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DESTINY-Breast03 PEACE-1 KEYNOTE-716 KEYNOTE-826 CheckMate-649

DESTINY-Breast03: T-DXd is shown to improve PFS of previously-treated patients with HER2+ unresectable/metastatic breast cancer when compared to T-DM1 in a randomized Phase III trial

Following the results of DESTINY-Breast01 (NCT03248492), trastuzumab deruxtecan (T-DXd) was approved as a treatment for patients with previously treated advanced HER2+ unresectable or metastatic breast cancer in the USA and the EU.1 T-DXd is an antibody-drug conjugate consisting of a HER2-targeting monoclonal antibody (trastuzumab) bound to a topoisomerase I inhibitor (deruxtecan).2

The results from DESTINY-Breast03 (NCT03529110) were presented for the first time at ESMO 2021, by Dr Javier Cortés, MD, PhD, Vall d’Hebron University Hospital, Barcelona, Spain. DESTINY-Breast 03 is a randomized, open-label Phase III trial comparing the use of T-DXd with ado-trastuzumab emtansine (T-DM1) for the treatment of patients with HER2+ unresectable or metastatic breast cancer who had previously been treated with trastuzumab and taxane.3

The primary endpoint of the trial was progression-free survival (PFS), with secondary endpoints including overall survival and duration of response. In total, 524 patients were enrolled in the trial.

The results reported at ESMO 2021 were highly promising for T-DXd. The median PFS for T-DXd has not yet been reached, while the median PFS for T-DM1 was 6.8 months (HR: 0.284, p=7.8×10-22). The estimated 12-month overall survival was 94.1% vs 85.9% for T-DXd and T-DM1, respectively (T-DXd 95% CI: 90.3-96.4, T-DM1 95% CI: 80.9-89.7; HR: 0.5546 [95% CI: 0.3587-0.8576, p=0.007172]). The median duration of treatment was 14.3 months vs 6.9 months for T-DXd and T-DM1, respectively and both T-Dxd and T-DM1 were well tolerated.

 

The results from DESTINY-Breast03 strongly support the use of T-DXd in this patient population, demonstrating a vastly significant improvement in PFS when compared to T-DM1. Results from DESTINY-Breast03 could be practice-changing and highlight a new line of care for patients with advanced HER2-positive breast cancer.

PEACE-1: Encouraging results from the Phase III study of the triplet combination of androgen deprivation therapy plus docetaxel plus abiraterone for patients with metastatic castration-sensitive prostate cancer

 

Androgen deprivation therapy (ADT) has been the standard of care for first-line treatment of metastatic prostate cancer.4 More recently, in PEACE-1 (NCT01957436), the efficacy of a triplet regimen of docetaxel plus abiraterone (abiraterone acetate plus prednisone) plus ADT has been investigated in men with metastatic castration-sensitive prostate cancer (mCSPC). Promising progression-free survival (PFS) results from the triplet combination were presented at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting.

The overall survival (OS) results of PEACE-1 were presented at the European Society for Medical Oncology (ESMO) Congress 2021 by Prof. Karim Fizazi, Institute Gustave Roussy and University of Paris-Saclay, Villejuif, France. This randomized Phase III trial, with a 2×2 factorial study design, compared ADT plus docetaxel with ADT plus docetaxel plus abiraterone. Two further arms of the trial studied the addition of radiotherapy to these two combinations.

In total, 1173 men were enrolled in the trial. Patients had either high volume (57%) or low volume (43%) de novo mCSPC.5 The primary endpoints were OS and radiographic PFS, 7.5 and 9.5 years after first inclusion, respectively. Secondary endpoints included castration resistance-free survival and PSA response rate.

After a median follow-up duration of 4.4 years, abiraterone was shown to have improved OS in the overall population (HR: 0.83, 95% CI: 0.69-0.99, p=0.034) and in the ADT plus docetaxel population, (HR: 0.75, 95% CI: 0.59-0.96, p=0.021). Among patients receiving ADT plus docetaxel, grade 3-5 adverse events which occurred in more than 5% of patients included neutropenic fever, neutropenia, liver toxicity, and hypertension.5

The results of this study show that a triplet combination of ADT plus docetaxel plus abiraterone improves OS and radiographic PFS in patients with mCSPC. Findings from PEACE-1 are likely to have a great impact on the standard of care for patients with mCSPC.

KEYNOTE-716: Adjuvant pembrolizumab reduces risk of recurrence in resected advanced melanoma by 35% compared to placebo

The use of pembrolizumab as an adjuvant therapy for advanced melanoma has achieved promising results in recent years. KEYNOTE-054 (NCT02362594) concluded that adjuvant pembrolizumab prolonged recurrence-free survival (RFS) in patients with resected stage III melanoma.6

KEYNOTE-716 (NCT03553836) is a randomized Phase III double-blind trial of pembrolizumab for patients with resected stage IIB or IIC melanoma. RFS results were presented for the first time at ESMO 2021, by Dr Jason Luke, MD, FACP, University of Pittsburgh, Pittsburgh, PA. In total, 976 patients were enrolled in the trial and randomized to either pembrolizumab (n = 487) or a placebo (n = 489).7 The primary endpoint was RFS, while secondary endpoints included overall survival and incidences of adverse events.

Pembrolizumab was shown to decrease the risk of recurrence by 35% (HR: 0.65, 95% CI: 0.46-0.92, p=0.00658) when compared to placebo, after a median follow-up of 14.4 months. Pembrolizumab achieved 90.5% RFS after 12 months, compared to 83.1% in patients enrolled in the placebo arm.7

During the study, 16.1% of patients receiving pembrolizumab experienced a drug-related adverse event of grade 3 or higher, compared to 4.3% of patients receiving placebo. Pembrolizumab did not cause any deaths related to adverse events; however, there were 4 adverse event-related deaths in the placebo arm. The most common immune-mediated adverse events were hypothyroidism and hyperthyroidism, occurring more often in the pembrolizumab arm than the placebo.7

 

 

In conclusion, these results show that pembrolizumab is an effective adjuvant therapy for resected advanced melanoma, by demonstrating a significant reduction in the risk of disease recurrence, which could impact on future clinical practice.

KEYNOTE-826: Pembrolizumab plus chemotherapy improves OS and PFS in patients with persistent, recurrent, or metastatic cervical cancer

 

The first interim analysis results of KEYNOTE-826 (NCT03635567), a randomized, double-blind, Phase III trial, were presented at ESMO 2021, by Dr Nicoletta Colombo, MD, European Institute of Oncology, Milan, Italy. KEYNOTE-826 enrolled 617 patients and compared pembrolizumab plus chemotherapy with placebo plus chemotherapy for patients with persistent, recurrent, or metastatic cervical cancer.8

The primary endpoints were progression free survival (PFS) according to RECIST 1.1 and overall survival (OS). Secondary endpoints included objective response rate, duration of response, and several measures of safety and toxicity, such as the incidence and severity of adverse events.

Pembrolizumab plus chemotherapy was shown to have a significant benefit over the placebo regimen. Pembrolizumab increased the median PFS irrespective of PD-L1 combined positive score (CPS), compared with placebo. Pembrolizumab achieved a median PFS of 10.4 months in the all-comer population vs the 8.2 months achieved by placebo in the PD-L1 CPS ≥ 1 population. Similarly, the patient group receiving pembrolizumab saw an improvement in OS, with median OS having not been met, compared to the 16.3-month OS of the placebo group.8

Pembrolizumab plus chemotherapy resulted in significant increases in the duration of both PFS and OS in patients with persistent, recurrent, or metastatic cervical cancer. These improvements were seen in all PD-L1 CPS patient populations, with an acceptable level of toxicity, leading to a likely prediction that this regimen could become the new standard of care for first-line treatment in this population.

CheckMate 649: Further evidence in support of using nivolumab plus chemotherapy for advanced or metastatic gastric or GEJ cancer

Nivolumab plus chemotherapy was approved in April 2021 by the FDA for treating gastric or gastroesophageal junction (GEJ) cancer, after showing significant improvements in overall survival (OS) compared to chemotherapy alone in the CheckMate 649 trial (NCT02872116).9

At ESMO 2021, Dr Yelena Janjigian, MD, Memorial Sloan Kettering Cancer Center, New York City, NY, presented updated results from the randomised, Phase III CheckMate 649 trial which compared nivolumab plus ipilimumab and nivolumab plus chemotherapy to chemotherapy alone for patients with gastric or GEJ cancer. These results included a long-term follow-up of patients treated with nivolumab plus chemotherapy, as well as the first presentation of results from the comparison of nivolumab plus ipilimumab and chemotherapy.10

Overall, 2031 patients with untreated, unresectable advanced/metastatic gastric or GEJ cancer were enrolled, excluding patients with HER2+ disease. The primary endpoints were overall survival (OS) and progression-free survival (PFS) of patients with a PD-L1 combined positive score (CPS) ≥ 5 who were treated with nivolumab plus chemotherapy vs chemotherapy alone. Secondary endpoints included OS in patients in these treatment regimens with PD-L1 CPS ≥ 1, as well as OS in patients with PD-L1 CPS ≥ 5 who were receiving nivolumab plus ipilimumab vs chemotherapy.10

Nivolumab plus ipilimumab did not achieve a longer median OS than chemotherapy. However, nivolumab plus chemotherapy continued to achieve encouraging results in a longer-term analysis, with a median OS of 14.4 months, which is more than 3 months longer than the 11.1-month median OS achieved by chemotherapy alone.

CheckMate 649 has provided further evidence that the addition of nivolumab to chemotherapy increases OS for patients with advanced or metastatic gastric or GEJ cancer, which will solidify its position as a standard of care.

References

  1. Kemp A. Enhertu reduced the risk of disease progression or death by 72% vs. trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. Astrazeneca.com. 2021 [cited 7 October 2021]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2021/enhertu-reduced-the-risk-of-disease-progression-or-death-by-72-vs-trastuzumab-emtansine-t-dm1-in-patients-with-her2-positive-metastatic-breast-cancer.html
  2. Kemp A. Trastuzumab deruxtecan recommended for approval in the EU by CHMP for HER2-positive metastatic breast cancer. Astrazeneca.com. 2020 [cited 4 October 2021]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2020/trastuzumab-deruxtecan-positive-chmp.html
  3. Cortés J, Kim S, Chung W, 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, Annals of Oncology. 2021; 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
  4. Perlmutter MA, Lepor H. Androgen deprivation therapy in the treatment of advanced prostate cancer. Reviews in urology. 2007;9(Suppl 1):S3.
  5. Fizazi K, Carles Galceran J, Foulon S 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, Annals of Oncology. 2021; 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
  6. Eggermont A, Blank C, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. New England Journal of Medicine. 2018;378(19):1789-1801.
  7. Luke JJ, Rutkowski P, Queirolo P, 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, Annals of Oncology. 2021; 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
  8. Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: Randomized, double-blind, phase III KEYNOTE-826 study, Annals of Oncology. 2021; 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
  9. FDA approves nivolumab in combination with chemotherapy for metastatic gastric cancer and esophageal adenocarcinoma. U.S. Food and Drug Administration. 2021 [cited 7 October 2021]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-chemotherapy-metastatic-gastric-cancer-and-esophageal
  10. Janjigian YY, Ajani JA, Moehler M, 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, Annals of Oncology. 2021; 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741

Written by Simon Ng

The content of VJOncology is intended for healthcare professionals