The European Society for Medical Oncology (ESMO) Congress 2023 held in Madrid reported out several eagerly awaited and potentially practice-changing trials, bringing forward promising new combination strategies in the targeted and immunotherapy space, and put to the test selective agents against standard-of-care chemotherapy in solid tumors. This year’s Congress was an especially exciting meeting for non–small cell lung cancers (NSCLC) and genitourinary cancers, where several practice-changing trials were presented. We highlight here some of the featured abstracts from ESMO, providing key takeaways and lessons learned.

GUEST EDITORS

So Yeon Kim, MD

Roy Herbst, MD, PhD

Dr. Kim is Assistant Professor of Medicine at Yale School of Medicine and a medical oncologist in the thoracic oncology program and developmental therapeutics program at Yale Cancer Center. Her research interests include targeted treatment and immunotherapy approaches in lung cancer. Dr. Herbst is Ensign Professor of Medicine (Medical Oncology), Deputy Director, and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital; and Assistant Dean for Translational Research at Yale School of Medicine. He is nationally recognized for his leadership and expertise in lung cancer treatment and research and is best known for his work in developmental therapeutics and the personalized therapy of non–small cell lung cancer.

NSCLC: Continued Progress in Targeted Therapy

Since the approval of osimertinib for first-line advanced EGFR-mutant NSCLC in 2018 based on the FLAURA trial,¹ osimertinib has been the leading first-line treatment option in patients with advanced NSCLC with EGFR exon-19 deletion (EGFRex19) and exon 21 L858R (L858R) mutations. The results of the phase III MARIPOSA trial brought forward an alternate contender in the front-line setting, in which the combination of amivantamab-vmjw and lazertinib led to a median progression-free survival improvement of 7.1 months compared to osimertinib in patients with EGFRex19/L858R mutations (hazard ratio [HR] = 0.70, P < .001).² This is the second phase III trial after FLAURA2,³ presented at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer, to report clinically meaningful progression-free survival improvement with combination osimertinib strategies in the first line for advanced EGFRex19/L858R NSCLC. Whether MARIPOSA or FLAURA2 will supplant osimertinib in advanced EGFRex19/L858R NSCLC will largely depend on overall survival outcomes and the impact on quality of life or toxicity associated with added infusional therapy (including infusional reactions and increased incidence of venous thromboembolism observed with amivantamab and lazertinib² and myelosuppression with chemotherapy and osimertinib³). Despite prior disappointments with the addition of a vascular endothelial growth factor receptor (VEGF) antagonist to osimertinib,⁴ the phase II RAMOSE trial demonstrated a progression-free survival benefit with the addition of ramucirumab, a VEGFR2 antagonist, to osimertinib,⁵ and is another eagerly awaited—potentially more tolerable—combination strategy pending further evaluation in a larger phase III trial.

Amivantamab also demonstrated clinical benefit in advanced EGFRex19/L858R NSCLC after disease progression on osimertinib (MARIPOSA-2)⁶ and in treatment-naive patients with advanced EGFR exon20 insertions (PAPILLON).⁷ Both phase III trials demonstrated a progression-free survival improvement with the addition of amivantamab to chemotherapy (MARIPOSA-2: 6.3 vs 4.2 months, HR = 0.48, P < .001⁶; PAPILLON: 11.4 vs 6.7 months, HR = 0.40, P < .001⁷). An intriguing observation was the improvement in central nervous system (CNS) progression-free survival with combination amivantamab and chemotherapy compared to chemotherapy in MARIPOSA-2,⁶ an unexpected finding based upon the poor CNS activity anticipated with amivantamab due to its large molecular size. The role of bispecific antibodies in the treatment or prevention of CNS metastases remains to be further evaluated.

Three years after the approval of adjuvant osimertinib in stage IB to IIIA EGFRex19/L858R mutant NSCLC (AJCC 7th edition) based on ADAURA,⁸ the phase III ALINA trial demonstrated meaningful disease-free survival benefit of adjuvant alectinib when administered for 2 years compared to adjuvant chemotherapy in resectable stage IB to IIIA (AJCC 7th edition) ALK fusion–positive NSCLC (3-year disease-free survival for stage II–IIIA: 88.3% for alectinib, 53.3% for chemotherapy).⁹ In contrast to ADAURA, patients on the alectinib arm did not have the option to receive adjuvant chemotherapy, and the role chemotherapy may play for these individuals with ALK fusion–positive resectable NSCLC remains unknown.^8,9 With two randomized trials now demonstrating clinically meaningful disease-free survival benefit with adjuvant targeted therapies, biomarker testing—especially for EGFR and ALK—becomes an integral aspect of clinical care in all stages.

In the nontargetable resectable space, the phase III CheckMate 77T trial again demonstrated the clinical benefit of perioperative chemoimmunotherapy compared to chemotherapy alone based on positive outcomes with neoadjuvant nivolumab and chemotherapy followed by 1 year of nivolumab in resectable stage IIA to IIIB NSCLC.¹⁰ Biomarkers that may identify patients who would benefit from additional adjuvant immunotherapy compared to neoadjuvant therapy alone will be key in minimizing unwanted immunotherapy toxicity.

This year’s ESMO Congress also reported an encouraging combination treatment strategy for advanced KRAS G12C–mutant NSCLC. The phase II KRYSTAL-7 trial demonstrated clinically meaningful antitumor activity with combination adagrasib and pembrolizumab, with an overall response rate of 63% in patients with PD-L1 ≥ 50%¹¹. The majority of liver toxicity was low grade, with most resolving with steroids. How this combination compares against immunotherapy monotherapy in advanced NSCLC with PD-L1 ≥ 50%, as well as the efficacy of the combination in patients with PD-L1 < 50%, will be of interest.

Despite the early encouraging data with TROP-2–targeting antibody-drug conjugates, the phase III TROPION-Lung01 evaluating datopotamab deruxtecan (Dato-DXd) compared with docetaxel, while a positive trial, was relatively disappointing with a median improvement in progression-free survival by a mere 0.7 months vs docetaxel (4.4 vs 3.7 months, HR = 0.75, P = .004).¹² While the progression-free survival benefit was marginal, TROPION-Lung01 highlighted Dato-DXd as a potentially less myelosuppressive option compared to docetaxel. Of note, however, was the observation of numerically higher grade 5 treatment-related interstitial lung disease (ILD),¹² which prompts cautionary use of Dato-Dxd in patients with poor lung reserve.

Genitourinary Cancers: Immunotherapy Combinations as New Front-Line Therapy

EV-302/KEYNOTE-A39 and CheckMate 901 were groundbreaking trials that established the role of immunotherapy in the front-line treatment for advanced urothelial cancers. In the phase III EV-302/KEYNOTE-A39 trial, combination enfortumab vedotin-ejfv, an antibody-drug conjugate targeting nectin-4, and pembrolizumab demonstrated a nearing doubling of overall survival compared to platinum doublet chemotherapy alone (31.5 vs 16.1 months, HR = 0.47, P < .00001), regardless of PD-L1 and platinum eligibility, without a compromise in toxicity.¹³ In the phase III CheckMate 901 trial, the addition of immunotherapy (nivolumab) to platinum doublet chemotherapy resulted in a clinically meaningful improvement in overall survival compared to chemotherapy alone (HR = 0.78, P = .02).¹⁴ Both EV-302/KEYNOTE-A39 and CheckMate 901 set a new standard of care in the treatment of advanced urothelial carcinoma and are practice-changing treatment options in the front-line setting.

RET-Mutant Cancers: RET Selection Is Key in Treatment for RET-Mutant Solid Tumors

The phase III LIBRETTO-531 and LIBRETTO-431 established selpercatinib, a RET-selective tyrosine kinase inhibitor, as the preferred treatment for RET-mutant medullary thyroid carcinoma and RET fusion–positive advanced NSCLC, respectively. Selpercatinib not only demonstrated a clinically significant improvement in progression-free survival compared to the standard-of-care multikinase inhibitors cabozantinib or vandetinib in RET-mutant medullary thyroid carcinoma (not reached vs 16.8 months, HR = 0.28, P < .001), but it was also better tolerated, with 4.7% treatment discontinuation with selpercatinib compared to 26.8% treatment discontinuation with cabozantinib or vandetinib.¹⁵ As expected, selpercatinib also demonstrated improved progression-free survival and CNS response rate compared to chemotherapy with or without immunotherapy in RET fusion–positive advanced NSCLC, confirming the RET-selective inhibitor as the preferred treatment option in advanced RET fusion–positive advanced NSCLC.¹⁶

GI Cancers: Combination Strategies in Metastatic and Resectable Disease

In contrast to advanced KRAS G12C–mutant NSCLC, KRAS G12C inhibition in KRAS G12C–mutant colorectal cancer has demonstrated only marginal response rates of 10% due to the feedback reactivation of EGFR signaling in colorectal cancer with KRAS inhibition.¹⁷ The phase III CodeBreaK 300 trial evaluated the strategy of combining EGFR-directed therapy with KRAS G12C inhibition and demonstrated an improvement in progression-free survival with combination sotorasib (960 mg, 240 mg) and panitumumab against trifluridine/tipiracil or regorafenib in chemotherapy-refractory advanced KRAS G12C–mutant colorectal cancer.¹⁸ While progression-free survival data were encouraging, the Kaplan-Meier overall survival curves were largely overlapping, and how the difference in overall survival with the combination strategy will play out as data mature will be of interest.

The evaluation of the role for perioperative immunotherapy in solid tumors was expanded to gastric and gastroesophageal junction (GEJ) adenocarcinomas through the MATTERHORN study. In this phase III study, the addition of durvalumab to perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) demonstrated an improvement in pathologic complete response compared to placebo and FLOT in stage II to IVA gastric and GEJ adenocarcinomas (pathologic complete response: 19% vs 7%, odds ratio = 3.08, P < .00001).¹⁹ Whether this improvement in pathologic complete response translates into improvement in event-free survival or overall survival in gastric/GEJ adenocarcinomas will be especially important in this patient population where surgical morbidity may significantly impact quality of life.

Breast Cancer: Continued Role of TROP-2–Targeting Antibody-Drug Conjugate

Finally, progression-free survival data on Dato-DXd in patients with metastatic hormone receptor–positive breast cancer who have experienced disease progression after one to two lines of chemotherapy were presented in the phase III TROPION-Breast01 trial. Dato-DXd demonstrated a 2-month progression-free survival improvement over chemotherapy (HR = 0.63, P < .001).²⁰ While survival outcomes remain immature, TROPION-Breast01 provides oncologists with a second TROP-2–targeting antibody-drug conjugate for the treatment of metastatic hormone receptor–positive breast cancers in addition to sacituzumab govitecan-hziy. Though still in its early stages, combination strategies with TROP-2–targeting antibody-drug conjugates also remain a potentially exciting therapeutic strategy, especially in the front-line treatment of metastatic triple-negative breast cancer. Indeed, the phase I/II BEGONIA trial demonstrated an impressive overall response rate of 79% and median progression-free survival of 13.8 months with combination Dato-DXd and durvalumab.²¹

In summary, ESMO Congress 2023 highlighted several practice-changing phase III trials in the targeted space, bringing forward precision medicine to not only advanced stage, but also to early-stage disease. Immunotherapy continues to play an integral role in resectable disease, and early biomarker screening remains key in treatment selection. This year’s Congress again magnifies the importance of biomarker development in identifying patients who would most benefit from targeted therapies and immunotherapy in all stages while minimizing potential treatment toxicity. 

DISCLOSURE: Dr. Kim has served as a consultant or advisor for Amgen. Dr. Herbst has held a leadership role with the American Association for Cancer Research, Immunocore, International Association for the Study of Lung Cancer, Jun Shi Pharmaceuticals, Society for Immunotherapy of Cancer, and the Southwest Oncology Group; owns stock with Bolt Biotherapeutics, Checkpoint Therapeutics, Immunocore, and Normunity; has served as a consultant or advisor for AbbVie, AstraZeneca, Bolt Biotherapeutics, Bristol-Myers Squibb, Candel Therapeutics, Inc., Checkpoint Therapeutics, Cybrexa Therapeutics, DynamiCure Biotechnology, LLC, eFFECTOR Therapeutics, Inc., EMD Serono, Genentech/Roche, Gilead/Forty Seven, HiberCell, Inc., IMAB Biopharma, Immune-Onc Therapeutics, Inc., Janssen, Johnson and Johnson, Jun Shi Pharmaceuticals, Lilly, Loxo, Merck, Mirati Therapeutics, NextCure, Normunity, Novartis, Ocean Biomedical, Inc., Oncocyte Corp, Oncternal Therapeutics, Pfizer, Refactor Health, Inc., Regeneron, Revelar, Ribbon Therapeutics, Sanofi, Seattle Genetics, and Xencor, Inc; has received research funding from AstraZeneca, Genentech/Roche, Lilly, and Merck; and has received travel expenses from the American Cancer Society, IASLC, and SWOG.

REFERENCES

1. Soria J-C, Ohe Y, Vansteenkiste J, et al: Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med 378:113-125, 2017.

2. Cho BC, Felip E, Spira AI, et al: Amvantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer: Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. ESMO Congress 2023. Abstract LBA14. Presented October 23, 2023.

3.  Jänne P, Planchard D, Cheng, et al: Osimertinib with/without platinum-based chemotherapy as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA2). 2023 World Conference on Lung Cancer. Abstract PL03.13. Presented September 11, 2023.

4. Kenmotsu H, Wakuda K, Mori K, et al: Randomized phase 2 study of osimertinib plus bevacizumab versus osimertinib for untreated patients with nonsquamous NSCLC harboring EGFR mutations: WJOG9717L study. J Thorac Oncol 17:1098-1108, 2022.

5. Le X, Patel J, Shum E, et al: A multi-centre open-label randomized phase II study of osimertinib with and without ramucirumab in TKI-naive EGFR-mutant metastatic NSCLC (RAMOSE trial interim analysis). ESMO Congress 2023. Abstract LBA71. Presented October 21, 2023.

6. Passaro A, Cho BC, Wang Y, et al: Amivantamab plus chemotherapy (with or without lazertinib) vs chemotherapy in EGFR-mutated advanced NSCLC after progression on osimertinib: MARIPOSA-2, a phase III, global, randomized, controlled trial. ESMO Congress 2023. Abstract LBA15. Presented October 23, 2023.

7. Zhou C, Tang K-J, Cho BC, et al: Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl J Med. October 21, 2023 (early release online).

8. Tsuboi M, Herbst RS, John T, et al: Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med 389:137-147, 2023.

9.  Solomon BJ, Ahn JS, Dziadziuszko R, et al: Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer. ESMO Congress 2023. Abstract LBA2. Presented October 21, 2023.

10. Cascone T, Awad M, Spicer J, et al: CheckMate 77T: Phase III study comparing neoadjuvant nivolumab plus chemotherapy vs neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab or placebo for previously untreated, resectable stage II-IIIb NSCLC. ESMO Congress 2023. Abstract LBA1. Presented October 21, 2023.

11. Garassino MC, Theelen WSME, Jotte R, et al: KRYSTAL-7: Efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naive, advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. ESMO Congress 2023. Abstract LBA65. Presented October 20, 2023.

12. Ahn M, Lisberg AE, Paz-Ares L, et al: Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic non-small cell lung cancer: Results of the randomized phase III study TROPION-Lung01. ESMO Congress 2023. Abstract LBA12. Presented October 23, 2023.

13. Powles T, Perez-Valderrama B, Gupta S, et al: EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab vs chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma. ESMO Congress 2023. Abstract LBA6. Presented October 22, 2023.

14. van der Heijden MS, Sonpavde G, Powles T, et al: Nivolumab plus gemcitabine–cisplatin in advanced urothelial carcinoma. N Engl J Med 389:1778-1789, 2023.

15. Hadoux J, Elisei R, Brose MS, et al: Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med. October 21, 2023 (early release online).

16. Loong HHF, Goto K, Solomon BJ, et al: Randomized phase III study of first-line selpercatinib versus chemotherapy and pembrolizumab in RET fusion-positive NSCLC. ESMO Congress 2023. Abstract LBA4. Presented October 21, 2023.

17. Fakih MG, Kopetz S, Kuboki Y, et al: Sotorasib for previously treated colorectal cancers with KRAS(G12C) mutation (CodeBreaK100): A prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol 23:115-124, 2022.

18. Fakih MG, Salvatore L, Esaki T, et al: Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl Med. October 22, 2023 (early release online).

19. Janjigian YY, Al-Batran SE, Wainberg ZA, et al: Pathological complete response to durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel in resectable gastric and gastroesophageal junction cancer: Interim results of the global, phase III MATTERHORN study. ESMO Congress 2023. Abstract LBA73. Presented October 20, 2023.

20. Bardia A, Jhaveri K, Im SA, et al: Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Primary results from the randomised phase III TROPION-Breast01 trial. ESMO Congress 2023. Abstract LBA11. Presented October 23, 2023.

21. Schmid P, Wysocki PJ, Ma CX, et al: Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): Updated results from BEGONIA, a phase Ib/II study. ESMO Congress 2023. Abstract 379M0. Presented October 22, 2023.