The hottest studies at a glance

Every year, ESMO presents the most relevant research results of its congress within the framework of so-called Presidential Symposia. Also at this year’s virtual execution, the presentation of those studies that are likely to have the greatest impact on clinical action in the medium and long term was eagerly awaited.

Especially for the treatment of esophageal and gastric cancer, as well as prostate cancer and NSCLC, groundbreaking new findings were presented at this year’s ESMO Congress. But also in the field of breast and renal cell carcinomas, two studies of particular relevance made it into the Presidential Symposia.

Breast cancer: abemaciclib for high-risk patients

In an interim analysis of the open-label phase III MonarchE study [1], the CDK4/6 inhibitor abemaciclib in combination with endocrine therapy was clearly superior to endocrine treatment alone in terms of Invasive Disease-Free Survival (IDFS) . The compound, which has so far only been used in advanced breast cancer, was tested for adjuvant therapy of HR+, HER- patients with early stages of disease and special risk factors. The oral drug and the placebo, respectively, were taken by more than 5500 patients over 2 years. There was a resulting 25.3% risk reduction in invasive disease progression in the abemaciclib arm, with IDFS rates of 92.2% in the treatment group and 88.7% in the placebo arm at 2 years. Other endpoints such as Distant Relapse-Free Survival showed similarly promising results. Thus, for the high-risk patients among those who receive an early-stage breast cancer diagnosis, abemaciclib, as the first CDK4/6 inhibitor in the adjuvant setting, could significantly improve prognosis.

Personalized medicine in therapy of advanced prostate carcinoma.

For the first time, the phase III PROfound study [2] demonstrated an overall survival benefit for patients with metastatic castration-resistant prostate cancer (mCRPC) in the second-line setting by treatment with a PARP inhibitor. Until now, sequential enzalutamide or abiraterone therapy has been extremely limited for this patient population. In particular, in the presence of a BRCA1, BRCA2, or ATM mutation, the risk of death was significantly reduced by 31% with the administration of olaparib. The effect was seen despite a relevant crossover of approximately 66% from the control to the olaparib arm, further highlighting the potency of PARPi therapy in this context. The median follow-up was 21 months.

Relevant findings have also been made in first-line therapy of mCRPC. Thus, ipatasertib, an inhibitor of protein kinase B or AKT, was successfully used in the phase III randomized-controlled IPATential150 trial [3]. In combination with abiraterone in terms of dual pathway inhibition, namely of the androgen receptor and AKT pathways, the use of ipatasertib resulted in significantly improved PFS. This therapy was compared with the administration of abiraterone plus placebo. The observed significant benefit of a two-month prolonged PFS was limited to the subgroup of patients who had PTEN loss. The overall population also showed a corresponding trend, but this did not reach statistical significance. The additional side effects of ipatasertib should not be ignored.

These two new therapeutic approaches argue for increasing personalization of mCRPC treatment. In the future, therefore, genetic analysis could play an even greater role in this tumor as well.

NSCLC: New data on adjuvant radiotherapy, new agents, and metastatic patterns with osimertinib.

Critical data were presented on adjuvant radiotherapy for NSCLC with IIIAN2 status. In the large-scale, prospective LungART [4] study, the authors concluded that postoperative radiotherapy (PORT) offered no survival benefit. Although there was a trend toward longer disease-free survival (DFS) and less mediastinal progression in the group of patients receiving radiation, these effects were not reflected in overall survival . A discrepancy that may also be due to the toxicity of PORT. The bottom line is that these results challenge the common indication and are certainly also an indication of the high value of toxicity management in radiotherapy.

Two drug trials yielded more positive results. Thus, the randomized phase III CROWN trial [5] tested another ALK inhibitor for first-line treatment of advanced ALK-positive NSCLC. Compared to crizotinib, treatment with lorlatinib was observed to have a longer PFS and a higher response rate, among other benefits. Promising data, therefore, although the altered side effect spectrum with, for example, extreme weight gain, must not go unmentioned.

Further compelling data were presented for adjuvant TKI therapy in EGFR mutated NSCLC in stages IB to IIIA. A follow-up analysis of the ADAURA study [6], which had already demonstrated impressive DFS benefits with osimertinib therapy, now addressed the metastatic pattern after resection. In particular, CNS recurrences regressed under osimertinib therapy. After 12 months, only <1% of patients in the intervention group had CNS metastases, compared with 7% in the placebo group.

Combination of immunotherapy and multikinase inhibition in renal cell carcinoma.

Results of a new treatment approach for renal cell carcinoma, which is often frustrating from a therapeutic point of view, were also presented at ESMO 2020, raising faint hopes. The randomized phase III CheckMate-9ER trial [7] compared therapy with nivolumab and cabozantinib with current single-agent TKI therapy in the first-line treatment of advanced clear cell renal cell carcinoma. In addition to longer PFS and OS in the intervention group, a significantly higher response rate was also observed. These results suggest that a combination of the two agents, which are often used individually, could improve the prognosis in renal cell carcinoma in the future.

Immunotherapy – an option for esophageal and gastric cancer?

A full four studies addressed this question. The global CheckMate 649 [8] and Asian ATTRACTION-4 (ONO-4538-37) [9] trials evaluated the potential value of adding nivolumab therapy in first-line advanced HER2- gastric cancer. While the authors of the Asian study observed an improvement in PFS and response rate with nivolumab, but no statistically significant difference in OS was demonstrated, the authors of the CheckMate 649 study reported a clear advance in all three parameters in patients with PD-L1 expression. Thus, especially in PD-L1 expressing tumors, nivolumab appears to have a relevant clinical benefit in addition to chemotherapy. However, the ATTRACTION-4 study, which did not classify by PD-L1 status, suggests that the benefit may persist even without expression of the marker.

The phase III KEYNOTE-590 study [10], which is very similar in principle, addressed the additive use of pembrolizumab in advanced esophageal cancer. Compared with first-line chemotherapy alone, combination treatment with chemotherapy and pembrolizumab resulted in better PFS, longer OS, and a higher response rate. The effect was most impressive in squamous cell carcinoma with PD-L1 expression. In this subgroup in particular, therefore, a new standard of care is likely to have emerged.

Esophageal cancer was also the subject of the CheckMate-577 study [11]. The authors evaluated the adjuvant use of nivolumab after neoadjuvant radiochemotherapy and resection in patients with histologically residual tumor. With a significantly prolonged DFS compared to placebo, they were able to demonstrate for the first time a benefit of adjuvant therapy in this disease setting. While the median DFS in the control group was only 11 months, it was 22.4 months under treatment with nivolumab.

Source: ESMO 2020 Virtual

Literature:

Johnston SRD, et al: Abemaciclib in high risk early breast cancer. Annals of Oncology 2020; 31(suppl_4): 1142-1215.
de Bono JS, et al: Final overall survival (OS) analysis of PROfound: olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations. Annals of Oncology 2020; 31(suppl_4): 507-549.
de Bono JS, et al: IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). Annals of Oncology 2020; 31(suppl_4): 1142-1215.
Le Pechoux C, et al: An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement: primary end-point analysis of LungART (IFCT-0503, UK NCRI, SAKK) NCT00410683. Annals of Oncology 2020; 31(suppl_4): 1142-1215.
Solomon B, et al: Lorlatinib vs crizotinib in the first-line treatment of patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC): Results of the phase III CROWN study. Annals of Oncology 2020; 31(suppl_4): 1142-1215.
Tsuboi M, et al: Osimertinib adjuvant therapy in patients (pts) with resected EGFR mutated (EGFRm) NSCLC (ADAURA): central nervous system (CNS) disease recurrence. Annals of Oncology 2020; 31(suppl_4): 1142-1215.
Choueiri TK, et al: Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. Annals of Oncology 2020; 31(suppl_4): 1142-1215.
Moehler M, et al: Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study. Annals of Oncology 2020; 31(suppl_4): 1142-1215.
Boku N, et al: Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. Annals of Oncology 2020; 31(suppl_4): 1142-1215.
Kato K, et al: Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study. Annals of Oncology 2020; 31(suppl_4): 1142-1215.
Kelly RJ, et al: Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiation therapy (CRT): First results of the CheckMate 577 study. Annals of Oncology 2020; 31(suppl_4): 1142-1215.