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VISION IMpower010 OlympiA RELATIVITY-047

Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION)

Despite significant progress in the treatment landscape for patients with metastatic castration-resistant prostate cancer (mCRPC), the disease remains incurable, although men suffering from mCRPC are living considerably longer.1 Prostate-specific membrane antigen (PSMA) has been the subject of extensive evaluation in the past two decades as a promising molecular target for prostate cancer imaging and therapy.

At the American Society of Clinical Oncology (ASCO) 2021 plenary session, the results of the Phase III study of lutetium-177-PSMA-617 were presented.2 177Lu-PSMA-617 is a targeted radioligand therapy that delivers ß-particle radiation to PSMA-expressing cells as well as the surrounding microenvironment, resulting in DNA damage that inhibits tumor growth and replication.

VISION (NCT03511664) was an international, prospective, randomized, open-label Phase III study evaluating 177Lu-PSMA-617 in patients with PSMA expressing mCRPC who were previously treated with androgen deprivation therapy (ADT) and 1-2 taxane regimens. In total, 831 patients were randomized 2:1 to receive the radioligand therapy plus standard of care (n = 551), or standard of care alone (n = 280). The dual primary endpoints of the study were radiographic progression-free survival (rPFS) and overall survival (OS). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), and time to first symptomatic skeletal event (SSE).

At a median study follow-up of 20.9 months, 177Lu-PSMA-617 plus standard of care significantly improved rPFS when compared to standard of care alone (median rPFS, 8.7 vs 3.4 months; HR, 0.40 [99.2% CI: 0.29, 0.57]; p < 0.001).

OS was also significantly improved with the addition of 177Lu-PSMA-617 with a median OS of 15.3 months in the experimental arm, versus 11.3 months with standard of care alone (HR, 0.62 [95% CI: 0.52, 0.74]; p < 0.001). In addition, ORR, DCR and SSE were also statistically significantly improved in men who received 177Lu-PSMA-617 plus standard of care.

177Lu-PSMA-617 plus standard of care was associated with a higher rate of high-grade treatment-emergent adverse events (52.7% versus 38.0%) but overall, the treatment was determined to be well tolerated.

In conclusion, in this study the addition of 177Lu-PSMA-617 to standard of care in patients with mCRPC after ADT and chemotherapy delayed radiographic disease progression and extended OS. 177Lu-PSMA-617 was well tolerated and the findings of VISION may warrant adoption of 177Lu-PSMA-617 as a new treatment option for men with mCRPC.

IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC)

In patients with fully resected, high-risk early-stage non-small cell lung cancer (NSCLC), adjuvant platinum-based chemotherapy changed the standard of care over 15 years ago.3 Recently, osimertinib demonstrated a substantial disease-free survival benefit in patients with EGFR mutations,4 however, there remains a high unmet clinical need for improved adjuvant therapies in other patients with NSCLC.

Heather A. Wakelee, FASCO, MD, Stanford University Medical Center, Stanford, CA presented the primary results of IMpower010 (NCT02486718) at the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting.5 IMpower010 is a Phase III global study evaluating atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in patients with resected, stage IB-IIIA NSCLC.

A total of 1280 patients were enrolled in IMpower010, and 1269 patients received adjuvant cisplatin-based chemotherapy. Of these, 1005 were randomized 1:1 to 16 cycles of atezolizumab (n = 507) or best supportive care (n = 498). The primary endpoint of IMpower010 was investigator-assessed disease-free survival (DFS); key secondary endpoints included overall survival (OS).

In the intention to treat (ITT) population, median follow-up was 32.2 months and atezolizumab demonstrated statistically significant disease-free survival benefit versus best supportive care in the PD-L1 TC ≥1% stage II-IIIA and all randomized stage II-IIIA populations. The significance boundary was not crossed for DFS in the ITT population; OS data were immature and not formally tested however a trend toward OS improvement with atezolizumab was seen in the PD-L1 TC ≥1% stage II-IIIA population.

Grade 3/4 adverse events (AEs) occurred in 21.8% of patients who received atezolizumab versus 11.5% in the best supportive care cohort. In addition, AEs leading to atezolizumab discontinuation occurred in 18.2% of atezolizumab-treated patients, however, these remain consistent with prior experience of atezolizumab monotherapy.

IMpower010 is the first Phase III study of immunotherapy to demonstrate disease-free survival improvement in the adjuvant NSCLC setting following platinum-based chemotherapy. Atezolizumab may be considered a practice-changing adjuvant treatment approach for patients with PD-L1 TC ≥1% stage II-IIIA NSCLC.

 

OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors represent a promising therapeutic approach against cancers with homologous recombination repair deficiencies. The PARP1 inhibitor, olaparib is currently approved by the United States FDA based on progression-free survival in BRCA1/2 associated breast6, ovarian7, prostate8 and pancreatic cancer.9

The role of olaparib in the adjuvant setting in any germline BRCA mutant malignancy is untested, and at the plenary session of the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting, the results of OlympiA was presented which aimed to evaluate the activity of adjuvant olaparib in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer.10

OlympiA (NCT02032823) is a randomized, double-blind, Phase III study that enrolled patients with germline BRCA-mutated and HER2 negative high-risk early breast cancer after primary local treatment and adjuvant or neoadjuvant chemotherapy. 1836 patients were enrolled and randomized 1:1 to receive either continuous oral olaparib (n = 921) or placebo (n = 915). The primary endpoint was invasive disease-free survival (IDFS) in the intention to treat population; secondary endpoints included distant disease-free survival (DDFS), overall survival (OS) and safety.

At 2.5 years median follow-up, there was a significant improvement in IDFS in patients treated with olaparib with IDFS events occurring in 106/921 and 178/915 patients treated with olaparib and placebo respectively.

In addition, DDFS was significantly improved with olaparib (87.5% vs. 80.4%). OS, a secondary endpoint, was greater for those patients treated with olaparib however this difference was not determined to be statistically significant (HR 0.68; 99.0% CI 0.44, 1.05; p = 0.024); 3-yr OS% 92.0% vs 88.3%.

The incidence of adverse events (AEs) was consistent with those associated with olaparib; grade 3+ AEs occurred in less than 1% of patients treated with olaparib and included anemia (8.7%), neutropenia (4.8%), and other hematological toxicities.

In conclusion, OlympiA successfully demonstrated that adjuvant olaparib following completion of local treatment and neoadjuvant chemotherapy significantly improved both invasive and distant DFS. OS benefit was not significant, and follow-up continues, but the findings of OlympiA may prove practice-changing for patients with high-risk HER2-negative early breast cancer and germline BRCA1/2 mutations.

Relatlimab plus nivolumab versus nivolumab in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047)

Immune checkpoint inhibitors have dramatically improved the prognosis of several advanced cancers, including melanoma, and have now become standards of care in patients with metastatic melanoma. However, there is still a need to optimize the benefit-risk profile to allow more patients to benefit from dual immunotherapy regimens.

Lymphocyte-activation gene 3 (LAG-3) is an important immune checkpoint that inhibits T-cell activation and is upregulated in many tumor types, including melanoma.11 Relatlimab is a fully human LAG3-specific monoclonal antibody which in preclinical models, has demonstrated synergistic anti-tumor activity when combined with PD-1 blockade,12 as well as clinically meaningful anti-tumor activity in patients with melanoma refractory to anti-PD-1 approaches.13

At the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting, Evan J. Lipson, John Hopkins University School of Medicine, Baltimore, MD, presented the primary results of RELATIVITY-047 (NCT03470922), a Phase III study evaluating relatlimab in combination with nivolumab, a PD-1 targeting antibody, in first-line advanced melanoma.14

714 patients were randomized 1:1 to receive relatlimab and nivolumab as a fixed-dose combination (n = 355) or nivolumab monotherapy (n = 359). The primary endpoint of the study was progression-free survival (PFS), and important secondary endpoints include overall survival (OS) and objective response rate (ORR).

At a median follow-up of 13.2 months, the median PFS in the experimental arm (10.1 months [95% CI, 6.4–15.7]) was significantly longer than patients enrolled in the nivolumab monotherapy arm (4.6 months [95% CI, 3.4–5.6]). The incidence of grade 3/4 adverse events (AEs) was higher in the dual checkpoint blockade arm (18.9% versus 9.7%) however no unexpected safety signals were observed.

In summary, relatlimab and nivolumab as a fixed-dose combination demonstrated superior progression-free survival when compared to nivolumab alone and was associated with a manageable safety profile. Dual LAG-3 and PD-1 blockade may be a potential new treatment option for patients with advanced melanoma, bringing the benefits of dual checkpoint inhibition to more patients.

References

  1. Sumanasuriya S, De Bono J. Treatment of Advanced Prostate Cancer—A Review of Current Therapies and Future Promise. Cold Spring Harbor Perspectives in Medicine. 2017;8(6):a030635.
  2. Morris M, De Bono J, Chi KN et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol 39, 2021 (suppl 15; abstr LBA4)
  3. Ettinger D, Wood D, Aisner D et al. NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 2.2021. Journal of the National Comprehensive Cancer Network. 2021;19(3):254-266.
  4. Wu Y, Tsuboi M, He J et al. Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2020;383(18):1711-1723.
  5. Wakelee H, Altorki N, Zhou C et al. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol 39, 2021 (suppl 15; abstr 8500)
  6. Robson M, Im S, Senkus E et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. New England Journal of Medicine. 2017;377(6):523-533.
  7. Moore K, Colombo N, Scambia G et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. New England Journal of Medicine. 2018;379(26):2495-2505.
  8. de Bono J, Mateo J, Fizazi K et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2020;382(22):2091-2102.
  9. Golan T, Hammel P, Reni M et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. New England Journal of Medicine. 2019;381(4):317-327.
  10. Tutt A, Garber J, Kaufman et al. OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer. J Clin Oncol 39, 2021 (suppl 15; abstr LBA1)
  11. Durham N, Nirschl C, Jackson C et al. Lymphocyte Activation Gene 3 (LAG-3) Modulates the Ability of CD4 T-cells to Be Suppressed In Vivo. PLoS ONE. 2014;9(11):e109080.
  12. Woo S, Turnis M, Goldberg M et al. Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape. Cancer Research. 2011;72(4):917-927.
  13. Ascierto P, Bono P, Bhatia S et al. 4998 – Efficacy of BMS-986016, a Monoclonal Antibody That Targets Lymphocyte Activation Gene-3 (LAG-3), in Combination With Nivolumab in Pts With Melanoma Who Progressed During Prior Anti–PD-1/PD-L1 Therapy (mel prior IO) in All-Comer and Biomarker-Enriched Populations. Annals of Oncology. 2017 28 (suppl_5): v605-v649. 10.1093/annonc/mdx440
  14. Lipson E, Tawbi H, Schadendorf D et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol 39, 2021 (suppl 15; abstr 9503)
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