Oncology

Large adjuvant RCT (>9,300 postmenopausal women with early breast cancer) comparing the aromatase inhibitor anastrozole, tamoxifen, or both. Anastrozole significantly prolonged disease-free survival versus tamoxifen in hormone-receptor–positive disease, with fewer contralateral cancers and fewer thromboembolic/endometrial events (more arthralgia and fractures). The combination offered no advantage over tamoxifen alone. Board takeaway: ATAC established aromatase inhibitors as preferred adjuvant endocrine therapy for postmenopausal HR-positive early breast cancer.

Baum M, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359(9324):2131-9. PMID 12090977 →

Phase 3 RCT in HER2-positive metastatic breast cancer comparing docetaxel + trastuzumab with or without pertuzumab. Adding pertuzumab (dual HER2 blockade) significantly improved progression-free survival and, in later follow-up, overall survival, without added cardiotoxicity. Board takeaway: dual HER2 blockade (pertuzumab + trastuzumab + taxane) is first-line standard of care for HER2-positive metastatic breast cancer.

Baselga J, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-19. PMID 22149875 →

Phase 3 RCT in HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane, comparing the antibody-drug conjugate T-DM1 (trastuzumab emtansine) with lapatinib + capecitabine. T-DM1 significantly improved progression-free and overall survival with less toxicity. Board takeaway: T-DM1 became the standard second-line option for HER2-positive metastatic disease and validated the antibody-drug conjugate strategy in breast cancer.

Verma S, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-91. PMID 23020162 →

Phase 3 RCT in postmenopausal HR-positive, HER2-negative advanced breast cancer comparing letrozole + ribociclib (a CDK4/6 inhibitor) versus letrozole + placebo. Adding ribociclib significantly prolonged progression-free survival; later follow-up showed an overall survival benefit. Board takeaway: CDK4/6 inhibitors added to endocrine therapy are first-line standard for HR-positive/HER2-negative metastatic breast cancer.

Hortobagyi GN, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016;375(18):1738-1748. PMID 27717303 →

Phase 3 RCT in early-stage triple-negative breast cancer adding pembrolizumab to neoadjuvant chemotherapy (then adjuvant pembrolizumab). The pembrolizumab arm significantly increased the pathologic complete response rate and improved event-free survival regardless of PD-L1 status. Board takeaway: neoadjuvant chemo-immunotherapy with pembrolizumab is standard for high-risk early TNBC.

Schmid P, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020;382(9):810-821. PMID 32101663 →

Phase 3 RCT of one year of adjuvant olaparib (a PARP inhibitor) versus placebo in high-risk, HER2-negative early breast cancer with germline BRCA1/2 mutations after completing local therapy and chemotherapy. Olaparib significantly improved invasive and distant disease-free survival, with a later overall survival benefit. Board takeaway: test for germline BRCA mutations; adjuvant olaparib is indicated for high-risk gBRCA-mutated HER2-negative early breast cancer.

Tutt ANJ, et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021;384(25):2394-2405. PMID 34081848 →

Phase 3 RCT in previously treated HER2-low (IHC 1+ or 2+/ISH-negative) metastatic breast cancer comparing the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) with physician's-choice chemotherapy. T-DXd significantly improved progression-free and overall survival. Board takeaway: "HER2-low" is now an actionable category; T-DXd carries a notable risk of interstitial lung disease/pneumonitis.

Modi S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20. PMID 35665782 →

Phase 3 RCT in East Asian never/light-smoker adenocarcinoma patients comparing first-line gefitinib (EGFR TKI) with carboplatin-paclitaxel. Benefit was driven by EGFR mutation status: mutation-positive patients did markedly better with gefitinib, while EGFR wild-type patients did better with chemotherapy. Board takeaway: IPASS established that EGFR-mutant NSCLC benefits from up-front EGFR TKI therapy and cemented biomarker-driven treatment selection.

Mok TS, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-57. PMID 19692680 →

Phase 3 RCT in untreated metastatic NSCLC with PD-L1 tumor proportion score ≥50% and no EGFR/ALK alterations, comparing first-line pembrolizumab with platinum chemotherapy. Pembrolizumab significantly improved progression-free and overall survival with fewer adverse events. Board takeaway: single-agent pembrolizumab is first-line standard for high-PD-L1 (≥50%) advanced NSCLC without a targetable driver.

Reck M, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-1833. PMID 27718847 →

Phase 3 RCT in unresectable stage III NSCLC without progression after concurrent chemoradiotherapy, comparing consolidation durvalumab (anti–PD-L1) with placebo. Durvalumab significantly prolonged progression-free survival (and later overall survival). Board takeaway: consolidation durvalumab is standard of care after chemoradiation for unresectable stage III NSCLC.

Antonia SJ, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919-1929. PMID 28885881 →

Phase 3 RCT in untreated EGFR-mutated (exon 19 del/L858R) advanced NSCLC comparing the third-generation EGFR TKI osimertinib with first-generation TKIs (gefitinib/erlotinib). Osimertinib significantly improved progression-free survival and, in the 2020 companion analysis, overall survival, with better CNS activity and tolerability. Board takeaway: osimertinib is the preferred first-line EGFR TKI for EGFR-mutant metastatic NSCLC.

Soria JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113-125. (OS results: Ramalingam SS, et al. N Engl J Med. 2020;382(1):41-50; PMID 31751012.) PMID 29151359 →

Phase 3 RCT in extensive-stage small-cell lung cancer adding atezolizumab (anti–PD-L1) to first-line carboplatin/etoposide. The immunotherapy arm significantly improved overall and progression-free survival. Board takeaway: chemo-immunotherapy (platinum/etoposide + a PD-L1 inhibitor) became first-line standard for extensive-stage SCLC — the first major advance in decades.

Horn L, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379(23):2220-2229. PMID 30280641 →

Phase 3 RCT of adjuvant osimertinib versus placebo in resected stage IB–IIIA EGFR-mutated NSCLC. Adjuvant osimertinib dramatically improved disease-free survival (with a large reduction in CNS recurrence); a later analysis showed an overall survival benefit. Board takeaway: adjuvant osimertinib is standard after complete resection of EGFR-mutant NSCLC — reinforcing molecular testing even in early-stage disease.

Wu YL, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383(18):1711-1723. PMID 32955177 →

Phase 3 RCT in resected stage II–III colon cancer comparing adjuvant FOLFOX (adding oxaliplatin to 5-FU/leucovorin) with 5-FU/leucovorin alone. FOLFOX significantly improved disease-free survival, with an overall survival benefit in stage III on longer follow-up (at the cost of oxaliplatin-related neuropathy). Board takeaway: MOSAIC established oxaliplatin-based FOLFOX as adjuvant standard for stage III colon cancer.

André T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343-51. PMID 15175436 →

Phase 3 RCT in HER2-positive advanced gastric/GEJ cancer comparing chemotherapy (fluoropyrimidine + cisplatin) with or without trastuzumab. Adding trastuzumab significantly improved overall survival. Board takeaway: test for HER2 in advanced gastric/GEJ cancer; trastuzumab + chemotherapy is first-line standard for HER2-positive disease.

Bang YJ, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA). Lancet. 2010;376(9742):687-97. PMID 20728210 →

Phase 3 RCT (PRODIGE 24/CCTG PA.6) in resected pancreatic ductal adenocarcinoma comparing adjuvant modified FOLFIRINOX with gemcitabine. mFOLFIRINOX significantly improved disease-free and overall survival (median OS ~54 vs ~35 months) in fit patients, with more toxicity. Board takeaway: adjuvant mFOLFIRINOX is preferred after resection for good-performance-status pancreatic cancer.

Conroy T, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018;379(25):2395-2406. PMID 30575490 →

Prospective pooled analysis of six trials testing 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy (FOLFOX/CAPOX) in stage III colon cancer. Non-inferiority of 3 months was not formally met overall, but 3 months was comparable in lower-risk disease (T1-3 N1) — especially with CAPOX — with substantially less neuropathy. Board takeaway: adjuvant duration can be risk-stratified; 3 months is reasonable for lower-risk stage III to limit neurotoxicity.

Grothey A, et al. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med. 2018;378(13):1177-1188. PMID 29590544 →

Phase 3 RCT in untreated MSI-high/dMMR metastatic colorectal cancer comparing first-line pembrolizumab with chemotherapy. Pembrolizumab roughly doubled progression-free survival with fewer treatment-related adverse events. Board takeaway: first-line pembrolizumab (checkpoint inhibitor) is standard for MSI-H/dMMR metastatic CRC — biomarker testing before treatment is essential.

André T, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020;383(23):2207-2218. PMID 33264544 →

Phase 3 RCT in unresectable hepatocellular carcinoma testing the STRIDE regimen (single priming dose of tremelimumab [anti–CTLA-4] plus durvalumab [anti–PD-L1]) versus sorafenib. STRIDE significantly improved overall survival versus sorafenib; durvalumab monotherapy was non-inferior. Board takeaway: dual immunotherapy (tremelimumab + durvalumab) is a first-line option for unresectable HCC.

Abou-Alfa GK, et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070. PMID 38319892 →

Phase 3 RCT in advanced/metastatic biliary tract cancer adding durvalumab (anti–PD-L1) to gemcitabine-cisplatin. The immunotherapy arm significantly improved overall survival with a manageable safety profile. Board takeaway: gemcitabine-cisplatin plus durvalumab is a first-line standard for advanced biliary tract cancer — the first major chemo-immunotherapy advance in this setting.

Oh DY, et al. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evid. 2022;1(8):EVIDoa2200015. PMID 38319896 →

Phase 3 RCT in metastatic hormone-sensitive prostate cancer comparing androgen-deprivation therapy (ADT) with or without early docetaxel. Adding docetaxel significantly improved overall survival, with the largest benefit in high-volume disease. Board takeaway: CHAARTED launched up-front treatment intensification — adding docetaxel to ADT — for metastatic castration-sensitive prostate cancer, especially high-volume disease.

Sweeney CJ, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-46. PMID 26244877 →

Phase 3 RCT in newly diagnosed high-risk metastatic castration-sensitive prostate cancer comparing ADT plus abiraterone-prednisone with ADT plus placebo. Adding abiraterone significantly improved overall survival and radiographic progression-free survival. Board takeaway: abiraterone is another effective up-front intensification partner to ADT for high-risk metastatic castration-sensitive prostate cancer.

Fizazi K, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360. PMID 28578607 →

Phase 3 RCT in previously untreated advanced clear-cell renal-cell carcinoma comparing dual immunotherapy (nivolumab + ipilimumab) with sunitinib. In intermediate/poor-risk patients, the immunotherapy combination significantly improved overall survival and response. Board takeaway: nivolumab + ipilimumab is a first-line standard for intermediate/poor-risk advanced RCC — moving the field from VEGF monotherapy to immunotherapy-based combinations.

Motzer RJ, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290. PMID 29562145 →

Phase 3 RCT in untreated advanced clear-cell RCC comparing pembrolizumab + axitinib (immunotherapy plus VEGF TKI) with sunitinib. The combination significantly improved overall survival, progression-free survival, and response across risk groups. Board takeaway: IO + TKI combinations (e.g., pembrolizumab + axitinib) are first-line standards for advanced RCC.

Rini BI, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127. PMID 30779529 →

Phase 3 RCT in metastatic castration-resistant prostate cancer with homologous-recombination-repair (HRR) gene alterations, comparing the PARP inhibitor olaparib with enzalutamide or abiraterone after prior therapy. Olaparib improved imaging-based progression-free survival and overall survival, with the greatest benefit in BRCA1/2/ATM-altered tumors. Board takeaway: test for HRR mutations in mCRPC; olaparib is indicated for HRR-mutated (especially BRCA) disease.

de Bono J, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091-2102. PMID 32343890 →

Phase 3 RCT in advanced/metastatic urothelial carcinoma without progression after first-line platinum chemotherapy, comparing maintenance avelumab (anti–PD-L1) plus best supportive care with best supportive care alone. Maintenance avelumab significantly improved overall survival. Board takeaway: switch-maintenance avelumab is standard after response/stability on first-line platinum chemotherapy for advanced urothelial cancer.

Powles T, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383(13):1218-1230. PMID 32945632 →

Phase 3 RCT (EV-302/KEYNOTE-A39) in untreated locally advanced/metastatic urothelial carcinoma comparing enfortumab vedotin (a Nectin-4 antibody-drug conjugate) + pembrolizumab with platinum-based chemotherapy. The combination nearly doubled progression-free and overall survival. Board takeaway: enfortumab vedotin + pembrolizumab displaced platinum chemotherapy as first-line standard for advanced urothelial cancer.

Powles T, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390(10):875-888. (Presented ESMO 2023.) PMID 38446675 →

Prospective biomarker analysis of the multi-cohort phase 2 KEYNOTE-158 basket study evaluating pembrolizumab across advanced solid tumors. Patients with high tissue tumor mutational burden (TMB ≥10 mutations/Mb) had markedly higher objective response rates, supporting tissue-agnostic activity of pembrolizumab in TMB-high tumors. Board takeaway: TMB-high is a tissue-agnostic biomarker for pembrolizumab (alongside MSI-H/dMMR) — this helped establish biomarker-first, tissue-agnostic immunotherapy selection in selected previously treated advanced cancers. (A companion KEYNOTE-158 report, Marabelle et al. J Clin Oncol 2020;38:1-10 [PMID 31682550], addressed MSI-H/dMMR tumors.)

Marabelle A, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-1365. PMID 32919526 →

Pooled analysis of three phase 1/2 trials of the TRK inhibitor larotrectinib in adults and children with NTRK gene fusion–positive solid tumors spanning many histologies. High, durable objective response rates were seen regardless of tumor type. Board takeaway: NTRK-fusion cancers respond to TRK-targeted therapy tissue-agnostically — an example of biomarker-defined precision oncology. (The original registrational report: Drilon A, et al. N Engl J Med 2018;378:731-739 [PMID 29466156].)

Hong DS, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540. PMID 32105622 →