brand-name Revlimid® in the Treatment of Relapsed/Refractory Multiple Myeloma: A Retrospective Single-center Experience on Efficacy, Safety and Survival Outcome.

This study aimed to compare use of original brand-name lenalidomide (Revlimid®) vs. generic equivalent (Rivelime®) in terms of efficacy, safety and survival outcome in patients with relapsed/refractory multiple myeloma (RRMM) PATIENTS AND METHODS: A total of 184 patients RRMM (median age: 62 years, 60.9% were males) who received singlet, doublet or triplet lenalidomide-containing regimens including either Revlimid® (n=74) or Rivelime® (n=110) were included in this study. Treatment response was based on evaluation of objective response to treatment (ORR) including the sum of patients who achieved partial response (PR), very good partial responses (VGPR) or complete response (CR) to therapy. Progression-free survival (PFS), overall survival (OS) and safety data were also recorded. Revlimid® and Rivelime® groups were similar in terms of ORR (54.1 vs. 60.0%), CR (22.5 vs. 28.8%), VGPR (55.0 vs. 50.0%) and PR (22.5 vs. 21.2%) rates. Median (SE) PFS time were similar between Rivelime® vs. Revlimid® treated patients who were in the 2nd line (30.3(3.8) vs. 22.7(7.0) months, p=0.827) or 3rd line of therapy (38.1(12.1) vs. 20.1(0.9) months, p=0.147) at lenalidomide initiation. Two groups also had similar OS rate (83.8 vs. 73.6%) and OS time (mean 122.3 vs. 123.5 months). Side effects were manageable in both groups. In conclusion, replacing Revlimid® with its generic version Rivelime® in singlet, doublet or triplet lenalidomide containing RRMM regimens seems not to compromise the efficacy of treatment, and to yield a similarly improved response rates and survival outcome and no additional toxic effects, enabling a long-term therapy.

Significance of alterations in DNA damage repair (DDR) genes in advanced biliary cancers (ABCs) treated with second-line active-symptom-control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy (ASC+FOLFOX) in the randomised phase III, multicentre, open-label ABC-06 trial.

593 Background: The ABC-06 clinical trial established ASC+mFOLFOX as the standard of care treatment after Cisplatin and Gemcitabine (CisGem) for ABC. Translational research explored the role of alterations in DDR-related genes in the context of the ABC-06 clinical trial. Methods: Translational research using samples collected from the ABC-06 trial included all recruited patients with tissue sample containing &gt;20% tumour cellularity with sufficient DNA extracted for analysis. Primary objective: assess the prevalence of somatic mutations within DDR genes in ABC. Secondary objectives: explore the impact of somatic mutations in DDR genes on: A) Patient’s response to platinum-based chemotherapy (predictive biomarker): 1) Retrospectively, using progression-free survival (PFS) data from 1st-line chemotherapy and 2) Prospectively, by assessing the impact on PFS/radiological response to 2nd-line FOLFOX (vs. control) and B) Overall survival (prognostic biomarker). Survival analysis was performed with Kaplan-Meier and Cox Regression. Results: Of 162 pts randomised, 83 had a sample available for analysis; of these, analysis failed in 24 despite &gt;20% tumour content. Thus, a total of 59 patients (30 ASC arm, 29 ASC+FOLFOX arm) were eligible for this translational analysis: male 50.85%, metastatic 77.97%, intrahepatic cholangiocarcinoma 47.46%, adenocarcinoma 91.53%, median age 65.84 years (95% CI 63.36-68.91). Pathogenic mutations in DDR genes were identified in 22 patients (37.29%). PFS did not vary depending on the DDR-gene alterations either in the first-line setting with CisGem (n=59; 8.73 months vs 8.18 months; p-value 0.155) or with second-line FOLFOX (n=29; 3.19 months vs 3.45 months; p-value 0.098). Median OS for DDR-altered patients was 4.59 months (95% CI 2.17-5.88) (vs 7.23 months (95% CI 5.45-8.28) for DDR-wild-type); HR 2.63 (95% CI 1.48-4.67); p-value 0.001. This prognostic impact was confirmed when the prognostic model was adjusted for treatment arm and stratification factors (HR 3.75 (95% CI 1.99-7.09); p-value &lt;0.001). Conclusions: For ABC patients, the presence of DDR-related gene pathogenic mutations are present in around one third of patients. Despite presence of DDR-mutations having a negative prognostic impact, their predictive role is not confirmed either for first-line CisGem or second-line FOLFOX. Clinical trial information: NCT01926236 .

Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials

Background: Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC. Summary: In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6–11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8–10.7) months in studies before 2015 to 13.4 (95% CI: 11.03–15.24) months in studies from 2015 onwards (p < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9–4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality (p < 0.001). There was minimal heterogeneity in the estimates for OS (all I² ≤ 33). Key Messages: Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.

Clinical characteristics of Australian treatment-naïve patients with classical Hodgkin lymphoma from the lymphoma and related diseases registry.

Comprehensive clinical characteristics of Australian patients with classical Hodgkin Lymphoma (cHL) have not previously been systematically collected and described. We report real-world data of 498 eligible patients from the first 5 years of the Lymphoma and Related Diseases Registry (LaRDR), including baseline characteristics, histologic subtype, and treatment patterns in first-line therapy. Patient demographics and distribution of histopathological subtypes of cHL are similar to reported international cohorts. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the most common therapy for both early and advanced-stage disease, and 48% of patients with the early-stage disease received radiotherapy. Treatment patterns are consistent with international guidelines. In comorbid patients ≥60 years of age with advanced-stage disease, there is greater variation in treatment. In patients with a recorded response, the objective response rate (ORR) was 96% in early-stage disease, and 88% in advanced-stage disease. Early progression-free survival data suggest Australian patients with cHL have good outcomes, similar to other international studies.

Safety and efficacy of immune checkpoint inhibitors in advanced cancer patients with autoimmune disease: A meta-analysis

ABSTRACT Cancer patients with autoimmune disease (AID) are usually excluded from clinical trials involving immune checkpoint inhibitors (ICIs). The available electronic databases were systematically searched from inception until July 3, 2022. We recorded the incidence of immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS) data of included studies. This meta-analysis included 14 studies comprising 11511 participants; however, only 8716 participants were treated with ICI. Therefore, the analysis was conducted on 8716 patients (769 patients with AID compared to 7947 patients without AID). The pooled risk ratio (RR) for any grade and grade ≥3 irAEs was 1.74 (95% confidence interval [CI]: 1.27-2.37) and 1.43 (95% CI: 1.10-1.88), respectively. The irAEs in the same system as that of the AID were referred to as AID-homogeneous irAEs; in the other cases, there were referred to as AID-heterogeneous irAEs. Subgroup analysis found that the higher risk of AID-homogeneous irAEs contributed to the higher risk of overall irAEs among patients with AID. The pooled hazard ratio (HR) for PFS and OS was 1.09 (95% CI: 0.96–1.24) and 1.07 (95% CI: 0.94-1.22), respectively. The results of PFS and OS subgroup analyses matched the overall results. Patients with AID had a significantly higher risk of developing any grade and ≥3 grade irAEs under ICI therapy, specifically AID-homogeneous irAEs; however, the frequency of AID-heterogeneous irAEs in patients with AID was similar to irAEs in patients without AID. No statistically significant differences in PFS and OS were observed between the two groups.

Economic Evaluation of Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer in the United States.

Recently, the DESTINY-Breast04 trial revealed that significant benefits in both overall survival (OS) and progression-free survival (PFS) in patients with HER2-low advanced or metastatic breast cancer treated with trastuzumab deruxtecan (T-DXd) compared with chemotherapy. The current study assessed the cost-effectiveness of T-DXd from the perspective of the United States payer. We developed a partitioned survival model to project the disease course of breast cancer. The OS and PFS data were derived from the DESTINY-Breast04 trial. We extrapolate the survival data beyond the follow-up time to assess the long-term survival prognosis. Direct medical costs and utility data were collected. The incremental cost-utility ratio (ICUR) was the primary outcome that evaluated the cost-effectiveness of a therapy regimen. One-way sensitivity and probabilistic sensitivity analysis were implemented to explore the uncertainty of outputs. In the base-case, the ICUR of T-DXd versus chemotherapy is $346,571.8/QALY and $337,789.4/QALY for all patients group and hormone-receptor-positive (HR+) subgroup, respectively. One-way sensitivity analyses revealed that the hazard ratio of OS, the unit cost of T-DXd, and body weight had a relatively large impact on the base-case result. Probabilistic sensitivity analyses showed that the likelihood that T-DXd was cost-effective is 14.5% and 12.6% for all patients group and HR+ subgroup, respectively. The cost-effectiveness analysis suggested that, at current price, trastuzumab deruxtecan is unlikely to be a preferred option for patients with HER2-low breast cancer at a threshold of $150,000/QALY from a US payer perspective.