GUEST EDITORS
Lorenza Rimassa, MD
Matteo Simonelli, MD
The European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona featured several groundbreaking trials with the potential to significantly influence clinical practice. These studies highlighted the benefits of new combination immunotherapy strategies and innovative approaches in the treatment of solid tumors, including breast cancer (BC), small cell lung cancer (SCLC), hepatocellular carcinoma (HCC), gastrointestinal (GI) and genitourinary (GU) cancers, and melanoma. Here we highlight key abstracts from the congress and provide the most important takeaways and insights.
Breast Cancer: Incorporating New Strategies
Investigation of combination strategies with TROP2-targeting antibody-drug conjugate (ADC) in the management of early BC represents an exciting field of clinical research. Meghna S. Trivedi, MD, MS, presented results of the I-SPY2.2 trial, an adaptive phase II, multiple-assignment randomization trial, exploring a neoadjuvant strategy with datopotamab deruxtecan (Dato-DXd) plus durvalumab followed by chemotherapy when appropriate for high-risk early-stage BC of various subtypes.1 The highest pathologic complete response (pCR) rate (79%) was observed in the immune+ subtype, where > 50% of pCRs were achieved without standard chemotherapy and > 90% without the need of anthracycline. In the historical difficult-to-treat “all-negative” subtype (HR–/immune–/DRD–), the modeled pCR rate significantly outperformed the dynamic control (44% vs 16%), therefore graduating the strategy to be further explored in larger studies.
Hypofractionated radiotherapy has already become the standard for breast-alone irradiation, although this is not the case for nodal irradiation due to concerns about potential increased toxicity. At Presidential Symposium II, Sofia Rivera, MD, PhD, presented results of the randomized phase III HypoG-01 trial, comparing a moderately hypofractionated 3-week radiotherapy regimen (40 Gy/15 fractions) over standard fractionated 5-week radiotherapy (50 Gy/25 fractions) in patients with T1–3, N0–3, M0 BC requiring nodal irradiation.2 The primary endpoint of the trial was met, with a 5-year cumulative incidence of arm lymphedema of approximately 33% in both arms. No detrimental effects with hypofractionated regimen were observed in survival outcomes, shoulder motion, or safety profile. Results of the HypoG-01 study, along with data from the parallel Skagen 1 trial,3 are set to change the standard of care for patients with early BC requiring nodal irradiation.
The KEYNOTE-522 is a prospective phase III study in patients with high-risk, early-stage triple-negative breast cancer (TNBC) who were randomly assigned to receive neoadjuvant treatment with
pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo.4,5 KEYNOTE-522 already met its dual primary endpoints of increasing pCR (P < .001) and improving event-free survival, becoming the new standard of care in this setting worldwide. At Presidential Symposium II, Peter Schmid, MD, PhD, presented the results of the key secondary overall survival endpoint and updated event-free survival data after a 75.1-month median follow up.6 The 5-year overall survival analysis demonstrated a statistically significant and meaningful benefit of 5% in favor of the experimental arm. The overall survival benefit was consistent in all prespecified subgroups and was observed independently of pCR outcome. Results of this trial strongly reinforce neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as the standard regimen for patients with high-risk, early-stage TNBC.
Understanding the central nervous system (CNS) activity of novel ADCs is crucial to better define the treatment algorithm for patients with BC with brain metastases. DESTINY-Breast12 is a multicenter phase IIIb/IV, open-label, single-arm, two-cohort study of trastuzumab deruxtecan (T-DXd) in patients with previously treated HER2-positive metastatic BC with and without brain metastases, representing the largest prospective study of T-DXd in patients with brain metastases so far.7 Of 504 patients enrolled in the study, 263 had brain metastases, of which 157 were considered stable and 106 active. T-DXd showed substantial and durable intracranial clinical activity, with overall CNS response rate of 71.7% (79.2% in stable brain metastases and 62.3% in active brain metastases). The 12-month survival rates were 90.6% for patients without brain metastases and 90.3% for those with brain metastases. Results of DESTINY-Breast12 strongly support the use of T-DXd for patients with HER2-positive metastatic BC, irrespective of the presence of brain metastases.
Limited-Stage SCLC: Immunotherapy as a New Standard of Care
After no major progress in the treatment of limited-stage SCLC in the past decades, the phase III ADRIATIC trial established consolidation immunotherapy as the new standard of care.8 A previously presented interim analysis showed significant improvements in overall survival and progression-free survival with durvalumab vs placebo consolidation in patients with limited-stage SCLC without disease progression after chemoradiotherapy.9 Suresh Senan, MRCP, FRCR, PhD, reported a new subgroup analysis showing consistent benefits across subgroups supporting the use of durvalumab, regardless of prior chemotherapy regimen, radiotherapy schedule, and prophylactic cranial irradiation. Quite unexpectedly, better outcomes were observed in the carboplatin group compared with the cisplatin group. These findings finally establish a new global standard of care for patients with limited-stage SCLC.
HCC: Immunotherapy in Advanced and Intermediate Stages
Immunotherapy is the first-line standard of care for patients with advanced/unresectable HCC. In the phase III HIMALAYA study, the combination of a single priming dose of tremelimumab followed by durvalumab (STRIDE) significantly improved overall survival compared with sorafenib10 and demonstrated durable long-term survival in the 4-year follow-up analysis.11 In the 5-year updated analysis we (LR) presented, STRIDE confirmed the overall survival benefit vs sorafenib, with an unprecedented 5-year overall survival rate of 19.6% vs 9.4% with sorafenib, and an overall survival benefit for STRIDE vs sorafenib increasing over time. Also, the overall survival benefit was enhanced in patients with disease control, and the manageable safety profile was maintained, further strengthening the role of STRIDE in the first-line setting.12
For patients with intermediate-stage HCC, the standard of care is represented by locoregional therapy, although some patients do not benefit from the treatment. Recently, the phase III EMERALD-1 study showed a progression-free survival benefit with transarterial chemoembolization (TACE), durvalumab, and bevacizumab compared with TACE alone (15.0 vs 8.2 months).13 In this scenario, as reported by Josep Llovet, MD, PhD, the LEAP-012 phase III study tested the combination of TACE, lenvatinib, and pembrolizumab vs TACE and showed a significantly improved progression-free survival with the combination.14 With the combination of TACE and systemic therapy, there was a higher response rate, up to 71.3%, with 56.1% complete responses, and a trend in overall survival, although data are not mature. Based on these data, TACE combined with immunotherapy combinations may become a new therapeutic option for patients with intermediate HCC, potentially improving their prognosis.
GI Cancer: Combination Therapy
In the phase III KEYNOTE-811 trial, a statistically significant progression-free survival benefit was shown adding pembrolizumab to trastuzumab and chemotherapy in patients with treatment-naive, unresectable, HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma,15 and these findings led to the approval of the combination. Sara Lonardi, MD, reported the final per-protocol analysis that demonstrated a statistically significant overall survival benefit, with a median overall survival of 20.0 months vs 16.8, and a 36-month overall survival rate of 28% vs 23%.16 Of note, patients with PD-L1 expression (combined positive score [CPS] ≥ 1) had similar benefit as the overall population. However, no benefit from the addition of immunotherapy was shown in the group of patients with a PD-L1 CPS < 1, but this result was likely affected by the small sample size. Of note, the safety profile remained unchanged at the final analysis. These findings further strength the role of pembrolizumab combined with trastuzumab and chemotherapy as first-line standard of care for patients with PD-L1–positive advanced HER2-positive gastric or GEJ adenocarcinoma.
GU Cancer: New Therapies for Prostate Cancer
After previous disappointing results (negative data from the ERA-223 study17), ESMO Congress 2024 finally represented a moment of peace between theranostics and prostate cancer. In the phase III PEACE-3/EORTC 1333 trial, Silke Gillessen, MD, explored the combination of six cycles of radium-223 plus enzalutamide vs enzalutamide alone as first-line therapy for 446 patients with metastatic castration-resistant prostate cancer and bone metastases.18 Main findings of the study were a risk reduction of 31% in radiological progression–free survival, a clinically meaningful improvement in overall survival, and a significant improvement in time to next systemic therapy. These results support the combination of enzalutamide and radium-223 as a potential new first-line treatment option for patients with metastatic castration-resistant prostate cancer and bone metastases.
Neoadjuvant Treatment of Melanoma: Confirmation for Immunotherapy
Neoadjuvant therapy is the standard of care for patients with resectable stage III melanoma. Updated results from the phase III NADINA trial19 and the International Neoadjuvant Melanoma Consortium (INMC) were presented this year, showing the long-term benefit of this strategy, strengthening its role as the current standard of care, and reinforcing pCR as the best predictor of outcomes. Minke Lucas, MD, reported the updated analysis of the NADINA trial, showing an 18-month event-free survival of 80.8% in the neoadjuvant arm vs 53.9% in the control arm, and a distant metastasis–free survival of 85.7% vs 62.4%.20 Of note, most of the patients in the neoadjuvant arm had a pCR or near-complete response.
In the update of the INMC, presented by Georgina V. Long, PhD, MBBS, combination checkpoint inhibition achieved the highest rates of major pCR (58%–67%), relapse-free survival, and event-free survival (78% at 3 years), whereas no benefit was observed for BRAF/MEK inhibition.21 Magnitude of response was confirmed as a predictor of event-free survival, with a 3-year overall survival rate of approximately 90% for patients with pCR or near-complete response. Based on these findings, neoadjuvant immunotherapy should be a new standard of care in this setting.
DISCLOSURE: Dr. Rimassa has received honoraria (lecture fees) from AstraZeneca, Bayer, BMS Guerbet, Incyte, Ipsen, Roche, and Servier; has served as a consultant or advisor to AbbVie, AstraZeneca, Basilea, Bayer, BMS, Eisai, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medial Sciences, Roche, Servier, Taiho Oncology, and Zymeworks; has received institutional research funding from AbbVie, Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Jazz Pharmaceuticals, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, TransThera Sciences, and Zymeworks; and has been reimbursed for travel and accommodations for congresses from AstraZeneca. Dr. Simonelli reported no conflicts of interest.
REFERENCES
1. Trivedi MS, et al: ESMO Congress 2024. Abstract LBA15. Presented September 14, 2024.
2. Rivera S, et al: ESMO Congress 2024. Abstract 231O. Presented September 15, 2024.
3. Thorsen LBJ, et al: ESTRO Congress 2022. Abstract PD-0740. Presented May 9, 2022.
4. Schmid P, et al: N Engl J Med 382:810-821, 2020.
5. Schmid P, et al: N Engl J Med 386:556-567, 2022.
6. Schmid P, et al: ESMO Congress 2024. Abstract LBA4. Presented September 15, 2024.
7. Lin N, et al: ESMO Congress 2024. Abstract LBA18. Presented September 13, 2024.
8. Senan S, et al: ESMO Congress 2024. Abstract LBA81. Presented September 13, 2024.
9. Spigel DR, et al: 2024 ASCO Annual Meeting. Abstract LBA5. Presented June 2, 2024.
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11. Sangro B, et al: Ann Oncol 35:448-457, 2024.
12. Rimassa L, et al: ESMO Congress 2024. Abstract 947MO. Presented September 16, 2024.
13. Lencioni R, et al: 2024 ASCO GI Annual Meeting. Abstract LBA432. Presented January 19, 2024.
14. Llovet JM, et al: ESMO Congress 2024. Abstract LBA3. Presented September 14, 2024.
15. Janjigian YY, et al: Lancet 402:2197-2208, 2023.
16. Janjigian YY, et al: ESMO Congress 2024. Abstract 1400O. Presented September 14, 2024.
17. Smith M, et al: Lancet Oncol 20:408-419, 2019.
18. Gillessen, S, et al: ESMO Congress 2024. Abstract LBA1. Presented September 14, 2024.
19. Blank CU, et al: N Engl J Med 391:1696-1708, 2024.
20. Lucas MW, et al: ESMO Congress 2024. Abstract LBA42. Presented September 14, 2024.
21. Long GV, et al: ESMO Congress 2024. Abstract LBA41. Presented September 14, 2024.
