Highlights of ESMO Congress 2022
By: Dennis Chang, Ph.D., Alissa Clear Ph.D., Krisstel Gomez, Andrew Hayden, Claudia Lanauze-Torres, Ph.D., and Natalie Thovmasian, Ph.D.
There were over 3000+ abstracts at this year’s conference. In the following article, our Clarion oncology team shares key highlights from ESMO 2022.
DETERMINING THE RIGHT PLACE FOR IMMUNOTHERAPY IN EARLY-STAGE DISEASE
Many IO experts have long argued that immunotherapy has greater potential for efficacy if used earlier, and therefore efficacy seen in the metastatic setting may predict even greater efficacy in the (neo)adjuvant settings. However, a series of failed phase 3 trials at ESMO indicate that it is not as straightforward as it may seem.
- Three phase 3 RCC failures at ESMO 2022 challenge the positive results seen in KEYNOTE-564, which led to approval of adjuvant pembrolizumab (pembro; Keytruda) for intermediate-high or high-risk patients in Nov 2021:
- IMmotion010 demonstrated no significant difference in DFS for intermediate-high risk RCC patients treated with adjuvant atezolizumab (atezo; Tecentriq) vs. placebo (57.2 mo vs. 49.5 mo, HR 0.93; p=0.495) [LBA66].
- CheckMate-914 failed to demonstrate significant DFS difference for high-risk RCC patients receiving adjuvant nivolumab + ipilimumab (nivo + ipi; Opdivo + Yervoy) vs. nivo + placebo (NR vs. 50.7 mo, HR 0.92; p=0.5347) [LBA4].
- Phase 3 failure in HNSCC. Negative results were also presented in locally advanced HNSCC, where adding pembro to definitive CRT in KEYNOTE-412 did not improve EFS (NR vs. 46.6 mo in placebo arm, HR 0.83; P =.0429) or OS (NR in both arms, HR 0.90) [LBA5].
- But positive results in CRC, E/GEJ, and melanoma. ESMO did see some encouraging readouts, including NICHE-2 studying neoadjuvant nivo + ipi in dMMR CRC [LBA7], Apexigen’s phase 2 exploring sotigalimab (anti-CD40 mAb) + neoadjuvant CRT in E/GEJ cancers [1229P], and 5-yr results of phase 2 trial confirming benefits of neoadjuvant oncolytic virus therapy talimogene laherparepvec (T-VEC; Imlygic) + CRT in resectable melanoma [LBA39].
Overall, the mixed results serve as a reminder that study of IO in earlier settings is still relatively new, and further research is needed to better understand when and for whom these therapies may provide a benefit to.
CONTINUING ADVANCES FOR ANTIBODY DRUG CONJUGATES
Antibody drug conjugates (ADCs) continue to impress, with further signs of benefit for approved agents, encouraging signs of efficacy from newcomers, and positive results across numerous indications and targets.
- Approved ADCs continue the winning streak: Trastuzumab deruxtecan (T-DXd; Enhertu) data support accelerated approval as the first HER2-targeted agent in HER2-mutant NSCLC (53.8% ORR at approved 5.4 mg/kg dose) [LBA55] Updated data for sacituzumab govitecan (Trodelvy) from the TROPiCS-02 trial in HR+ HER2- BC show a statistically significant OS benefit of 3.2 months. However, T-DXd previously set a high bar to beat in HR+ HER2-low BC and continues to push the HER2-low boundary closer to zero with ongoing DESTINY-Breast06. [214MO, LBA76],.
- ADC combination therapy is emerging as an attractive approach: Enfortumab vedotin (Padcev) is already standard of care for late-line advanced urothelial cancer, and now shows promise in combination with pembrolizumab in 1L cisplatin-ineligible urothelial cancer (22.3 mo mOS, 64.5% ORR by BICR) [LBA73], to be confirmed in the potentially practice-changing phase 3 EV-302 trial.
- Novel ADCs generate encouraging results: As an example of ADCs expanding to new targets, B7-H3-directed DS-7300 elicited tumor responses in SCLC (53% ORR), mCRPC (28% ORR), ESCC (18% ORR), and squamous NSCLC patients (40% ORR) in its first-in-human trial [453O]. Bispecific ADCs are also emerging: zanidatamab zovodotin (ZW49) targeting two HER2 epitopes shrank HER2+ tumors in TNBC (13% ORR) and GEA (36%) patients, with additional responses in endometrial, anal, and bladder cancer in its phase 1 trial [460MO].
- ctDNA changes as early predictors of benefit on KRAS agents: In KRAS mutated colorectal cancer, Cardiff Oncology’s PLK1 inhibitor onvansertib, in combination with FOLFIRI and bevacizumab showed clinical responses across different KRAS variants (ORR 35%). Reduction in KRAS mutant allele frequency (MAFs) may be an early predictor of response [397P]. In early phase 1a data, Genentech’s KRAS-G12C inhibitor, GDC-3036, had a confirmed ORR of 31% (at 400mg QD), and reductions in ctDNA fractions were associated with tumor response [362P]. Finally, KRAS neoantigen-specific vaccines (Gritstone bio) in combination with checkpoint inhibition achieved a decrease in KRAS-mutant ctDNA. NSCLC, MSS-CRC and PDAC patients who achieved this ‘molecular response’ had longer survival [736MO].
- Bispecific in R/R Ovarian Cancer with encouraging durability: In early data from an ongoing phase 1/2 trial, Regeneron’s ubamatamab, (MUC16 x CD3 bispecific antibody, REGN4018) showed 31% ORR in patients with high MUC16 expression, and these responses had a median duration of over one year. The phase 2 portion of this study is now recruiting [523MO].
- SPEAR T-Cell Therapy in Solid Tumors early data: Adaptimmune reports new SURPASS phase 1 data for its MAGE-A4 cell therapy treatment in HLA-A*02-eligible patients with MAGE-A4+ ovarian, esophageal, or urothelial caner. Confirmed ORR was 28%; however, median duration of response was only 12-weeks [735MO].
- Tumor infiltrating lymphocytes (TILs) cell therapy in melanoma: The Dutch Cancer Society presented positive results from their phase 3 trial of TILs in R/R metastatic melanoma. TIL therapy was associated with a significantly improved mPFS (7.2 vs 3.1 months) and ORR (49% vs 21%) compared to ipilimumab in anti-PD-1 refractory patients. The results mark a new milestone reached for cell therapy, as this was the first randomized study to show improved survival outcomes in patients with solid tumors [LBA3]. A phase 1 trial of Iovance’s TILs therapy Lifileucel also reported positive response data in treatment refractory metastatic melanoma patients [844P].
THE CHALLENGE OF GLOBAL ACCESS, AND OTHER TOPICS
Although ESMO may be best known for the abundance of clinical trial readouts, the meeting is also a forum for world experts to discuss a variety of important topics.
- Shining a light on disparities of access: One of the highlights was a preliminary readout of the ESMO-led Antineoplastic Medicines Survey (ANMS) 2.0, assessing the cost and access to cancer therapeutics across 106 countries [Trapani, 2022-09-10]. The survey found that in high-income countries, cancer medicines deemed ‘essential’ by the WHO or deemed to offer ‘substantial benefit’ by the ESMO-MCBS framework were generally available free of charge or with <25% of the cost paid out-of-pocket by the patient. However, in low-income and many middle-income countries, patients had to bear the full cost of many of the same medicines, if they were available at all. Furthermore, these countries experienced a greater disruption of medicine availability due to the COVID-19 pandemic. The task to address these disparities remains enormous, but stakeholders are now armed with a rich dataset for identifying specific needs and for benchmarking progress.
- How digital technologies could reshape oncology care: Other sessions of note discussed how digital tools/apps could improve patient-HCP communication and quality of life, and how artificial intelligence/machine learning (AI/ML) technologies could transform clinical practice from detection and diagnosis to treatment. Stay tuned for Clarion’s upcoming blog posts on those topics for more details.
List of abbreviations used:
- 1L = First line
- BICR = Blinded independent committee review
- DFS = disease free survival
- EFS = event free survival
- ESCC = Esophageal squamous cell carcinoma
- GEA = Gastro-esophageal adenocarcinoma
- HNSCC = head and neck squamous cell carcinoma
- HR = Hormone receptor or Hazard ratio
- mCRPC = Metastatic castration-resistant prostate cancer
- NR = not reached
- NSCLC = Non-small cell lung cancer
- ORR = Objective response rate
- PFS = progression-free survival
- RCC = renal cell carcinoma
- RFS = relapse-free survival
- SCLC = Small cell lung cancer
- SoC = standard of care
- TNBC = Triple-negative breast cancer
- TPC = Treatment of physician’s choice
- T-VEC = Talimogene Laherparepvec
If you are interested in learning more about our current insights in the oncology space, Clarion is a life sciences strategy and organizational consultancy that works together with its clients to envision, craft, and enable growth through scientific and commercial innovation and leadership. Connect with us to learn how we can help you today. For more information, visit www.clarionhealthcare.com and follow us on Instagram and LinkedIn.
 Bex, A., et al. LBA66 – IMmotion010: Efficacy and safety from the phase III study of atezolizumab (atezo) vs placebo (pbo) as adjuvant therapy in patients with renal cell carcinoma (RCC) at increased risk of recurrence after resection. Annals of Oncology, 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Motzer, R.J., et al. LBA4 – Adjuvant nivolumab plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: Results from the randomized, phase III CheckMate 914 trial. Annals of Oncology, 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Allaf, M., et al. LBA67 – Phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients (Pts) with renal cell carcinoma (RCC) undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. Annals of Oncology, 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Machiels, J., et al. LBA5 – Primary results of the phase III KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). Annals of Oncology, 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Chalabi, M., et al. LBA7 – Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. Annals of Oncology, 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Ko, A.H., et al. 1229P – A multicenter phase II study of sotigalimab (CD40 agonist) in combination with neoadjuvant chemoradiation for resectable esophageal and gastroesophageal junction (GEJ) cancers. Annals of Oncology, 2022; 33 (suppl_7): S555-S580. 10.1016/annonc/annonc1065
 Dummer, R., et al. LBA39 – Final 5-year results of the phase II, multicenter, randomized, open-label trial of talimogene laherparepvec (T-VEC) neoadjuvant treatment (Tx) plus surgery vs immediate surgery in patients (pts) with resectable stage IIIB-IVM1a melanoma (MEL). Annals of Oncology, 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Goto, K.,et al. LBA55 – Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial. Annals of Oncology, 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Schmid, P., et al. 214MO – Sacituzumab govitecan (SG) efficacy in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) metastatic breast cancer (MBC) by HER2 immunohistochemistry (IHC) status in the phase III TROPiCS-02 study. Annals of Oncology, 2022; 33 (suppl_7): S88-S121. 10.1016/annonc/annonc1040
 Rugo, H.S., et al. LBA76 – Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC). Annals of Oncology, 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Rosenberg, J.E., et al. LBA73 – Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Annals of Oncology, 2022; 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Doi, T., et al. 453O – DS-7300 (B7-H3 DXd antibody-drug conjugate [ADC]) shows durable antitumor activity in advanced solid tumors: Extended follow-up of a phase I/II study. Annals of Oncology, 2022; 33 (suppl_7): S197-S224. 10.1016/annonc/annonc1049
 Jhaveri, K., et al. 460MO – Preliminary results from a phase I study using the bispecific, human epidermal growth factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers. Annals of Oncology, 2022; 33 (suppl_7): S197-S224. 10.1016/annonc/annonc1049
 Lenz, H., et al. 397P – Early decreases in KRAS mutant allele frequency (MAF) predicts clinical benefit to the PLK1 inhibitor onvansertib in combination with FOLFIRI/bev in 2L treatment of metastatic colorectal carcinoma (mCRC). Annals of Oncology, 2022; 33 (suppl_7): S136-S196. 10.1016/annonc/annonc1048
 Desai, J., et al. 362P – Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation. Annals of Oncology, 2022; 33 (suppl_7): 136-S196. 10.1016/annonc/annonc1048
 Kyi, C.K., et al. 736MO – Personalized, off-the-shelf KRAS neoantigen-specific immunotherapy for the treatment of advanced solid tumors: Clinical benefit associated with decreases in ctDNA (SLATE-KRAS). Annals of Oncology, 2022; 33 (suppl_7): S331-S355. 10.1016/annonc/annonc1058
 Nieuwenhuysen, Van E., et al. 523MO – Ubamatamab (REGN4018, MUC16xCD3 bispecific antibody) monotherapy in patients with recurrent ovarian cancer (OC): Phase I dose-escalation analysis. Annals of Oncology, 2022; 33 (suppl_7): S235-S282. 10.1016/annonc/annonc1054
 Hong, D.S., et al. 735MO – Updated safety and efficacy from SURPASS, the phase I trial of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy, in previously treated patients with unresectable or metastatic tumors. Annals of Oncology, 2022; 33 (suppl_7): S331-S355. 10.1016/annonc/annonc1058
 Haanen, J.B.A.G., et al. LBA3 – Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: Results from a multicenter, randomized phase III trial. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
 Larkin, J., et al. 844P – Efficacy and safety of lifileucel, an investigational autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma previously treated with anti-LAG3 antibody. Annals of Oncology, 2022; 33 (suppl_7): S356-S409. 10.1016/annonc/annonc1059
 Trapani, D. (2022). The Universal Health Coverage (UHC) dilemma: Can we afford to pay for what we want? ESMO. Paris