Median Prolonged Progression-free Survival Research Articles

TCL-150: The ECHELON-2 Trial: 5-Year Results of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in Frontline Treatment of Patients with CD30-Positive Peripheral T-Cell Lymphoma

Objective Brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) significantly prolonged progression-free survival (PFS) and overall survival (OS) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with systemic anaplastic large-cell lymphoma (sALCL) or other CD30-positive peripheral T-cell lymphomas (PTCL) in ECHELON-2 (Horwitz S et al., Lancet 2019). We report updated results; median follow-up was 47.6 months for PFS and 66.8 months for OS. Design This phase 3, double-blind study (NCT01777152) randomized patients aged ≥18 years with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) to A+CHP or CHOP for 6 or 8 cycles. Primary endpoint of PFS was assessed per investigator in this updated analysis. Key secondary endpoints included OS and PFS in sALCL. BV or BV-containing regimens were permitted as subsequent/retreatment therapies. Results 452 patients were enrolled (226 patients in each arm); 316 (70%) patients had sALCL. Patients with advanced disease were included (stage III [27%] and stage IV [53%]; International Prognostic Index ≥2 [78%]). Data continues to favor A+CHP: HRs were 0.70 (95% CI: 0.53–0.91, P=0.0077) for PFS per investigator and 0.72 (95% CI: 0.53–0.99, P=0.0424) for OS. 5-year PFS was 51.4% (95% CI: 42.8–59.4) with A+CHP versus 43.0% (95% CI: 35.8–50.0) with CHOP; median PFS was 62.3 months (95% CI: 42.0–not evaluable) with A+CHP and 23.8 months (95% CI: 13.6–60.8) with CHOP. 5-year OS was 70.1% (95% CI: 63.3–75.9) and 61.0% (95% CI: 54.0–67.3) with A+CHP and CHOP, respectively. Median OS was not reached in either arm. PFS favored A+CHP (HR: 0.55 [95% CI: 0.39–0.79]) in sALCL. 29 (13%) and 54 (24%) patients with A+CHP and CHOP received subsequent BV, respectively. Treatment-emergent peripheral neuropathy (PN), resolved/improved in 72% (n=84/117) and 78% (n=97/124) of patients with PN on A+CHP and CHOP, respectively; 98% and 97% of ongoing PN events were grade 1/2 with A+CHP and CHOP, respectively. Conclusions At this important 5-year milestone, A+CHP still provides clinically meaningful improvement in both PFS and OS versus CHOP, with a manageable safety profile, including continued resolution/improvement of PN. Funded by NIH/NCI Support Grant P30 CA008748.

Adverse events as a potential clinical marker of antitumor efficacy in ovarian cancer patients treated with poly ADP-ribose polymerase (PARP) inhibitor

<h3>Objectives:</h3> PARP inhibitor (PARPi) is an important progress in ovarian cancer treatment. The available evidence suggests that <i>BRCAm</i> and HRD-positive are effective biological markers for PARPi. We investigated the relationship between adverse events (AEs) and efficacy of PARPi in ovarian cancer patients. <h3>Methods:</h3> A total of 78 ovarian cancer patients underwent Olaparib and Niraparib were retrospectively analyzed, including from July 2018 to July 2020. AEs were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE) v5.0. Chi-square test or fisher exact tests was performed to see the association between categorical variables. Logistic regression analysis was conducted to investigate the association between independent variables and the disease control. The progression-free survival(PFS) was compared between AEs variables by the log-rank test. <h3>Results:</h3> Patients with AEs in the first one week had a higher disease control rate (DCR) compared with after one week (86.11% versus 60.98%, p=0.013). Serious AEs (SAEs) had a significantly higher DCR (81.40% versus 60.60%, p=0.045). There were associations between anemia and DCR in both occurrence(79.63% versus 56.52%, p=0.037) and grade(100% versus 73.17%, p=0.048). The PFS among patients with hematological toxicity was longer (median: 30 weeks [95% CI: 20.78, 39.22]) than with no-hematological toxicity patients (median: 20 weeks [95% CI: 13.61, 26.39], hazard ratio[HR]: 0.56, p=0.047). Patients with hematological toxicity within four weeks had prolonged median PFS than who with hematological toxicity after four weeks (40 versus 22 weeks, HR:0.36, p=0.003). <h3>Conclusions:</h3> The early presence of AEs, and SAEs of PARPi were related to the antitumor efficacy, which may be a valid and easily measurable clinical marker in ovarian cancer patients

Efficacy and safety of palbociclib in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer with preexisting conditions: A post hoc analysis of PALOMA-2

ObjectiveIn the PALOMA-2 trial, palbociclib in combination with letrozole prolonged progression-free survival (PFS) and exhibited an acceptable safety profile in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). This post hoc analysis of PALOMA-2 evaluated the efficacy and safety of palbociclib plus letrozole in patients with preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). MethodsPostmenopausal patients without prior treatment for ABC were randomized 2:1 to receive palbociclib (125 mg/d on a 3 weeks on/1 week off schedule) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. Patients were grouped by the following MedDRA SOC preexisting conditions: gastrointestinal, musculoskeletal, metabolic, and vascular/cardiac. Median PFS was estimated by the Kaplan-Meier method, and treatment emergent adverse events (AEs) were compared between treatment arms within each preexisting condition subgroup. ResultsAt baseline, 276 (41.4 %) patients had preexisting gastrointestinal disorders, 390 (58.6 %) had musculoskeletal disorders, 259 (38.9 %) had metabolic disorders, and 382 (57.4 %) had vascular/cardiac disorders. Baseline characteristics were similar between subgroups and between each arm within subgroups. Regardless of baseline preexisting condition, palbociclib plus letrozole prolonged PFS compared with placebo plus letrozole. Treatment-emergent AEs associated with palbociclib plus letrozole and dose modifications due to AEs were similar across preexisting condition subgroups. ConclusionThis post hoc analysis of PALOMA-2 demonstrated a favorable effect of palbociclib on PFS and a safety profile consistent with previous observations, regardless of underlying preexisting condition. Pfizer Inc (NCT01740427).

Association of somatic mutations in BRCA2 BRC domain with chemotherapy sensitivity and survival in high grade serous ovarian cancer

BackgroundMutations at sites crucial for the interaction between RAD51 and BRC domains impair the ability of BRCA2 homologous recombination. We aimed to clarify whether BRCA2 BRC domain-associated mutation correlates with sensibility of platinum-based chemotherapy and survival in high-grade serous ovarian cancer (HGSOC). MethodsWe identified BRCA2 BRC domain mutations by sequencing PCR-amplified amplicons of genomic DNA isolated from tumor tissues and peripheral blood leukocytes (PBL)in 113 patients with advanced EOC, and assessed platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). Results21.23% (24 of 113) cases with somatic missense mutation but not germline mutation were identified. Among 24 cases with mutation, 33.3% (8 of 24) cases with nonsense mutation (C-terminal truncation) significantly prolonged median PFI (37 vs 8 months,P = 0.000), PFS (43 vs 14 months, p = 0.000) and OS (56 vs 31 months, P = 0.002); 66.7% (16 of 24) cases with missense mutation also prolonged median PFI (15 vs 8 months, P = 0.044), PFS (21 vs 14 months, P = 0.049) and OS (38 vs 31 months, P = 0.037), compared to those without any mutation. ConclusionsSomatic mutations in BRCA2 BRC domain confer a higher sensitivity to platinum-based therapy and are associated with a favourable survival in HGSOC.

Immune checkpoint inhibitors plus anlotinib versus anlotinib alone as third-line treatment in advanced non-small-cell lung cancer: a retrospective study.

Aim: This study was conducted to evaluate the efficacy of immune checkpoint inhibitors (ICIs) plus anlotinib versus anlotinib alone to provide guidance for clinical treatment of non-small-cell lung cancer. Patients & methods: The records of 139 patients with advanced non-small-cell lung cancer who received at least one dose of ICIs plus anlotinib (IA group) or single-agent anlotinib(AA group)were retrospectively reviewed. The efficacy of the treatments, survival outcomes and adverse events were analyzed. The primary end point was investigator-assessed progression-free survival (PFS). Result: The IA group had a significantly prolonged median PFS (mPFS: 5.8 vs 4.2months; p=0.022) compared with the AA group (hazard ratio: 0.68; 95% CI: 0.68-0.97). In patients with brain metastases, the IA group exhibited improved efficacy (mPFS: 6.0 vs 3.8months; p=0.034) compared with the AA group (hazard ratio: 0.49; 95% CI: 0.23-1.05). Conclusion: ICIs plus anlotinib significantly improved efficacy compared with anlotinib alone and showed substantial potential for the control of intracranial lesions.

Efficacy and Safety of Bendamustine and Rituximab As First Salvage Treatment in Chronic Lymphocytic Leukemia: Results of the Gimema-Eric LLC1315 Study

Introduction. In chronic lymphocytic leukemia (CLL), chemoimmunotherapy produced high overall response rates (ORR), prolonged progression free survival (PFS) and overall survival (OS). In the absence of a TP53 disruption, recent European guidelines recommend a chemoimmunotherapy regimen in first-line and in second line in patients who have attained a long PFS with the previous regimen. Uncertainty in the recommendations on first salvage treatment may partially derive from the consideration that the majority of studies have described efficacy data in an aggregate fashion including all relapsed/refractory setting. Since bendamustine and rituximab (BR) is one of most widely adopted second line regimen we performed a retrospective study within the GIMEMA-ERIC network to collect data on the efficacy and the safety of the BR regimen in second-line in a real-world setting. Comparison of the BR data with 114 Italian and UK non-trial patients treated with ibrutinib at first relapse will be presented at the meeting when additional follow-up is available for the ibrutinib-treated cohort.Methods . 237 CLL patients treated between January 2008 and December 2014 at 35 GIMEMA-ERIC centers were enrolled. Inclusion criteria were: i) CLL diagnosis according to the NCI-WG guidelines, ii) age ≥18 years, iii) one previous treatment with alkylating agents and/or purine analogues with or without monoclonal antibodies, iv) progression requiring second-line treatment according to the NCI criteria, v) at least 1 day of second-line treatment with BR (B 70mg/m2 days 1-2 and R 375 mg/m2 for the 1st course and 500 mg/m2 subsequently). The study was registered at ClinicalTrials.gov (NCT02491398). The primary endpoint was PFS at 12 months. The secondary endpoints were ORR, time to next antileukemic treatment (TTNT) and OS. Results. The median age was 70 years (range 39-87); 58.3% had ≥2 comorbidities, 46.9% a creatinine clearance ≤70 ml/min and 21.4% an advanced stage (i.e. Rai III-IV or Binet C). 73% had unmutated IGHV and 33.4% 11q- and/or 17p-. First-line treatment was chemoimmunotherapy in 59% of the cases; the remaining patients received chemotherapy. 18 patients (9,4%) were refractory to first line treatment. Treatment was discontinued in 72 patients (30.4%) because of toxicity (n=39), withdrawal of consent (n=7), progressive disease (n= 6) or other reasons (n=20). Treatment delay occurred in 22.5% of cases. 95 patients (40.4%) received 6 cycles without dose reduction. The PFS was 78.6%, 30.9% and 16.2% at 12, 30 and 60 months, respectively (Fig. 1a). Median PFS was 25 months with a median follow-up of 37.1 months. 17p- (p=0.0004; Fig. 1b), unmutated IGHV (p=0.0299; Fig. 1c) and advanced stage (p=0.0192) were associated with a shorter PFS at multivariate analysis, while a Disclosures Cuneo: Gilead: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria, Other: Advisory Board; Roche: Honoraria, Other: Advisory Board. Rigolin: Celgene: Honoraria, Other: Advisory Board; Mundipharma: Other: Advisory Board; Gilead: Honoraria. Moreno: Janssen: Consultancy; Gilead: Consultancy, Research Funding. Galieni: Takeda: Other: Advisory Board; Abbvie: Other: Advisory Board. Laurenti: Roche: Other: Advisory Board; Gilead: Other: Advisory Board; Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board. Molica: Roche: Other: Advisory Board; Jansen: Other: Advisory Board; AbbVie: Other: Advisory Board; Gilead: Other: Advisory Board. Montillo: Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Research Funding; Novartis: Honoraria; Genetech: Research Funding. Coscia: Abbvie: Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Orlandi: Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Re: Gilead: Membership on an entity9s Board of Directors or advisory committees. Gaidano: Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Foa: Roche: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Follows: Roche: Other: advisory board and lecturing; Janssen: Other: advisory board and lecturing; Abbvie: Other: advisory board and lecturing; Gilead: Other: advisory board and lecturing. Ghia: AbbVie: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria.

Anlotinib plus docetaxel versus docetaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC): Updated results from a phase I/II study.

e21055 Background: Second-line chemotherapy alone, such as docetaxel, is standard of care for patients (pts) with advanced NSCLC, but the efficacy is poor. Anti-angiogenic drugs plus chemotherapy had shown to significantly prolong progression-free survival (PFS) in advanced NSCLC (REVEL and LUME-LUNG1). The REVEL trial had demonstrated that East Asian pts with advanced NSCLC receiving docetaxel (60 mg/m2, not 75mg/m2) and ramucirumab had a better safety profile. Anlotinib, a novel oral multitarget tyrosine kinase inhibitor, significantly improved PFS and overall survival (OS) of advanced NSCLC in the ALTER0303 trial. In the phase I study, 10mg (QD, d1 to 14 of a 21-day cycle) was identified as the maximum tolerated dose (MTD) of anlotinib when combined with docetaxel (60mg/m2) by a 3+3 dose de-escalation exploration. Here, we presented the updated efficacy and safety of anlotinib plus docetaxel versus docetaxel as second-line treatment for driver-negative advanced NSCLC in the phase II study. Methods: This open-label, multicenter, randomized phase II study enrolled advanced NSCLC pts who had progressed after first-line platinum-based chemotherapy, without sensitizing EGFR/ALK/ROS1 alterations, and with ECOG PS 0-1. Eligible pts were randomized 2:1 to receive anlotinib (10mg, p.o, QD, d1 to 14 of a 21-day cycle) plus docetaxel (60mg/m2, q3w, 4-6 cycles) (A+D arm) or docetaxel (60mg/m2, q3w, 4-6 cycles) alone (D arm) until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included the objective response rate (ORR), the disease control rate (DCR), OS and safety. Results: From Jun. 2019 to Dec. 2020, 36 pts were enrolled, 24 pts (median age: 63.0, squamous cell carcinoma: 50.0%, ECOG PS 1: 87.5%) in the A+D arm and 12 pts (median age: 60.0, squamous cell carcinoma: 50.0%, ECOG PS 1: 83.3%) in the D arm. As of Jan. 20, 2021, the median PFS were 6.2 months (95% Cl: 0.00-12.82) in the A+D arm vs 1.4 months (95% Cl: 0.71-2.09) in the D arm (HR: 0.30; 95% Cl: 0.11-0.78, p = 0.007), which remain immature because of the shorter follow-up time. The median OS was not reached. For tumor response, 32 pts were evaluable. The ORR was 27.3% in the A+D arm vs 0% in the D arm (p = 0.142), and the A+D arm showed a significantly higher DCR than the D arm (100.0% vs 50.0%, p = 0.001). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 33.3% (A+D arm) and 0.0% (D arm). The most commonly reported grade 3/4 TRAEs in the A+D arm included neutropenia (8.3%, 2/24), leukopenia (8.3%, 2/24), oral mucositis (8.3%, 2/24) and hypertension (8.3%, 2/24). No grade 5 TRAEs or deaths were observed. Conclusions: Anlotinib plus docetaxel continues to show the better clinical benefit as second-line treatment for driver-negative advanced NSCLC. The safety profile was manageable and consistent with previously reported studies. The longer follow-up time is required. Clinical trial information: NCT03726736.

Real-world experience of olaparib as maintenance therapy in BRCA-mutated recurrent ovarian cancer.

The primary objective of our study was to investigate the effectiveness and safety of olaparib maintenance therapy in patients with BRCA-mutated recurrent ovarian cancer in daily practice. The secondary objective of this study was to identify prognostic factors associated with prolonged progression-free survival (PFS) in such patients. We conducted a retrospective analysis of 40 patients who received olaparib maintenance treatment. Data on clinicopathological factors, oncological outcomes, and adverse events were obtained from medical records and analyzed. All patients had high-grade serous recurrent ovarian cancer with BRCA mutation and achieved complete or partial response to the most recent platinum-based chemotherapy. After a median follow-up of 14.3months, the median PFS was 23.7months (95% confidence interval, 14.1-33.4); however, the median overall survival was not reached. In the log-rank test, the PFS was significantly longer for patients with most recent platinum-free interval (PFI) ≥ 12months, complete response to the last platinum-based chemotherapy, and less than three lines of previous chemotherapy (p = 0.005, p = 0.016, and p = 0.023, respectively). Most hematologic and non-hematologic adverse events were of grade 1 or 2, and the common adverse events were mostly related to myelosuppression. Olaparib maintenance treatment in BRCA-mutated recurrent ovarian cancer is effective and safe in clinical practice. Most recent PFI, response to the last platinum-based chemotherapy, and the number of previous chemotherapy lines were associated with PFS in patients with BRCA-mutated recurrent ovarian cancer.

Comparative Efficacy of Cabozantinib and Ramucirumab After Sorafenib for Patients with Hepatocellular Carcinoma and Alpha-fetoprotein ≥ 400 ng/mL: A Matching-Adjusted Indirect Comparison

IntroductionCabozantinib and ramucirumab are approved for the treatment of adults with hepatocellular carcinoma (HCC) following prior sorafenib treatment; ramucirumab is restricted to use in patients with serum alpha-fetoprotein (AFP) ≥ 400 ng/mL. This matching-adjusted indirect comparison evaluated the efficacy and safety of both drugs after sorafenib in patients with HCC and AFP ≥ 400 ng/mL.MethodsIndividual patient data (IPD) from the CELESTIAL trial (cabozantinib) and population-level data from the REACH-2 trial (ramucirumab) were used. To align with REACH-2, the CELESTIAL population was limited to patients who received first-line sorafenib only and had baseline serum AFP ≥ 400 ng/mL. The IPD from CELESTIAL were weighted to balance the distribution of 11 effect-modifying baseline characteristics with those of REACH-2. Overall survival (OS; primary endpoint) and progression-free survival (PFS) were compared for the CELESTIAL (matching-adjusted) and REACH-2 populations using weighted Kaplan-Meier (KM) curves and parametric (OS, Weibull; PFS, log-logistic) modeling. Rates of treatment-related adverse events (TRAEs) and TRAE-related discontinuations were also compared.ResultsAfter matching and weighting, baseline characteristics were balanced between populations (REACH-2, N = 292; CELESTIAL, effective sample size = 105). Weighted KM estimates for OS (median [95% CI]) were not significantly different between cabozantinib and ramucirumab (10.6 [9.5–17.3] months versus 8.7 [7.3–10.8] months; p = 0.104), but PFS was significantly longer for cabozantinib than for ramucirumab (5.5 [4.6–7.4] months versus 2.8 [2.7–4.1] months; p = 0.016). Parametric modeling results were consistent with the weighted KM analysis. Rates of some grade 3 or 4 TRAEs were lower with ramucirumab than with cabozantinib; however, TRAE-related discontinuation rates were similar (p = 0.271).ConclusionIn this MAIC, cabozantinib significantly prolonged median PFS compared with ramucirumab after prior sorafenib treatment in patients with HCC and AFP ≥ 400 ng/mL; rates of some grade 3 or 4 TRAEs were lower with ramucirumab than cabozantinib but related discontinuation rates were not significantly different between treatments.Trial RegistrationClinical trials.gov identifiers: CELESTIAL trial (NCT01908426) and REACH-2 trial (NCT02435433).Graphic abstractThese slides can be retrieved under Electronic Supplementary Material. Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01700-2.

Efficacy of First Line Systemic Chemotherapy and Multikinase Inhibitors in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis

BackgroundHepatocellular carcinoma (HCC) is the third most fatal cancer, with a 5-year survival rate of 18%. Standard frontline-therapy is multikinase inhibitors (MKIs), but accessibility is still limited, particularly in developing countries. This network meta-analysis (NMA) aimed to compare the efficacy of usual chemotherapy vs MKIs.MethodRandomised-controlled trials (RCTs) comparing any among chemotherapy vs MKIs in treatment-naïve patients with advanced HCCs were identified from MEDLINE and SCOPUS databases. Overall survival (OS) and progression-free survival (PFS) probabilities and times were extracted from Kaplan-Meier curves using Digitizer, and then converted to individual patient time-to-event data. A one-stage mixed-effect survival model was applied to estimate median OS and PFS. A two-stage NMA was applied for the overall response rate and adverse events (AEs) outcome.ResultsA total of 20 RCTs were eligible for NMA. Lenvatinib was the best treatment among single MKIs, with median OS and PFS of 9 and 6.3 months, without significant differences in AEs relative to other MKIs. Median OS and PFS were 0.70 (-0.42, 1.83) and 2.17 (1.41, 2.93) months longer with Lenvatinib than Sorafenib. Among chemotherapy agents, FOLFOX4 had the longest median OS and PFS at 7.9 and 4.3 months, respectively, without significant AEs compared to other chemotherapies. The combination of Sorafenib+Doxorubicin prolonged median OS and PFS to 12.7 and 6.3 months, respectively.ConclusionUse of the MKIs Lenvatinib or Sorafenib as first line systemic treatment for advanced HCC could be beneficial. However, FOLFOX4 might be the optimal choice in a developing country where the health-care budget is limited.

Isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma according to prior lines of treatment and refractory status: ICARIA-MM subgroup analysis

Patients with relapsed/refractory multiple myeloma (RRMM) experience several relapses, and become refractory to successive therapies. In the ICARIA-MM trial (NCT02990338), isatuximab plus pomalidomide-dexamethasone prolonged median progression-free survival (PFS) in patients with RRMM. This subgroup analysis of ICARIA-MM assessed the treatment benefit of isatuximab by prior lines of therapy and refractory status. A total of 307 patients were randomized to isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, then every other week. Standard pomalidomide-dexamethasone doses were given. PFS was assessed by prior lines and refractory status. Overall, 102 (66 %) patients receiving isatuximab-pomalidomide-dexamethasone and 101 (66 %) patients receiving pomalidomide-dexamethasone had received 2–3 prior lines; 52 (34 %) and 52 (34 %) had received >3 prior lines, respectively. Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who received 2–3 prior lines of therapy (12.3 vs. 7.8 months) and >3 prior lines of therapy (9.4 vs. 4.3 months). Median PFS was higher with isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone for patients who were lenalidomide-refractory (11.4 vs. 5.6 months), lenalidomide-refractory at last line (11.6 vs. 5.7 months), refractory to a proteasome inhibitor (PI) (11.4 vs. 5.6 months), and double-refractory (11.2 vs. 4.8 months). Overall response rate (ORR) in patients receiving isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone was 59.0 % versus 31.4 % in lenalidomide-refractory; 60.2 % versus 32.2 % in PI-refractory; and 58.6 % versus 29.9 % in double-refractory patients. Isatuximab-pomalidomide-dexamethasone improved PFS and ORR regardless of prior lines of therapy or refractory status, consistent with the benefit in the overall population.

Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy.

Simple SummaryThough patients with sensitizing epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer have been known to have rapid and durable responses to tyrosine kinase inhibitors, a subset of patients have inferior outcomes and may benefit from therapy escalation. Neutrophil-to-lymphocyte ratio (NLR) has been recognized as one indicator of poor prognosis in patients with various cancers, including non-small cell lung cancer. It is associated with cancer cachexia and treatment resistance. The aim of our study is to assess the serial predictive value of NLR and other markers of cachexia and chronic inflammation in the subset of patients with advanced non-small cell lung cancer who harbor the epidermal growth factor receptor mutation and who are undergoing treatment with tyrosine kinase inhibitor therapy.Background: First-line treatment for patients with non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor (EGFR) mutation is a tyrosine kinase inhibitor (TKI). Despite higher response rates and prolonged progression free survival (PFS) compared with platinum doublet chemotherapy, a subset of these patients do not receive prolonged benefit from these agents. We investigate if the neutrophil-to-lymphocyte ratio (NLR) and other markers of cachexia and chronic inflammation correlate with worse outcomes in these patients. Methods: This study is a retrospective review of 137 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and University of Chicago Medicine from August 2011 to July 2019, with outcomes followed through July 2020. The predictive value of NLR and body mass index (BMI) was assessed at the start of therapy, and after 6 and 12 weeks of treatment by univariable and multivariable analyses. Results: On univariable analysis, NLR ≥ 5 or higher NLR on a continuous scale were both associated with significantly worse PFS and overall survival (OS) at treatment initiation, and after 6 or 12 weeks of treatment. On multivariable analysis, NLR ≥ 5 was associated with increased risk of death at 12 weeks of therapy (HR 3.002, 95% CI 1.282–7.029, p = 0.011), as was higher NLR on a continuous scale (HR 1.231, 95% CI 1.063–1.425, p = 0.0054). There was no difference in PFS and OS and amongst BMI categories though number of disease sites and Eastern Cooperative Oncology Group (ECOG) performance status was associated with worse PFS and OS. Conclusions: Patients with NLR ≥ 5 have a worse median PFS and median OS than patients with NLR < 5. NLR may have value as a predictive biomarker and may be useful for selecting patients for therapy intensification in the front-line setting either at diagnosis or after 12 weeks on therapy. NLR needs to be validated prospectively.

Daratumumab as Single Agent in Relapsed/Refractory Myeloma Patients: A Retrospective Real-Life Survey.

BackgroundThe anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who received at least three prior lines of therapy, including proteasome inhibitor and immunomodulatory agent. A retrospective multicentric study was designed to evaluate feasibility, tolerability, and efficacy of daratumumab in monotherapy in RRMM.MethodsThis study included 44 consecutive RRMM patients that underwent daratumumab monotherapy after a median number of four prior therapies (range 2–9). Patients were treated in seven Sicilian centers, as part of Sicilian Myeloma Network and three Calabrian centers outside of controlled clinical trials from August 2016 through July 2020.ResultsThe regimen was well tolerated with few grade 3–4 haematological and rare non-haematological adverse events, such as pneumonia. Definitive discontinuation was due to disease progression in 25 (57%) patients. Since three patients did not complete at least one full cycle, a total of 41 patients was evaluated for response. Overall response rate was 37%, and the disease control rate (stable disease or better) was high (73%). The best achieved responses within 6 months were very good partial remission or better (27%), partial remission (10%), minimal response (14%) and stable disease (22%). After a median follow up of 7.8 months, median progression free survival (PFS) was 7.2 months and overall survival (OS) 7.8 months. Univariate analysis showed that patients with PR or better after 6 months of therapy had longer median PFS and OS (respectively 29.5 vs 3.6 months, p=0.0001 and 30.6 vs 3.9 months p=0.0001), confirmed by multivariate analysis. Furthermore, standard cytogenetic risk and biochemical relapse type had prolonged median PFS, but not OS (respectively unreached vs 2.6, p=0.03 and 23.9 vs 6.2, p=0.05) in both univariate and multivariate analysis. Additionally, univariate analysis showed that patients treated with carfilzomib-lenalidomide-dexamethasone prior to daratumumab had significantly shorter PFS compared to pomalidomide-dexamethasone (3.4 months vs 9.3 months, p=0.03), that multivariate analysis failed to confirm.ConclusionsOur findings indicate that daratumumab as single agent is safe and well-tolerated regimen in real-life, associated to prolonged PFS and OS in responding patients. No new safety signals were identified.

Abstract PS10-14: Efficacy and safety of palbociclib (PAL) in patients (pts) with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with preexisting conditions: A post hoc analysis of PALOMA-2

Abstract Background: In the PALOMA-2 trial, PAL + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in pts with ER+/HER2– ABC. This post hoc analysis assessed efficacy and safety of PAL + LET in pts from PALOMA-2 with baseline preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Methods: Postmenopausal pts with ER+/HER2– ABC received PAL (125 mg/d, 3/1 schedule) + LET (2.5 mg/d, continuous) or PBO + LET. Pts were grouped by the following MedDRA SOC preexisting conditions: Gastrointestinal, Musculoskeletal, Metabolism, and Vascular/Cardiac. Baseline characteristics, PFS, and safety were assessed. Results: At baseline, 41.4% of pts had preexisting gastrointestinal disorders, 58.6% musculoskeletal disorders, 38.9% metabolism disorders, and 57.4% vascular/cardiac disorders. Baseline characteristics were similar between treatment arms within each subgroup and also between subgroups. Within each subgroup, ≥40% of pts also had ≥1 of the other coexisting conditions. Median PFS (mPFS) was significantly longer with PAL + LET vs PBO + LET regardless of preexisting condition (Table). In general, adverse events (AEs) were more frequent with PAL + LET in all subgroups; neutropenia was most common. Within each treatment arm, AEs and dose modifications due to AEs were similar regardless of preexisting condition. Conclusion: PAL + LET showed prolonged PFS and a consistent safety profile regardless of baseline preexisting condition in pts with ER+/HER2– ABC. Clinical trial identification: Pfizer Inc (NCT01740427) TablePreexisting ConditionPAL + LETPBO + LETPAL + LET vs PBO + LETnmPFS (95% CI)nmPFS (95% CI)HR (95% CI)P ValueGastrointestinal17627.6 (17.5–33.1)10013.6 (11.0–18.5)0.57 (0.42–0.78)&amp;lt;0.001Musculoskeletal25227.6 (21.4–33.1)13816.3 (11.2–19.1)0.53 (0.41–0.69)&amp;lt;0.001Metabolism18627.6 (19.3–30.6)7313.8 (8.3–27.4)0.62 (0.44–0.87)0.003Vascular/Cardiac25430.4 (25.1–36.2)12814.5 (11.0–18.5)0.51 (0.39–0.66)&amp;lt;0.001 Citation Format: Karen Gelmon, Janice M Walshe, Reshma Mahtani, Anil A Joy, Meghan Karuturi, Patrick Neven, Dongrui Ray Lu, Sindy Kim, Patrick Schnell, Eustratios Bananis, Lee Schwartzberg. Efficacy and safety of palbociclib (PAL) in patients (pts) with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with preexisting conditions: A post hoc analysis of PALOMA-2 [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 PS10-14.

Abstract PD2-06: Clinical outcomes of alpelisib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer with PIK3CA alterations detected in plasma ctDNA by next-generation sequencing: Biomarker analysis from the SOLAR-1 study

Abstract Introduction: The PI3K pathway is often hyperactivated in cancer as a result of an altered PI3K isoform and/or loss of phosphatase and tensin homolog function. Approximately 40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC) have tumors with mutations in PIK3CA, which encodes the α-isoform of PI3K, p110α. These mutations are known to cause hyperactivation of the PI3K pathway, which contributes to cell proliferation, drug resistance, and poor prognoses. Alpelisib (ALP) is an α-selective PI3K inhibitor that, in combination with fulvestrant (FUL), prolonged median progression-free survival (mPFS) in pts with HR+, HER2−, PIK3CA-mutant ABC following progression on/after prior aromatase inhibitor in the phase 3 SOLAR-1 trial. In SOLAR-1, prospective PIK3CA mutation testing was performed on tumor tissue using PCR-based assays. Through retrospective analysis, efficacy of ALP was demonstrated in subgroups of pts with PIK3CA alteration(s) in tumor tissue and mutation(s) in ctDNA, detected by next-generation sequencing (NGS) and PCR, respectively. In this exploratory biomarker analysis, we assessed clinical outcomes of pts with PIK3CA alteration(s), detected in ctDNA by NGS.Methods: SOLAR-1 is a phase 3, randomized, double-blind, placebo-controlled study of ALP 300 mg vs placebo taken daily with FUL 500 mg every 28 days + Cycle 1 Day 15 in men and postmenopausal women with HR+, HER2- ABC. Retrospectively, the full exonic region of the PIK3CA gene was sequenced using the Foundation Medicine 324-gene ctDNA panel in plasma ctDNA collected at baseline. mPFS was assessed using Kaplan-Meier methodology per investigator assessment.Results: Of 572 pts in SOLAR-1, 381 pts (66.6%) across both PIK3CA-mutant and nonmutant cohorts had valid plasma ctDNA data. Of these pts, 193 (50.7%) had a PIK3CA alteration; 168 (87%) had PCR-detectable mutations and 147 (76%) had a single alteration. A total of 70 (36%) and 102 (53%) pts had alterations in exons 9 and 20, respectively. ALP plus FUL prolonged mPFS in pts with PIK3CA alterations detected in plasma ctDNA by NGS (n=101; Table). Clinical benefit was also observed in pts with PCR-detectable mutations (n=88), single mutations (n=83), and pts with mutations in exon 9 (n=34) and exon 20 (n=54). Pt numbers were low, and wide 95% CIs were observed in groups with alterations not detectable by PCR (n=13) and in pts with multiple alterations. Some limitations of this retrospective plasma analysis include that this is a subgroup (66.6%) of the SOLAR-1 pt population and that the subgroup of pts with non-altered PIK3CA included pts with a PIK3CA mutation in their tumor tissue. Conclusions: ALP plus FUL demonstrated clinical benefit in pts with PIK3CA mutations detected in plasma ctDNA by NGS, in pts with single alterations, and in pts with alterations in exons 9 and 20. Results were consistent across pt groups, except in those with alterations not detectable by PCR. In conclusion, these data demonstrate a consistent clinical benefit of ALP plus FUL in various groups of pts with PIK3CA alterations detected in ctDNA by NGS. Clinical Outcomes of Patients With PIK3CA Alterations Detected in Plasma ctDNA by NGS in SOLAR-1Alpelisib + fulvestrantPlacebo + fulvestrantHR (95% CI)Events/N (%)mPFS, mo (95% CI)Events/N(%)mPFS, mo (95% CI)PIK3CA altered vs non-alteredAltered58/101(57.4)11.04(7.72-16.16)73/92(79.3)3.65(2.86-6.80)0.47(0.33-0.67)Non-altered40/87(46.0)10.87(5.59-16.76)60/101(59.4)5.45(3.75-9.00)0.60(0.40-0.91)PIK3CA: alteration detectable by PCR vs alteration not detectable by PCRDetectable52/88(59.1)12.48(7.36-18.37)66/80(82.5)3.58(2.37-5.65)0.44(0.30-0.64)Not detectable6/13(46.2)8.48(2.69-NA)7/12(58.3)7.39(1.87-12.98)1.12(0.35-3.56)PIK3CA: number of alterationsSingle45/83(54.2)12.88(7.36-18.50)50/64(78.1)3.58(1.87-6.11)0.43(0.28-0.65)Multiple13/18(72.2)9.00(3.68-18.37)23/28(82.1)4.63(3.48-9.63)0.55(0.25-1.20)PIK3CA alterations in exon 9 or exon 20Exon 918/34(52.9)15.21(7.03-NA)29/36(80.6)3.66(2.86-7.36)0.31(0.16-0.61)Exon 2034/54(63.0)10.91(5.72-18.37)40/48(83.3)3.52(1.87-6.11)0.51(0.31-0.82)CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; mPFS, median progression-free survival; mo, months; NA, not available; NGS, next-generation sequencing. Citation Format: Eva M. Ciruelos, Sibylle Loibl, Ingrid A. Mayer, Mario Campone, Hope S. Rugo, Monica Arnedos, Hiroji Iwata, Pier Franco Conte, Fabrice André, Albert Reising, Chong Ma, Michelle Miller, Naveen Babbar, Dejan Juric. Clinical outcomes of alpelisib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer with PIK3CA alterations detected in plasma ctDNA by next-generation sequencing: Biomarker analysis from the SOLAR-1 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 PD2-06.

External Validity of Somatostatin Analogs Trials in Advanced Neuroendocrine Neoplasms: The GETNE-TRASGU Study

Introduction: Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs. Methods: We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs. Results: The dataset contained 535 patients with a median age of 62 years (range: 26–89). The median Ki-67% was 4 (range: 0–20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1–32.0) for octreotide versus 30.1 months (95% CI: 23.1–38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71–1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively. Conclusion: Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs.

Results of biomarker analysis from phase II trial of nivolumab in refractory biliary tract cancer.

338 Background: Our previous phase II study demonstrated that nivolumab provides modest but durable clinical efficacy in patients (pts) with refractory biliary tract cancer (BTC), suggesting the significant clinical benefit of nivolumab in selected pts and identification of potential predictive biomarkers. Here, we report outcomes from the biomarker analysis. Methods: Pre-treatment tumor samples were obtained and assessed for immunohistochemistry (IHC) with PD-1 and PDL-1 antibodies, mRNA sequencing (RNAseq), and whole exome sequencing (WES). Clinical efficacy was correlated with the molecular analysis. Prior cisplatin exposure was reviewed to evaluate the impact of cisplatin on the tumor mutational burden (TMB) and clinical outcome. Results: Among 46 pts who had tumor response evaluation, 31 pts received cisplatin prior to nivolumab, and 15 were cisplatin-naive. Pre-treatment tumor samples were assessed for IHC (n = 42), RNAseq (n = 11), and WES (n = 11) based on tissue availability. There was no statistically significant correlation between prior cisplatin exposure and clinical outcome. Among 42 available tumor samples, 18 (43%) expressed PD-L1 positivity ( &gt; 1%), which was associated with a statistically significant prolonged progression free survival (PFS). Median PFS was 10.4 months for PD-L1 positive vs 2.4 months for PD-L1 negative (HR 0.23, 95% CI 0.10-0.51; P &lt; 0.001), while there was no statistically significant correlation between PD-1 expressing tumor infiltrating lymphocytes and clinical outcome. There was also no statistically significant difference in TMB of cisplatin-exposed (n = 8) vs. cisplatin-naïve tumor samples (n = 3) (9162, SD = 150 vs. 8898, SD = 806, p = 0.62). In comparing the group with prolonged disease control of at least 16 weeks (n = 4) to those with rapid disease progression (n = 7) who had mRNA sequencing performed, levels of AC005609.1, FAT3, TMEM151A, ADARB2, FAM153A were all significantly upregulated (p &lt; 0.01), while levels of CLCA1, MUC2, IGHV3-43, SWORA6, and CRISP3 were all significantly downregulated (p &lt; 0.01). Conclusions: Prior cisplatin exposure did not lead to statistically significant differences in clinical outcome or TMB in advanced BTC pts treated with nivolumab. However, PD-L1 expression &gt; 1% correlated with improved PFS, and variations in level of certain mRNA sequences were noted when comparing pts who had rapid disease progression vs. prolonged disease control with nivolumab. This suggests that BTC pts with positive PD-L1 expression and a particular mRNA profile may have a favorable response to nivolumab. Further studies are needed to confirm these findings. Clinical trial information: NCT02829918.

Effect of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF v600-mutated metastatic colorectal cancer: a real-world study in Spain

BackgroundOutcomes are poorer in metastatic colorectal cancer (mCRC) patients with BRAF V600E mutations than those without it, but the effect of these mutations on treatment response is unclear. This real-world study assessed the effects of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF V600-mutated mCRC.MethodsThis real-world, multicenter, retrospective, observational study included patients with BRAF V600-mutated mCRC treated in eight hospitals in Spain. The primary endpoints were overall survival (OS) and progression-free survival (PFS); overall response rate (ORR) and disease control rate (DCR) were also assessed. The effect of first- and second-line treatment type on OS, PFS, ORR, and DCR were evaluated, plus the impact of systemic inflammatory markers on these outcomes. A systemic inflammation score (SIS) of 1–3 was assigned based on one point each for platelet-lymphocyte ratio (PLR) ≥200, neutrophil-lymphocyte ratio (NLR) ≥3, and serum albumin < 3.6 g/dL.ResultsOf 72 patients, data from 64 were analyzed. After a median of 69.1 months, median OS was 11.9 months and median first-line PFS was 4.4 months. First-line treatment was triplet chemotherapy-antiangiogenic (12.5%), doublet chemotherapy-antiangiogenic (47.2%), doublet chemotherapy-anti-EGFR (11.1%), or doublet chemotherapy (18.1%). Although first-line treatment showed no significant effect on OS, antiangiogenic-based regimens were associated with prolonged median PFS versus non-antiangiogenic regimens. Negative predictors of survival with antiangiogenic-based treatment were NLR, serum albumin, and SIS 1–3, but not PLR. Patients with SIS 1–3 showed significantly prolonged PFS with antiangiogenic-based treatment versus non-antiangiogenic-based treatment, while those with SIS=0 showed no PFS benefit.ConclusionsAntiangiogenic-based regimens, SIS, NLR, and albumin were predictors of survival in patients with mCRC, while SIS, NLR and serum albumin may predict response to antiangiogenic-based chemotherapy.Trial registrationGIT-BRAF-2017-01.

Patterns of treatment and outcome of palbociclib plus endocrine therapy in hormone receptor-positive/HER2 receptor-negative metastatic breast cancer: a real-world multicentre Italian study.

Background:The CDK4/6 inhibitor palbociclib combined with endocrine therapy (ET) has proven to prolong progression-free survival (PFS) in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). Few data are available regarding the efficacy of such a regimen outside the clinical trials.Patients and methods:This is a multicentre prospective real-world experience aimed at verifying the outcome of palbociclib plus ET in an unselected population of MBC patients. The primary aim was the clinical benefit rate (CBR); secondary aims were the median PFS, overall survival (OS) and safety. Patients received palbociclib plus letrozole 2.5 mg (cohort A) or fulvestrant 500 mg (cohort B).Results:In total, 191 patients (92 in cohort A, 99 in cohort B) were enrolled and treated, and 182 were evaluable for the analysis. Median age was 62 years (range 47–79); 54% had visceral involvement; 28% of patients had previously performed one treatment line (including chemotherapy and ET), 22.6% two lines and 15.9% three. An overall response rate of 34.6% was observed with 11 (6.0%) complete responses and 52 (28.6%) partial responses. Stable disease was achieved by 78 patients (42.9%) with an overall CBR of 59.8%. At a median follow-up of 24 months (range 6–32), median PFS was 13 months without significant differences between the cohorts. When analysed according to treatment line, PFS values were significantly prolonged when palbociclib-based therapy was administered as first-line treatment (14.0 months), to decrease progressively in second and subsequent lines (11.7 and 6.7 months, respectively). Median OS was 25 months, ranging from 28.0 months in 1st line to 18.0 and 13.0 months in 2nd and subsequent lines, respectively.Conclusions:Our data indicate that palbociclib plus ET is active and safe in HR+/HER2− MBC, also suggesting a better performance of the combinations in earlier treatment lines.

C-reactive protein flare-response predicts long-term efficacy to first-line anti-PD-1-based combination therapy in metastatic renal cell carcinoma.

ObjectivesImmune checkpoint blockade (IO) has revolutionised the treatment of metastatic renal cell carcinoma (mRCC). Early C‐reactive protein (CRP) kinetics, especially the recently introduced CRP flare‐response phenomenon, has shown promising results to predict IO efficacy in mRCC, but has only been studied in second line or later. Here, we aimed to validate the predictive value of early CRP kinetics for 1st‐line treatment of mRCC with αPD‐1 plus either αCTLA‐4 (IO+IO) or tyrosine kinase inhibitor (IO+TKI).MethodsIn this multicentre retrospective study, we investigated the predictive potential of early CRP kinetics during 1st‐line IO therapy. Ninety‐five patients with mRCC from six tertiary referral centres with either IO+IO (N = 59) or IO+TKI (N = 36) were included. Patients were classified as CRP flare‐responders, CRP responders or non‐CRP responders as previously described, and their oncological outcome was compared.ResultsOur data validate the predictive potential of early CRP kinetics in 1st‐line immunotherapy in mRCC. CRP responders, especially CRP flare‐responders, had significantly prolonged progression‐free survival (PFS) compared with non‐CRP responders (median PFS: CRP flare‐responder: 19.2 months vs. responders: 16.2 vs. non‐CRP responders: 5.6, P < 0.001). In both the IO+IO and IO+TKI subgroups, early CRP kinetics remained significantly associated with improved PFS. CRP flare‐response was also associated with long‐term response ≥ 12 months.ConclusionsEarly CRP kinetics appears to be a low‐cost and easy‐to‐implement on‐treatment biomarker to predict response to 1st‐line IO combination therapy. It has potential to optimise therapy monitoring and might represent a new standard of care biomarker for immunotherapy in mRCC.