The European Society of Medical Oncology (ESMO) Virtual Congress 2020 was held on 19–21 September 2020. Advances in immunotherapy featured prominently among the presentations and clinical trial updates. Below are some of the highlights of the late-stage clinical trial data that were presented.
A number of studies presented at ESMO 2020 provided evidence for the efficacy of immune checkpoint inhibitors as first-line and adjuvant therapy in patients with gastric and oesophageal cancers. Data from the CheckMate 649 study (ClinicalTrials.gov Identifier: NCT02872116) showed that, at a minimum follow up of 1 month, nivolumab (Opdivo®, Bristol Myers Squibb, New York, NY, USA) plus chemotherapy improved overall survival (OS; 14.4 months versus 11.1 months; hazard ratio [HR] 0.71; p<0.0001) and progression-free survival (PFS; 7.7 months versus 6.1 months; HR 0.68; p<0.0001) in patients with previously untreated, unresectable advanced, or metastatic gastric cancer, gastro-oesophageal junction cancer, or oesophageal adenocarcinoma, if they had a programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥5.1 This addition of nivolumab to chemotherapy should become the standard of care for these patients. Further study will be needed to establish whether there is any benefit of this combination in patients who have a PD-L1 CPS <5. The ATTRACTION 4 study (ClinicalTrials.gov Identifier: NCT02746796) was similar to CheckMate 649, but was only performed in Asian participants and with no pre-defined CPS. Results showed an improvement in PFS (10.5 months versus 8.3 months; HR 0.68) but not OS.2
In terms of oesophageal cancer, the KEYNOTE 590 study (ClinicalTrials.gov Identifier: NCT03189719) evaluated the addition of pembrolizumab (Keytruda®, Merck, Kenilworth, NJ, USA) to chemotherapy in patients with squamous cell carcinoma of the oesophagus, adenocarcinoma of the oesophagus, or Siewert type 1 gastro-oesophageal junction adenocarcinoma. Results showed an improvement in PFS (6.3 months versus 5.8 months; HR, 0.65; p<0.0001) and OS (12.4 months versus 9.8 months; HR, 0.73; p<0.0001).3 The standard of care has remained unchanged in advanced oesophageal cancer for some time, so these findings are particularly important.
Data were also presented from CheckMate 577 (ClinicalTrials.gov Identifier: NCT02743494), the first global, phase III study to report the efficacy and safety of an immune checkpoint inhibitor in the adjuvant setting following neoadjuvant chemoradiation therapy and complete surgical resection of oesophageal or gastro-oesophageal junction cancer. At a pre-specified interim analysis, adjuvant nivolumab showed a statistically significant improvement in disease-free survival compared with placebo (22.4 versus 11.0 months; p=0.0003). The majority of treatment-related adverse events were grade 1 or 2.4 This is a very important finding since approximately 50% of patients with oesophageal or gastro-oesophageal junction cancer who undergo neoadjuvant chemoradiation therapy followed by tumour resection will have disease recurrence within 4 years, and until now, there have been no treatment options for patients who fail to demonstrate a complete pathological response.5
ESMO 2020 also brought important findings in triple-negative breast cancer (TNBC). TNBC has a number of characteristics associated with enhanced response to immune checkpoint inhibitors, including increased tumour-infiltrating lymphocytes and PD-L1 expression.6 In 2018, findings from the IMpassion130 clinical trial (ClinicalTrials.gov Identifier: NCT02425891) showed that atezolizumab (Tecentriq®, Roche, Basel, Switzerland) in combination with nab-paclitaxel was the first immunotherapy to improve survival in metastatic TNBC.7 As a result, atezolizumab in combination with nab-paclitaxel has become the new standard of care for patients with PD-L1–positive metastatic TNBC. The final OS data were presented at ESMO, and showed a clinically meaningful OS benefit in PD-L1 positive patients (median 7.5-month improvement). The combination continued to be safe and tolerable, and no new safety signals were reported.8 Disappointingly, however, initial findings from the IMpassion131 clinical trial (ClinicalTrials.gov Identifier: NCT03125902), in which atezolizumab was combined with paclitaxel rather than nab-paclitaxel, showed no significant improvement in OS or PFS.9 One possible explanation was that there was much more steroid use in IMpassion131 compared to IMpassion130, which could have played a role in blunting the effect of the immune checkpoint inhibitor. However, steroid use has not attenuated the effect of other immune checkpoint inhibitors.10
Despite this setback, positive findings were reported from the IMpassion031 (ClinicalTrials.gov Identifier: NCT03197935) clinical trial of atezolizumab in TNBC in the neoadjuvant setting, and were simultaneously published in The Lancet. In this phase III study, 333 patients with early-stage, treatment-naïve TNBC were randomised to receive atezolizumab or placebo. All patients received nab-paclitaxel for 12 weeks followed by doxorubicin plus cyclophosphamide for 8 weeks. Patients then underwent surgery followed by atezolizumab or placebo for an additional 11 doses. Results showed a higher pathologic complete response at 20 months in the atezolizumab arm compared with placebo (57.6% versus 41.1%; p=0.0044), with an acceptable safety profile.11
The news for immune checkpoint inhibitors in bladder cancer was less encouraging. In the KEYNOTE-361 study (ClinicalTrials.gov Identifier: NCT02853305) pembrolizumab was evaluated as first-line therapy in patients with advanced urothelial cancer. Patients were randomised to pembrolizumab monotherapy, pembrolizumab plus chemotherapy, or standard of care chemotherapy alone. Although an improvement was seen in OS and PFS for patients treated with pembrolizumab plus chemotherapy, these results did not meet statistical significance.12 However, pembrolizumab has proved effective in the second-line treatment setting, and research into identifying biomarkers of response will continue.
Negative findings were also reported from IMagyn050 (ClinicalTrials.gov Identifier: NCT03038100), a phase III trial investigating the combination of bevacizumab and atezolizumab for patients with advanced, newly diagnosed ovarian cancer. However, encouraging results were seen in some subgroups, in particular the PD-L1 highly positive population.13
The phase III CheckMate 9ER trial (ClinicalTrials.gov Identifier: NCT03141177) has identified an important new treatment option in kidney cancer. The combination of nivolumab and cabozantinib (Cabometyx®, Exelixis, Alameda, CA, USA) was investigated, since nivolumab promotes antitumor responses by preventing cancer from evading immune detection, while cabozantinib has both antiangiogenic and immunogenic properties that may prevent tumour-induced immunosuppression. A total of 651 patients with previously untreated advanced or metastatic renal cell carcinoma were randomly assigned to first-line treatment with nivolumab plus cabozantinib or standard of care oral sunitinib. At a median follow-up of 18.1 months, there was a doubling of PFS for the nivolumab plus cabozantinib group versus sunitinib (16.6 months versus 8.3 months, p<0.0001), as well as a doubling of the overall response rate, and significant improvement in OS.14
Finally, the long-term benefit of immune checkpoint inhibitors was discussed. A 5-year update of the KEYNOTE-024 trial (ClinicalTrials.gov Identifier: NCT02142738) shows that pembrolizumab continues to show improvements in for patients with metastatic non-small cell lung cancer with PD-L1 tumour proportion score ≥50%.15 In addition, 4-year follow-up data from the CheckMate 238 trial (ClinicalTrials.gov Identifier: NCT02388906) showed that nivolumab improved 4-year recurrence-free survival compared with ipilimumab (Yervoy®, Bristol Myers Squibb) in patients with resected stage IIIB-C or IV melanoma.16
These presentations have highlighted some important successes for clinical trials investigating immune checkpoint inhibitors in solid tumours, but also some notable failures. Genomic and immune profiles of tumours from patients treated with checkpoint blockade may provide new insights in the future into biomarkers of response, enabling us to maximise the impact of these treatments.
- Moehler M, Shitara K, Garrido 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. Ann Oncol. 2020;31(Suppl 4):S1191.
- Boku N, Ryu MH, Oh D-Y, 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) stud. Ann Oncol. 2020;31(Suppl 4):S1142–S215.
- Kato K, Sun J-M, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study. Ann Oncol. 2020;31(Suppl 4):S1192–S3.
- Kelly RJ, Ajani JA, Kuzdzai J, 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. Ann Oncol. 2020;31(Suppl 4):S1142–S215.
- Bristol Myers Squibb. CheckMate -577, a Phase 3 Trial Evaluating Opdivo (nivolumab) as Adjuvant Therapy for Patients with Resected Esophageal or Gastroesophageal Junction Cancer, Meets Primary Endpoint of Disease-Free Survival. 2020. Available at: https://news.bms.com/news/details/2020/CheckMate–577-a-Phase-3-Trial-Evaluating-Opdivo-nivolumab-as-Adjuvant-Therapy-for-Patients-with-Resected-Esophageal-or-Gastroesophageal-Junction-Cancer-Meets-Primary-Endpoint-of-Disease-Free-Survival/default.aspx (accessed 27 October 2020).
- Keenan TE, Tolaney SM. Role of immunotherapy in triple-negative breast cancer. J Natl Compr Canc Netw. 2020;18:479–89.
- Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21.
- Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Ann Oncol. 2020;31(Suppl 4):S1142–S215.
- Miles DW, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(Suppl 4):S1142–S215.
- The ASCO Post. IMpassion131: No Benefit for Atezolizumab Plus Paclitaxel in Triple-Negative Breast Cancer. 2020. Available at: https://ascopost.com/issues/october-10-2020/impassion131-no-benefit-for-atezolizumab-plus-paclitaxel-in-triple-negative-breast-cancer/ (accessed 27 October 2020).
- Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090–100.
- Alva A, Csőszi T, Ozguroglu M, et al. LBA23 Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361. Ann Oncol. 2020;31(Suppl 4):S1155.
- Moore KN, Bookman M, Sehouli J, et al. Primary results from IMagyn050/GOG 3015/ENGOT-OV39, adouble-blind placebo (pbo)-controlled randomised phase III trial ofbevacizumab (bev)-containing therapy +/- atezolizumab (atezo) fornewly diagnosed stage III/IV ovarian cancer (OC). Ann Oncol. 2020;31(Suppl 4):S1161–S2.
- Choueri T. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2020;31(Suppl 4):S1142–S215.
- Brahmer J. KEYNOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. Ann Oncol. 2020;31(Suppl 4):S1142–S215.
- Weber J, Del Vecchio M, Mandala M, et al. 1076O Adjuvant nivolumab (NIVO) vs ipilimumab (IPI) in resected stage III/IV melanoma: 4-y recurrence-free and overall survival (OS) results from CheckMate 238. Ann Oncol. 2020;31(Suppl 4):S731–2.
Disclosures: Katrina Mountfort is a freelance medical writer for Touch Medical Media Ltd., Goring-on-Thames, UK.
Support: Commissioned, edited and supported by Touch Medical Media.
Published: 29 October 2020
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