Garrido-Castro AC, Kim SE, Li T
… +36 more, Desrosiers J, Nanda R, Abdou Y, Clark AS, Sacks RL, O'Connor T, Sinclair N, Lo S, Augdahl G, Wrabel E, DiLullo M, Rahman T, Patel A, Hughes ME, Baginska J, Lange PB, O'Meara T, Keenan TE, Gorthi A, D'Ippolito A, Painter CA, Eaton M, Barrett JC, Koca B, Kurnia PT, Perry AN, Tejeda Zanudo JG, He M, Dillon DA, Lin NU, Burstein HJ, Mittendorf EA, Jeselsohn R, Rimm DL, Tayob N, Tolaney SM
BACKGROUND: Sacituzumab govitecan (SG), a TROP2-directed topoisomerase I-inhibitor (TOP1i) antibody-drug conjugate, is approved for chemo-refractory hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast c...BACKGROUND: Sacituzumab govitecan (SG), a TROP2-directed topoisomerase I-inhibitor (TOP1i) antibody-drug conjugate, is approved for chemo-refractory hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). To evaluate if pembrolizumab (PD-1 inhibitor) enhances the activity of SG, we conducted a randomized phase II study comparing SG with or without pembrolizumab in HR+/HER2- MBC. METHODS: Patients with HR+/HER2- MBC pretreated with endocrine therapy and 0-1 chemotherapy regimens for MBC (no prior TOP1i) were randomized 1:1 to receive SG+pembrolizumab or SG. Primary endpoint was progression-free survival (PFS). Key secondary endpoints included PFS in the PD-L1-positive population (pharmDx 22C3 CPS ≥1), overall survival (OS), objective response rate (ORR), and toxicity. Baseline tumor tissue and plasma samples were collected for correlative analyses. RESULTS: Between 03/2021-01/2024, 104 patients started treatment; 47% (49) had not received chemotherapy for MBC. At 15.5-month median follow-up, SG+pembrolizumab did not significantly improve PFS compared to SG (8.4 vs 6.7 months; HR 0.76, 95% CI 0.48-1.19, p=0.12). Median OS was 20.0 vs 18.0 months (p=0.18); ORR was 28.8% vs 19.2% (p=0.36). In the PD-L1-positive population (44%; 39/88 with tissue), median PFS (11.1 vs 5.6 months; HR 0.51, 95% CI 0.24-1.12, p=0.09) and OS (18.5 vs 12.5 months; HR 0.59, 95% CI 0.18-1.98, p=0.39) numerically increased with the combination. Most frequent grade ≥2 adverse events were neutropenia, alopecia, fatigue, anemia, nausea, leukopenia, and diarrhea. Neither TROP2 expression by immunohistochemistry, immunofluorescence, or plasma epigenome-based analysis, or tumor-infiltrating lymphocytes were associated with outcomes. Higher ctDNA fraction and PIK3CA mutations were associated with worse PFS. Plasma epigenome-pathway analysis suggested that high cell-cycle or EMT activation may confer sensitivity or resistance to SG, respectively. CONCLUSION: Addition of pembrolizumab to SG did not significantly improve outcomes in HR+/HER2- MBC unselected by PD-L1. In the PD-L1-positive population, the trend in PFS and OS favoring SG+pembrolizumab warrants further investigation in larger randomized trials.
Han F, Xiang YQ, Wang XH
… +28 more, Qu S, Tang LQ, Shu XL, Zhang P, Qiu SF, Zhou YJ, Guo Y, Xu GQ, Li Q, Yang KY, Du YQ, Xu MJ, Li JG, Wang F, Huang ST, Huang YJ, Wu H, Chen XZ, Wei Y, Wu WL, Pan SM, Lin HM, Xiao SW, Dou YW, Dai R, Zhang P, Jin YS, Xu RH
BACKGROUND: Patients with recurrent/metastatic nasopharyngeal carcinoma (NPC) had limited treatment option and dismal prognosis after failure to programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhi...BACKGROUND: Patients with recurrent/metastatic nasopharyngeal carcinoma (NPC) had limited treatment option and dismal prognosis after failure to programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors and chemotherapy. METHODS: This multicenter, open-label, randomized trial investigated anti-epidermal growth factor receptor antibody-drug conjugate becotatug vedotin in patients with recurrent/metastatic NPC after failure to ≥2 lines of systemic therapies, including chemotherapy and PD-1/PD-L1 inhibitors. Eligible participants were randomized 1:1 to receive becotatug vedotin 2.3 mg/kg every 3 weeks or chemotherapy (capecitabine or docetaxel). The co-primary endpoints were the independent review committee-confirmed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Between April 6, 2023, and December 27, 2023, a total of 173 patients were randomized, with 86 assigned to becotatug vedotin and 87 to chemotherapy. As of June 30, 2024, the ORR was significantly higher with becotatug vedotin than with chemotherapy (30.2% vs 11.5%; P = 0.003). With a median follow-up of 7.39 months, becotatug vedotin was associated with a significantly reduced risk of disease progression or death compared with chemotherapy (median PFS, 5.82 vs 2.83 months; hazard ratio, 0.63; 95% CI, 0.43-0.91; log-rank P = 0.01). As of December 30, 2024, the interim OS analysis showed a median OS of 17.08 months with becotatug vedotin and 11.99 months with chemotherapy (hazard ratio, 0.73; 95% CI, 0.48-1.12; log-rank P = 0.15), with a median follow-up of 13.47 months. The safety profiles were comparable between treatment groups. CONCLUSIONS: Among patients with heavily pretreated and immunotherapy-exposed recurrent or metastatic NPC, becotatug vedotin significantly improved ORR and PFS compared with chemotherapy, with comparable toxicity and encouraging but immature OS results.
Philips R, Mahajan A, Estephan L
… +25 more, Auger S, Haque W, Palmer D, McQueen J, MacCracken E, Argyris PP, Trzcinska A, Cipriani NA, Lingen M, Hussain I, Muzaffar M, Pasternak-Wise O, Curry J, Katipally R, Juloori A, Haraf D, Heinlen P, Choudhury NJ, Rosenberg A, Vokes E, Arshad H, Blair E, Agrawal N, Shah S, Pearson AT
BACKGROUND: Tumor board documentation is challenging due to complexity of multidisciplinary input. Ambient artificial intelligence (AI) for medical dictation uses generative methods to summarize voice data. Strategic pro...BACKGROUND: Tumor board documentation is challenging due to complexity of multidisciplinary input. Ambient artificial intelligence (AI) for medical dictation uses generative methods to summarize voice data. Strategic prompting can improve model output. We evaluated prompt-directed ambient AI for automated tumor board documentation and compared ambient AI with manual documentation. PATIENTS AND METHODS: We performed a prospective quality improvement study evaluating ambient AI for documentation of multidisciplinary head and neck cancer tumor board discussions at a tertiary institution in 2025. The primary intervention was verbal prompting during case discussions to improve documentation quality. Primary cohorts were unprompted and prompt-directed ambient AI tumor boards. A paired comparator sub analysis included manual and ambient AI documentation from the same meetings. We validated our prompted ambient AI workflow with additional tumor boards. Documentation was evaluated using a modified MODe (Metric for Observation of Decision Making)-based rubric across 5 domains: demographics, tumor characteristics, radiology findings, pathology findings, and discussion, with criteria rated on a 1-3 scale (1=incorrect/omitted, 2=partial, 3=complete documentation). RESULTS: We analyzed results of 12 tumor board across 4 cohorts: unprompted ambient AI, prompt-directed ambient AI, manual documentation, and internal validation. In the primary cohorts, prompt-directed ambient AI improved Tumor Characteristics domain score (q = 0.042) and total score (p = 0.005) versus unprompted ambient AI, with no difference in per-patient discussion time (p = 0.158). In the paired comparator analysis, ambient AI improved total score (p < 0.001) and Discussion domain score (q < 0.001) versus manual documentation, while reducing administrative time per patient (p < 0.001). The internal validation cohort showed statistically comparable scores across all domains. CONCLUSIONS: Directed prompting during head and neck tumor board improved generated summaries, without increasing discussion times. Compared with manual documentation, ambient AI improved documentation quality, while diminishing administrative burden.
BACKGROUND: Recent data show that glucagon-like peptide-1 receptor agonist (GLP-1RA) use is associated with decreased cancer incidence in diabetic and obese patients. However, there have been no studies exclusively inves...BACKGROUND: Recent data show that glucagon-like peptide-1 receptor agonist (GLP-1RA) use is associated with decreased cancer incidence in diabetic and obese patients. However, there have been no studies exclusively investigating the association of obesity-associated cancer (OAC) risks and GLP-1RAs in obese, nondiabetic patients. PATIENTS AND METHODS: We conducted a target trial emulation to evaluate the association between GLP-1RA use and risk of 13 OACs. Using TriNetX, a nationwide database of 113 million US patients, we identified obese, nondiabetic adults without prior OAC diagnosis from December 2014 to June 2025. Patients prescribed GLP-1RAs were 1:1 propensity score matched to those receiving diet or exercise counseling and validated using inverse probability of treatment weighting. The primary outcome compared the cumulative incidence of OACs among treatment groups. The secondary outcome analyzed cancer incidence across sex (female, male), body mass index (<40, ≥40 kg/m), race (white, black), and drug (semaglutide, tirzepatide). RESULTS: The cohort included 229 467 patients; 86 422 (37.7%) received GLP-1RAs, while 143 045 (62.3%) received diet or exercise consultation. After 1:1 propensity score matching, the study cohort included 161 798 patients: 80 899 GLP-1RA users versus 80 899 patients on diet or exercise consultation. Mean age of patients was 47.2 years (standard deviation 14.8). With a median follow-up of 2 years (interquartile range 1-2 years), the propensity score matching analysis showed a significantly lower incidence of any OACs among GLP-1RA users (hazard ratio 0.59, 95% confidence interval 0.53-0.67). Secondary analyses showed that in all subgroups, except for black race, GLP-1RA use was associated with a lower cumulative incidence of OACs. The inverse probability of treatment weighting analysis confirmed the findings. CONCLUSIONS: GLP-1RA use was associated with a significantly lower short-term incidence of OACs among obese, nondiabetic patients, with consistent results observed in subgroups, except for race. Prospective trials are needed to confirm causality.
BACKGROUND: Long-term androgen deprivation therapy (LT-ADT) with radiotherapy is standard-of-care for high-risk localized prostate cancer, with abiraterone added for clinically very high-risk disease. Given the toxicity...BACKGROUND: Long-term androgen deprivation therapy (LT-ADT) with radiotherapy is standard-of-care for high-risk localized prostate cancer, with abiraterone added for clinically very high-risk disease. Given the toxicity and cost of abiraterone, a predictive biomarker to refine patient selection is needed. We evaluated a digital pathology multimodal artificial intelligence (MMAI) model, previously validated as a prognostic biomarker, for prediction of abiraterone benefit amongst non-metastatic clinically very high-risk prostate cancer. PATIENTS AND METHODS: MMAI scores were generated for patients enrolled in two sequential abiraterone trials (no shared controls) in the STAMPEDE platform protocol (NCT00268476) using digital pathology images, prostate specific antigen (PSA), tumor stage, and age. We applied the previously-established 75 percentile threshold to classify patients as MMAI very high-risk or standard high-risk. The primary endpoint was metastasis-free survival (MFS). Treatment effects and risk estimates were obtained using Cox regression and Kaplan-Meier method, respectively. Prediction was assessed using a treatment-by-biomarker interaction Cox model. RESULTS: In total, 1137 patients randomized to LT-ADT (N=583) or LT-ADT with abiraterone (N=554), were included. The MMAI very high-risk group (N=268) demonstrated significant MFS improvement from adding abiraterone (HR 0.47; 95% CI 0.31-0.70), with 5-year MFS increasing from 62% (95% CI 53-70%) in LT-ADT to 81% (95% CI 74-87%) in LT-ADT with abiraterone. Limited abiraterone benefit was observed in the MMAI standard high-risk group (N=869; HR 0.83; 95% CI 0.63-1.09), with a 5-year MFS of 82% (95% CI 78-85%) versus 84% (95% CI 80-87%, interaction p-value=0.02). This differential effect was consistent in local node-negative and node-positive subgroups. CONCLUSIONS: In this post-hoc study of randomized clinical trial data, a locked digital pathology MMAI test displayed a strong prognostic association and predicted abiraterone efficacy in very high-risk, non-metastatic prostate cancer. This biomarker could be implemented clinically to maximize benefit from treatment intensification whilst avoiding unnecessary toxicity.
Francis PA, Pagani O, Fleming GF
… +37 more, Walley BA, Colleoni M, Rubovszky G, Tondini C, Ciruelos EM, Gomez HL, Bonnefoi HR, Burstein HJ, Chini C, Puglisi F, Spazzapan S, Bernardo A, Climent MA, Bellet M, Ruhstaller T, Bermejo B, Chia SKL, Martino S, Geyer CE, Goetz MP, Ingle JN, Stearns V, Davidson NE, Le Du F, Müller B, Coleman RE, Loibl S, Winer EP, Ruepp B, Loi S, Láng I, Coates AS, Gelber RD, Goldhirsch A, Regan MM, International Breast Cancer Study Group, SOFT and TEXT Investigators
BACKGROUND: The SOFT trial found adding ovarian function suppression (OFS) to tamoxifen (T) reduced breast cancer recurrence, and exemestane (E)+OFS further reduced recurrence. SOFT and TEXT combined analysis showed a si...BACKGROUND: The SOFT trial found adding ovarian function suppression (OFS) to tamoxifen (T) reduced breast cancer recurrence, and exemestane (E)+OFS further reduced recurrence. SOFT and TEXT combined analysis showed a significant reduction in distant recurrence with E+OFS versus T+OFS. We now report final 15-year outcomes. PATIENTS AND METHODS: Premenopausal women with hormone receptor-positive early breast cancer were enrolled, with 3047 in SOFT and 2660 in TEXT intention-to-treat populations. SOFT randomized to 5 years of T versus T+OFS versus E+OFS. TEXT randomized to 5 years of T+OFS versus E+OFS. Chemotherapy was optional, prior to SOFT entry with subsequent premenopausal oestradiol, or concurrent with OFS in TEXT. Endpoints included disease-free survival, breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI) and overall survival. 15-year Kaplan-Meier estimates, hazard ratios (HR) and 95% confidence intervals (CI) are reported. RESULTS: In SOFT, escalating endocrine therapy (ET) continued to reduce recurrence with 15-year BCFI 78.6% for E+OFS, 75.7% for T+OFS and 72.1% for T; T+OFS versus T, HR 0.82 (CI 0.69-0.98) P=0.03. In the SOFT no-chemotherapy cohort, OFS reduced breast cancer events at 15 years, while DRFI and overall survival remained high regardless of ET assignment. After prior chemotherapy for HER2-negative tumours (n=1257), SOFT 15-year overall survival was 81.0% with E+OFS versus 77.1% with T+OFS versus 76.8% with T. In women under age 35 with HER2-negative tumours (n=241), 15-year overall survival was 82.5% with E+OFS, 77.9% with T+OFS and 68.1% with T. In combined SOFT and TEXT analysis, among those with HER2-negative tumours (n=4035), E+OFS versus T+OFS reduced distant recurrence HR 0.75 (CI 0.63-0.90), with a smaller reduction in deaths HR 0.89 (CI 0.74-1.06), with absolute survival benefits largest with high-risk features, particularly young age or high-grade tumours. CONCLUSION: Meaningful overall survival benefit in hormone receptor-positive, HER2-negative breast cancer from adjuvant exemestane and/or OFS compared with tamoxifen alone is limited to high-risk premenopausal subgroups. Tamoxifen-based ET may not result in optimal outcomes in premenopausal high-grade HER2-negative tumours.
BACKGROUND: Adjuvant chemotherapy provides limited benefit in unselected stage II colon cancer. Post-operative circulating tumour DNA (ctDNA) has higher prognostic value than classical clinical markers, with ctDNA positi...BACKGROUND: Adjuvant chemotherapy provides limited benefit in unselected stage II colon cancer. Post-operative circulating tumour DNA (ctDNA) has higher prognostic value than classical clinical markers, with ctDNA positivity indicating an unfavourable outcome. PATIENTS AND METHODS: Patients with Union for International Cancer Control stage II, mismatch repair proficient/microsatellite stable colon cancer were tested for ctDNA using an academic, tumour-informed, next-generation sequencing-based test. ctDNA-positive patients were randomly assigned 2:1 to CHEMO (capecitabine ± oxaliplatin) or observation (OBS). ctDNA-negative patients were randomly assigned 1:4 to OBS or OFF-STUDY. ctDNA results were not disclosed in the OBS group. The primary endpoint was disease-free survival (DFS) in ctDNA-positive patients. All differences were tested using one-sided log-rank tests. The trial ended early due to funding expiry. RESULTS: From June 2020 to July 2025, 2126 patients were screened in Germany and Austria. Overall, 1396 patients (2.9% ctDNA-positive) were randomly assigned: 1083 to OFF-STUDY, 287 to OBS, and 26 to CHEMO, of whom 81% started therapy. DFS and overall survival (OS) were significantly worse in ctDNA-positive versus ctDNA-negative patients [3-year DFS 52% versus 87%, hazard ratio (HR) 4.28, 95% confidence interval (CI) 2.32-7.93, P < 0.001; 3-year OS 88% versus 98%, HR 5.48, 95% CI 1.64-18.28, P = 0.001]. In the intention-to-treat (ITT) cohort, the between-arm differences were not significant (3-year recurrence 36% versus 62%, HR 0.48, 95% CI 0.17-1.33, P = 0.075; 3-year DFS 61% versus 38%, HR 0.55, 95% CI 0.21-1.48, P = 0.12). In the per-protocol analysis (excluding untreated CHEMO patients), time to recurrence and DFS were improved with CHEMO compared with OBS (3-year recurrence 19% versus 62%, HR 0.23, 95% CI 0.06-0.87, P = 0.009; 3-year DFS 77% versus 38%, HR 0.31, 95% CI 0.09-1.03, P = 0.021). CONCLUSION: The primary ITT endpoint was not met, potentially related to the reduced power due to premature trial closure. The per-protocol analysis suggests a benefit from adjuvant therapy in ctDNA-positive patients, supporting ctDNA testing for adjuvant decision making in the future.
Kopetz S, Tabernero J, Lonardi S
… +17 more, Shen L, Wasan HS, Yoshino T, Van Cutsem E, Kim TW, Eng C, Ciardiello F, Desai J, Maughan TS, Yaeger R, Usari T, Zhang X, Beyzarov E, Mori A, Whalley E, Zhang X, Elez E
BACKGROUND: Encorafenib + cetuximab (EC) and mFOLFOX6 or irinotecan, leucovorin, and fluorouracil (FOLFIRI) is approved in several countries for BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on results from...BACKGROUND: Encorafenib + cetuximab (EC) and mFOLFOX6 or irinotecan, leucovorin, and fluorouracil (FOLFIRI) is approved in several countries for BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on results from the BREAKWATER trial. PATIENTS AND METHODS: In BREAKWATER Cohort 3, eligible patients with previously untreated BRAF V600E-mutant mCRC were randomly assigned 1:1 to receive EC+FOLFIRI or FOLFIRI with or without bevacizumab (control). The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR), and the key secondary endpoint was progression-free survival (PFS) by BICR. Other secondary endpoints included overall survival (OS) and safety. RESULTS: A total of 147 patients were randomly allocated in Cohort 3 (EC+FOLFIRI, n = 73; control, n = 74) with similar baseline demographics and disease characteristics across arms. EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvement in ORR by BICR {64.4% versus 39.2%, odds ratio = 2.756 [95% confidence interval (CI) 1.420-5.348], one-sided P-value = 0.0011}, meeting the primary endpoint (1 March 2025, data cutoff). At the 6 January 2026 data cutoff, the key secondary endpoint was met, with EC+FOLFIRI demonstrating a clinically meaningful and statistically significant PFS [hazard ratio = 0.44 (95% CI 0.27-0.70), one-sided P-value = 0.0002, 15.2 versus 8.3 months]. Prolonged OS was also observed with EC+FOLFIRI (hazard ratio = 0.56 [95% CI 0.34-0.94], not estimable versus 20.3 months). Serious adverse event rates were 49.3% versus 44.1% for the EC+FOLFIRI versus control arms, respectively. The safety profile was consistent with that known for each agent. CONCLUSIONS: EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvements in ORR and PFS, with prolonged OS versus control in BRAF V600E-mutant mCRC. The safety profile was generally manageable, with no new safety signals. These data support EC+FOLFIRI as an additional new standard of care for patients with BRAF V600E-mutant mCRC, enabling treatment personalisation.
Kim GM, Jung KH, Jeung HC
… +40 more, Lee J, Lee KS, Im SA, Kang SY, Kim SH, Kim HJ, Park KH, Chae YS, Koh SJ, Cho EK, Park KU, Lee SS, Kim JY, Choi IS, Baek SK, Moon YW, Kim SG, Lim ST, Lee KH, Kim HJ, Kim MH, Kim KH, Kim SI, Park S, Park HS, Kim JY, Kim YB, Kim SB, Ahn JH, Jeong JH, Kim JH, Jeong J, Park WC, Sim SH, Lee K, Nam CM, Park S, Paik S, Sohn J, Korean Cancer Study Group (KCSG)
BACKGROUND: Platinum agents have been shown to increase pathological complete response rates when added to neoadjuvant chemotherapy for triple-negative breast cancer (TNBC). The PEARLY multicenter, randomized, phase 3 tr...BACKGROUND: Platinum agents have been shown to increase pathological complete response rates when added to neoadjuvant chemotherapy for triple-negative breast cancer (TNBC). The PEARLY multicenter, randomized, phase 3 trial investigated the efficacy and safety of adding carboplatin to standard anthracycline-based/taxane chemotherapy for patients with early-stage TNBC in the neoadjuvant or adjuvant settings. PATIENTS AND METHODS: Patients with stage II or III TNBC were enrolled. Patients received either standard therapy with doxorubicin and cyclophosphamide followed by a taxane (control arm), or carboplatin in addition to a taxane following doxorubicin and cyclophosphamide (carboplatin arm). The primary endpoint was event-free survival. Secondary endpoints included overall survival (OS), invasive disease-free survival (IDFS), distant recurrence-free survival (DRFS), pathologic complete response rate (pCR), and safety. RESULTS: Between Jan 2016 and Jun 2020, 868 patients across 22 institutions in the Republic of Korea were randomly assigned to either control arm or carboplatin arm. At a median follow-up of 57.2 months, carboplatin significantly improved event-free survival compared with the control arm (hazard ratio, 0.67; 95% confidence interval [CI]: 0.49-0.92; P=0.012). The 5-year event-free survival rates increased from 75.1% to 82.3% with absolute 7.2% difference. Secondary endpoints, including OS, IDFS, and DRFS, showed directionally consistent trends favoring the carboplatin arm, though none reached statistical significance. Grade 3 or higher treatment-related adverse event rates were more frequent in the carboplatin arm (74.7%) than in the control arm (56.7%), driven primarily by hematological toxicity. CONCLUSION: The addition of carboplatin to doxorubicin and cyclophosphamide followed by taxane therapy significantly improved event-free survival in patients with early-stage TNBC. Despite a higher incidence of grade ≥3 adverse events in the carboplatin arm, no clinically meaningful deterioration in quality of life was observed, supporting a favorable risk-benefit profile for carboplatin incorporation into early TNBC treatment.
Shaw AT, Solomon BJ, Felip E
… +13 more, Bauer TM, Liu G, Goto Y, Wu YL, Soo RA, Mazieres J, Kim DW, Wang IM, Paolini J, Polli A, Rifi N, Toffalorio F, Mok TSK
BACKGROUND: Due to the unprecedented progression-free survival (PFS) benefit with lorlatinib after 5 years of follow-up in the phase III CROWN study, we aimed to quantify long-term outcomes at 7 years. PATIENTS AND METHO...BACKGROUND: Due to the unprecedented progression-free survival (PFS) benefit with lorlatinib after 5 years of follow-up in the phase III CROWN study, we aimed to quantify long-term outcomes at 7 years. PATIENTS AND METHODS: Treatment-naive patients (N = 296) with advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) were randomly assigned 1:1 to receive lorlatinib 100 mg once a day (n = 149) or crizotinib 250 mg twice a day (n = 147). This post hoc analysis presents investigator-assessed efficacy outcomes, safety, and biomarker analyses. RESULTS: With a median follow-up of 83.0 and 77.2 months, median PFS was not reached (NR) with lorlatinib [95% confidence interval (CI), 68.5-NR] and was 9.1 months (95% CI 7.4-10.9) with crizotinib [hazard ratio (HR) 0.19, 95% CI 0.13-0.26]; 7-year PFS was 55% and 3%, respectively. With lorlatinib, patients without a PFS event at the end of 24 months had a 79% probability of survival without progression at year 7. No new intracranial progression events occurred after the first 30 months on lorlatinib. Median time to intracranial progression was NR (95% CI NR-NR) with lorlatinib and 16.4 months (95% CI 12.7-21.9) with crizotinib (HR 0.06, 95% CI 0.03-0.12). Overall survival follow-up is ongoing; the number of events for a protocol-specified analysis has not been met. The safety profile was consistent with the 5-year results. With lorlatinib, treatment-related adverse events did not lead to discontinuations after the first 26 months. More genetic alterations were detected in circulating tumor DNA samples from early progressors than in long-term responders on lorlatinib; new potential resistance mechanisms were identified. CONCLUSIONS: With median PFS yet to be reached after 7 years of follow-up in CROWN, lorlatinib continues to show unprecedented long-term benefit in patients with advanced ALK-positive NSCLC. Patients without progression within 24 months on lorlatinib have a low risk of progression or death at year 7 and may continue long-term treatment. Findings suggest that sustained long-term disease control with first-line lorlatinib may enable advanced ALK-positive NSCLC to evolve toward a chronic condition.
de Azambuja E, Barrios CH, Bartsch R
… +13 more, Curigliano G, Dent R, Gennari A, Loi S, Paluch-Shimon S, Pistilli B, Saura C, Schmid P, Spanic T, Toi M, Tolaney SM, Harbeck N, ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org