Publications Spotlight – Gynae at ESMO 2023

What is ESMO 2023?

To stay at the forefront of clinical trial opportunities for our Australian gynaecological community, ANZGOG members are frequent and active contributors to international trial meetings and conferences, such as ESMO 2023.

ESMO is the European Society for Medical Oncology. Representing more than 34,000 oncology professionals in 170 countries, ESMO is a reference for oncology education and information. ESMO scientific and educational meetings are well-known platforms to present new clinical data and educational updates, offering great networking opportunities.

At meetings such as ESMO, ANZGOG’s home-grown trials receive recognition and support from our international colleagues and our participation in trials initiated elsewhere provide us access to critical drugs, complementing our clinical and translational pipeline of activity.

Prof Clare Scott AM attended ESMO 2023, along with several other ANZGOG members, and has provided a summary report of the meeting’s highlights.

Contributed by:

Professor Clare Scott AM

ANZGOG Chair & Clinician-Scientist, VIC

Highlights from ESMO 2023

What set ESMO 2023 apart from many conferences, was that the advances were notable for women with endometrial or cervical cancer. It has taken a long time to be able to compare results from multiple confirmatory phase 3 first-line trials for these under-researched gynaecological cancer types.

Endometrial cancer

Starting with endometrial cancer, four phase 3 trials now support for the use of chemotherapy immunotherapy combinations in the 1^st line.

• The AtTEnd trial (ANZGOG sites contributed more than 50 participants to this trial), showed that the combination of the immunotherapy agent, atezolizumab (a PD-L1 inhibitor) + chemotherapy was very effective in endometrial cancers with mismatch repair deficiency dMMR) – a subtype of cancer recognised for immune high characteristics. The addition of atezolizumab did not seem to provide additional benefit for mismatch repair proficient tumours (pMMR), unlike that observed in two similarly designed trials with PD-1 inhibitors (GY018 and Ruby). It is worth noting that the AtTEnd trial was not powered to show a difference in pMMR patients. (Abstract – LBA40)
• The GY018 trial of pembrolizumab (a PD-1 inhibitor) + chemotherapy was updated, confirming, in addition to an impressive benefit for the dMMR population, a benefit, although more modest, for patients with pMMR endometrial cancers as well (note GY018 was powered to show a difference in the pMMR population). In the first-line, with immunotherapy + chemotherapy, patients with either of the two main types of dMMR benefited – either dMMR due to mutated MMR genes or due to methylation (epigenetic silencing) of one or more MMR genes. This supports the use of immunotherapy + chemotherapy in the 1^st-line, to reduce the development of resistance in MMR-methylated endometrial cancers. (Abstract – LBA43)
• An update of the RUBY trial of dostarlimab (a PD-1 inhibitor) + chemotherapy, was the first 1^st line trial to report the effect of immunotherapy + chemotherapy in all four separate molecular subtypes of endometrial cancer (1) dMMR, 2) POLE (like super dMMR) and pMMR divided into 3) p53 mutant and 4) NSMP – no specific molecular profile subtypes). The striking benefit was similar in both the subgroup which is very hard to treat, known as p53 mutant, and the dMMR subgroup (POLE all did well but the NSMP type did not appear to benefit). This was new and unexpected information about the p53 subgroup, which should change clinical trial design. This should also apply pressure on clinical trial investigators and sponsors to report results for the four main molecular subtypes in all endometrial cancer trials, as without this we miss crucial information which helps us recommend the best treatment for each patient. (Abstract – 740MO)
• The DUO-E trial examined the use of chemotherapy with or without durvalumab (a PD-L1 inhibitor), and with or without olaparib (there was no olaparib-only maintenance arm) in the 1^st-line treatment of endometrial carcinoma. A striking improvement in progression-free survival (PFS) was seen for patients with dMMR endometrial cancer receiving durvalumab and this was not further improved by the addition of olaparib. However, for pMMR patients an improvement was seen both with durvalumab alone and a further improvement with the addition of olaparib to durvalumab, although there was not a statistically significant difference between the two experimental arms (DUO-E was not powered to show a difference with the addition of olaparib to durvalumab). This confirms the results seen in the AtTEnd trial with another PD-L1 inhibitor, durvalumab, for patients with dMMR endometrial cancer and is encouraging for patients with pMMR endometrial cancer. However, we are awaiting additional translational data from the DUO-E trial, such as the p53 and DNA repair status of cases in the pMMR group, to better understand which patients are likely to benefit from combination maintenance therapy. (Abstract – LBA41)

Cervical cancer

For cervical cancer, two new phase 3 trials investigating patients receiving standard chemo-radiation, reported improved outcomes from adding chemotherapy either alone before, or together with immunotherapy during or after chemo-radiation treatment.

• The important Presidential presentation of the GCIG phase III INTERLACE trial will be practice-changing immediately. By giving just six weeks of weekly chemotherapy before the standard 6 weeks of chemo-radiation for cervical cancer, an improvement of 8% was seen for overall survival, suggesting that additional chemotherapy prior to radiotherapy could prevent spread of cancer cells, particularly for patients with stage III cervical cancer. This can be prescribed without waiting for approval or reimbursement in most places. (Abstract – LBA8)
• The KEYNOTE-A18 phase 3 first-line locally advanced cervical cancer trial added pembrolizumab during standard chemo-radiation, with further pembrolizumab to follow, with an impressive improvement in progression free survival (it was too early to say whether overall survival was extended). (Abstract – LBA38)
• This was in keeping with a trial reported previously, the KEYNOTE-826 trial of pembrolizumab + chemotherapy after chemo-radiation, for patients with persistent, metastatic, or recurrent cervical cancer.
• Subtle differences in timing of delivery are seemingly important, ANZGOG’s OUTBACK trial showed that additional chemotherapy alone, without immunotherapy, after chemo-radiation did not improve outcomes for women with locally advanced cervical cancer.

Endometrial & cervical cancer

Finally, for both endometrial and cervical cancer, a huge amount of new information was presented, about new and exciting Antibody Drug Conjugates (ADCs). These drugs deliver high concentrations of a cancer drug directly to the cancer cell, hopefully increasing potency of treatment and reducing off-target side effects for patients. We do have a lot to learn about the intricacies of the three components of an ADC – the drug chosen to be delivered, the type of linker, and the best target on the cancer cell to direct the drug to – otherwise side effects will also limit these newer treatments.

• A second gynae presidential presentation described what could become the new standard 2^nd line treatment for cervical cancer, for those with access. In a phase 3 trial of the ADC, tisotumab vedotin (known as TV), which directs the MMAE microtubule inhibitor drug to Tissue Factor (expressed on cervical cancer cells), resulted in a 30% reduction in the risk of death, compared with those receiving chemotherapy alone, as well as improvements in overall response rates, progression free survival and overall survival, which is outstanding. (Abstract – LBA9)
• Phase II trials were presented of the ADC, T-DXd, which targets a topoisomerase I inhibitor (deruxatecan) to the HER-2 (ERBB2) receptor with deep and durable responses in many cancer types with either over-expression of the HER-2 protein or mutation or amplification of the HER-2 gene. Durable responses of around a year or more were seen particularly in endometrial and cervical cancer, with a smaller number of ovarian cancers included in the trials. For the endometrial and cervical cancer subsets, the overall response rates were 85% and 75% respectively for the highest expressing cancers (3+), which is very exciting and will be followed up by a series of phase III trials, to allow us to understand who responds best to the T-DXd and why. Having demonstrated impressive effects in at least eight independent cancer types, T-DXd will be considered for a pan-tumor approval by the FDA and EMA. (Abstract – 1321MO)

ANZGOG is committed to keeping members up to date with the latest developments in global gynaecological oncology. Thank you to Prof Scott AM for providing this report. We look forward to sharing more reports with members in 2024.