The most important studies at a glance

As usual, at this year’s Congress of the European Society for Medical Oncology (ESMO), those studies with the greatest impact on daily practice were presented in three so-called Presidential Symposia. We have taken a close look at the eleven works presented and summarized them for you – in a nutshell.

In addition to four Phase III studies on checkpoint inhibitors in cervical carcinoma, melanoma, non-small cell lung cancer (NSCLC) and adenocarcinoma of the stomach, two studies each on the use of abiraterone in prostate carcinoma and on COVID-19 immunity in cancer patients were also presented at this year’s ESMO Congress as Practice Changing classified (Tab.1). In addition, the two agents trastuzumab deruxtecan (T-DXd) and adagrasib, which have not yet been approved in Switzerland, were characterized in more detail – with promising results in HER2+ breast carcinoma and colorectal carcinoma. As an absolute rarity, pheochromocytoma made it into the third Presidential Symposium: for the first time, the efficacy of systemic therapy of advanced cases was confirmed.

Immunotherapy on the rise

The assessment of no less than four checkpoint inhibitor studies as highly clinically relevant continues the trend of recent years. Pembrolizumab, atezolizumab, and co. are moving into earlier and earlier lines of treatment for a wide variety of entities. A clear PFS and OS benefit was achieved in the Keynote 826 trial by adding pembrolizumab to chemotherapy in first-line treatment of persistent, recurrent, or metastatic cervical cancer, independent of PD-L1 expression [1]. The addition of nivolumab to chemotherapy in first-line advanced or metastatic adenocarcinoma of the stomach, gastroesophageal junction, and esophagus has shown similar promise [2]. Dual immunotherapy using nivolumab plus ipilimumab did not prevail over standard chemotherapy in this setting. At most, this appears to provide clinical benefit in tumors with high microsatellite instability (MSI-H) – with significantly increased toxicity.

Adjuvant use of pembrolizumab in stage II malignant melanoma was also discussed at the Presidential Symposia [3]. This is already approved today in stage III and has now been tested in less advanced tumors [4]. Although a 35% reduction in the relative risk of relapse was shown in high-risk stage IIB and IIC patients, a careful risk-benefit assessment must be performed. In particular, the toxicity of anti-PD-L1 therapy must be considered, since curative options now exist for stages III and IV. To prevent relapse, according to the current data, 14 patients must be treated adjuvantly with pembrolizumab in stage II, of whom approximately one in six develops grade 3 or 4 adverse drug reactions. Whether, in view of these circumstances, an extension of approval will follow remains to be seen.

In contrast, the starting position in the adjuvant situation is clearer in stage IB to IIIA NSCLC – at least with high PD-L1 expression. Here, the administration of atezolizumab after adjuvant chemotherapy appears to be clearly superior to placebo, even when the potential side effects are included [5]. Sequential therapy using adjuvant chemotherapy and immunotherapy after surgery may soon change clinical practice and hopefully prognosis, as currently about 60% of stage I-III NSCLC patients relapse. If, as expected, approval is limited to cases with PD-L1 expression ≥50%, approximately 12% of NSCLC patients undergoing surgery could benefit from the new therapy.

New standards in prostate cancer

At this year’s ESMO Congress, abiraterone was the clear focus of attention in prostate cancer. On the one hand, this was tested in the treatment of high-risk non-metastatic prostate carcinoma, and on the other hand, in the therapy of de novo metastatic hormone-sensitive prostate carcinoma (mCSPC). In both the non-metastatic setting and in first-line mCSPC, the addition of abiraterone to androgen deprivation therapy (ADT) failed to slow disease progression and improve overall survival [6,7]. The way is thus paved for increased advancement of this compound into first-line therapy of metastatic cases as well as into earlier stages of disease. alkflasf alk falsfalf asalfm.

A guest with rarity value: The pheochromocytoma

For the first time this year, the benefit of systemic therapy in advanced pheochromocytoma/paraganglioma was confirmed in a randomized trial – with corresponding fanfare [8]. To date, no clear standards exist for the treatment of this very rare condition with an incidence of <1/million. In the phase II FIRSTMAPPP trial, the tyrosine kinase inhibitor sunitinib was compared with placebo and delivered impressive results. Thus, the sunitinib arm showed a median progression-free survival (PFS) of 8.9 months, compared with 3.6 months in the placebo arm. Based on these data, there would now be a first systemic treatment for advanced malignant pheochromocytomas/paragangliomas with acceptable toxicity. Only the approval is currently pending.

Focus on new active ingredients

Two studies with substances not yet approved in Switzerland were also presented at the Presidential Symposia. On the one hand, it was about the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which was convincing in the second-line therapy of metastatic HER2+ breast carcinoma, and on the other hand about the KRASG12C inhibitor adagrasib, which could be used in the future in KRASG12C-mutated colorectal carcinoma.

The latter agent irreversibly and selectively binds to KRASG12C, arresting the enzyme in its inactive form. In addition to blocking KRASG12C, this also leads to increased efficacy of the anti-EGFR antibody cetuximab. Indeed, this is decreased in KRASG12C mutated tumors, which account for 3-4% of colorectal carcinomas. For this reason, the phase I/II KRYSTAL-1 trial evaluated both adagrasib alone in metastatic KRASG12C-mutated colorectal cancer after failure of standard therapy and combination therapy with adagrasib and cetuximab [9]. The new substance proved to be a well-tolerated monotherapy with promising activity. This could be further increased by the addition of cetuximab. The task now is to confirm this early data. To this end, the phase III KRYSTAL-10 trial is currently underway, evaluating the use of adagrasib plus cetuximab in the second-line setting in patients with KRASG12C-mutated colorectal cancer.

Unlike adagrasib, data on T-DXd are already available from the phase III DESTINY-Breast03 trial [10]. This compared monotherapy with T-DXd with the now established second-line treatment with trastuzumab emtansine (T-DM1) in metastatic HER2+ breast cancer. As with T-DM1, T-DXd is an antibody-drug conjugate directed against HER2 – but with a modified linker and a different cytotoxic agent present in a higher ratio to the antibody. Impressive results in terms of both PFS and OS were reported from the study, regardless of prior therapy and metastasis location. According to the experts at the ESMO congress, a new second-line standard should soon be established here – provided approval is granted.

Brand new: Corona

Given the current global situation, two studies on immunity after SARS-CoV-2 infection or vaccination were also presented in the Presidential Symposia [11,12]. These showed one thing above all: mRNA vaccination is safe and effective for patients with solid tumors – regardless of their oncological therapy. Exceptions to this are anti-CD20 antibodies, which attenuate the humoral immune response, and checkpoint inhibitors, which impair the cellular immune response. In contrast to patients with solid tumors, those with hematologic diseases appear to respond with a reduced antibody and also cellular immune response to infection and/or vaccination. Beta and delta variants of the virus in particular can thus become more dangerous for these patients than for the healthy population.

Literature:

Colombo N, et al: Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: Randomized, double-blind, phase III KEYNOTE-826 study. ESMO Congress 2021, Presidential Symposium 1, Abstract #LBA2_PR.
Janjigian YY, et al: Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 study. ESMO Congress 2021, Presidential Symposium 2, Abstract #LBA7.
Luke JJ, et al: Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. ESMO Congress 2021, Presidential Symposium 1, Abstract #LBA3_PR.
Swissmedic Medicinal Product Information: www.swissmedicinfo.ch (last accessed 10/14/2021).
Felip E, et al: IMpower010: Sites of relapse and subsequent therapy from a phase III study of atezolizumab vs best supportive care after adjuvant chemotherapy in stage IB-IIIA NSCLC. ESMO Congress 2021, Presidential Symposium 3, Abstract #LBA9.
Attard G, et al: Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer (PCa): Combined analysis from two comparisons in the STAMPEDE platform protocol. ESMO Congress 2021, Presidential Symposium 2, Abstract #LBA4_PR.
Fizazi K, et al: A phase III trial with a 2×2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: overall survival with abiraterone acetate plus prednisone in PEACE-1. ESMO Congress 2021, Presidential Symposium 2, Abstract #LBA5_PR.
Baudin E, et al: First International Randomized Study in Malignant Progressive Pheochromocytoma and Paragangliomas (FIRSTMAPPP): An academic double-blind trial investigating sunitinib. ESMO Congress 2021, Presidential Symposium 3, Abstract #5670_PR.
Weiss J, et al: KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. ESMO Congress 2021, Presidential Symposium 2, Abstract #LBA6.
Cortés J, et al: Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. ESMO Congress 2021, Presidential Symposium 1, Abstract #LBA1.
Shepherd STC, et al: Adaptive immunity to SARS-CoV-2 infection and vaccination in cancer patients: The CAPTURE study. ESMO Congress 2021, Presidential Symposium 3, Abstract #15570.
Oosting S, et al: Vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors. ESMO Congress 2021, Presidential Symposium 3, Abstract #LBA8.