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PALOMA-3 NIAGARA KEYNOTE-522 NADINA

PALOMA-3: subcutaneous amivantamab with lazertinib as a potential new route of administration in EGFR-mutated metastatic NSCLC

 

On August 19th 2024, the Food and Drug Administration (FDA) approved amivantamab, a bispecific monoclonal antibody simultaneously targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET), with lazertinib, a third-generation tyrosine kinase inhibitor (TKI), as a first-line treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC).1,2 The approval was based on results from the Phase III MARIPOSA trial (NCT04487080), which demonstrated that the combination therapy resulted in superior efficacy and improved progression free-survival (PFS) compared to osimertinib in patients with untreated EGFR-mutated NSCLC.3

The Phase III PALOMA-3 trial (NCT05388669) investigated the efficacy of subcutaneous versus intravenous administration of

 

amivantamab with lazertinib in patients with EGFR-mutated metastatic NSCLC, who showed progression of cancer after osimertinib and platinum-based chemotherapy. A cohort of 418 patients were randomized in a 1:1 ratio to either the subcutaneous group (n=206) or the intravenous group (n=212). Primary endpoints looked at observed serum concentrations (for day 1 of cycles 2 and 4) and the area under the curve for cycle 2 from day 1 to day 15. Secondary endpoints looked at objective response rate (ORR) and PFS. Additional exploratory analysis included the overall survival (OS).

Primary results from the trial, which were presented at the American Society of Clinical Oncology (ASCO) 2024 Annual Congress, showed that both primary endpoints were met. The ORR for the subcutaneous cohort was 30%, and 33% for the intravenous cohort, with a median PFS of 6.1 months and 6.3 months respectively. The OS of patients in the subcutaneous group was significantly longer than the intravenous group (95% CI: 0.42 to 0.92).  Subcutaneous amivantamab had a  safety profile consistent with intravenous administration and had significantly lower rates of infusion-related reactions and venous thromboembolic events (VTE).4

Subcutaneous infusions offer patients a faster and more convenient administration option with prolonged survival. Subcutaneous administration was found to improve overall patient experience due to lower resource utilization and significantly higher patient satisfaction.5

NIAGARA: The addition of perioperative durvalumab with neoadjuvant chemotherapy for MIBC

 

Almost 50% of patients with muscle-invasive bladder cancer (MIBC) develop recurrence within 3 years of standard treatment with neoadjuvant chemotherapy (cisplatin and gemcitabine) and radical cystectomy.6 The single-arm Phase II SAKK 06/17 trial (NCT03406650) previously suggested that the addition of perioperative durvalumab, an anti-programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitor (ICI), may provide higher rates of event-free survival and overall survival at 2 years for patients with MIBC.7 A Phase I/II trial (NCT01693562) additionally demonstrated that durvalumab is safe and efficacious in patients with locally advanced urothelial carcinoma.8

The Phase III open-label NIAGARA trial (NCT03732677) investigated the safety and efficacy of introducing durvalumab to standard immunotherapy in the perioperative setting. A cohort of 1063 adult patients with cisplatin-eligibility were randomized in a 1:1 fashion. The first arm (n=533) received neoadjuvant cisplatin-based chemotherapy (cisplatin and gemcitabine) and durvalumab followed by radial cystectomy and then adjuvant treatment with durvalumab alone. The second arm (n=530) received neoadjuvant chemotherapy with cisplatin and gemcitabine, followed by radial cystectomy alone. The main primary outcome measure was event-free survival (EFS), and overall survival (OS) was the main secondary outcome measure.9

Results were presented at the European Society for Medical Oncology (ESMO) 2024 Congress, which showed that estimated EFS

 

at 24 months was 67.8% (95% CI: 63.6 to 71.7) for the durvalumab cohort. Estimated OS at 24 months was 82.2% in the durvalumab group (95% CI: 78.7 to 85.2). Addition of durvalumab was also tolerable and grade 3/4 adverse events were similar in both arms. 9

This approach provides a potential practice-changing solution to reducing post-surgery recurrence rates in patients with MIBC. The FDA has recently granted priority review for perioperative durvalumab plus neoadjuvant chemotherapy before radical cystectomy based on the promising results from the NIAGARA trial. The prospective approval will make durvalumab plus neoadjuvant chemotherapy the first perioperative immunotherapy therapeutic strategy for patients with MIBC.6

KEYNOTE-522: Pembrolizumab with chemotherapy improved OS in patients with TNBC

 

Triple negative breast cancer (TNBC) is an aggressive subtype, which is prone to failure from standard breast cancer treatment due to a lack of therapeutic targets. The KEYNOTE-355 trial (NCT02819518) has previously shown that pembrolizumab, a PD-(L)1 inhibitor, administered in the neoadjuvant and adjuvant settings combined with chemotherapy enhanced the PFS of patients with high PD-L1 expressing tumors.10 The significant findings from this study led to the FDA approval of pembrolizumab and chemotherapy in 2020 for patients with locally recurrent unresectable or metastatic TNBC, whose tumors had a PD-L1 combined positive score of at least 10.11

The Phase III KEYNOTE-522 trial (NCT03036488) reported the overall survival rates for the safety and efficacy of pembrolizumab with platinum-containing chemotherapy in neoadjuvant and adjuvant settings for patients with untreated stage II or III early-stage triple-negative breast cancer (TNBC). 1174 patients were randomized in a

 

2:1 ratio to receive either pembrolizumab-chemotherapy (n=784) or placebo-chemotherapy (n=390). All patients received neoadjuvant treatment of either pembrolizumab or placebo with chemotherapy for 24 weeks, then underwent surgery 3 to 6 weeks after the last cycle of neoadjuvant therapy, followed by single agent adjuvant therapy of either pembrolizumab or placebo for 27 weeks post-surgery. Platinum-based chemotherapy involved paclitaxel and carboplatin for the neoadjuvant phase, followed by doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide in the adjuvant phase. Primary outcome measures looked at pathologic complete response (pCR) and event-free survival (EFS), and main secondary outcome was overall survival (OS).12,13

Preliminary findings, which were presented at the ESMO 2024 Congress, revealed that the estimated EFS at 36 months was 84.5% (95% CI: 81.7 to 86.9) and the percentage of patients showing a pCR was 64.8% in the pembrolizumab-chemotherapy group.12 The updated results found that the estimated OS at 60 months was 86.6% for the pembrolizumab-chemotherapy group (95% CI: 84.0 to 88.8).13 Adverse events observed were similar to the established safety profile of pembrolizumab and chemotherapy in previous studies.10

The preliminary results on the significant pCR and EFS rates from the KEYNOTE-522 trial led to the FDA approval of this combination therapy for patients with high-risk early-stage TNBC in 2021.14 The final OS results in 2024 further confirm the safety and efficacy of this combination therapy, which provides patients with prolonged survival and revolutionizes the treatment regimen of advanced TNBC.

NADINA: Efficacy of neoadjuvant nivolumab with ipilimumab for macroscopic, resectable stage III melanoma

 

Standard of care for advanced melanoma includes surgery followed by adjuvant therapy with immune checkpoint inhibitors (ICIs) like nivolumab, pembrolizumab or dabrafenib and trametinib for BRAF-mutated melanoma, which target PD-1.15 The CheckMate 067 trial (NCT01844505) 5howed that nivolumab with ipilimumab, an anti-CTLA4 (cytotoxic T-lymphocyte associated protein 4) ICI has provided longer survival benefits for patients with advanced melanoma.16 Subsequently the Phase II SWOG S1801 trial (NCT03698019) has demonstrated that the addition of pembrolizumab in the neoadjuvant setting was superior to adjuvant pembrolizumab alone in patients with stage III or IV melanoma.17 These trial findings provided the rationale for clinical investigations of neoadjuvant nivolumab and ipilimumab for advanced melanoma treatment.

The global Phase III NADINA trial (NCT04949113) investigated the efficacy of neoadjuvant nivolumab and ipilimumab in patients with macroscopic, resectable stage III melanoma. 423 patients were randomized 1:1 to one of two arms. The first arm received 2 cycles of neoadjuvant nivolumab and ipilimumab every 3 weeks followed by total lymph node dissection (TNLD) surgery, and resection of metastases if necessary, and the second arm underwent surgery followed by 12 cycles of adjuvant therapy with nivolumab every 4 weeks. The primary outcome looked at event-free survival (EFS).17

The primary results from the trial, presented at the showed that the estimated 12-month EFS was 83.7% for the neoadjuvant group (95%

 

CI: 73.8 to 94.8). Additionally, 59% of patients had a complete pathologic response, of which 95.1% were estimated to have 12-month recurrence-free survival. Patients in the neoadjuvant group that had a partial response (8%) or non-response (26.4%) to treatment were given adjuvant therapy. Of these, the estimated 12-month recurrence-free survival was 76.1% for those with a partial response and 57% for those who were non-responsive.15

The NADINA trial is the first Phase III trial to successfully investigate the efficacy of neoadjuvant therapy with ICIs alone against the standard regimen for advanced melanoma treatment. Neoadjuvant nivolumab and ipilimumab followed by response-appropriate adjuvant therapy can positively improve event-free survival rates for patients with resectable, macroscopic stage III melanoma.15

 

References

  1. Cho BC, Simi A, Sabari J, Vijayaraghavan S, Moores S, Spira A. Amivantamab, an Epidermal Growth Factor Receptor (EGFR) and Mesenchymal-epithelial Transition Factor (MET) Bispecific Antibody, Designed to Enable Multiple Mechanisms of Action and Broad Clinical Applications. Clinical Lung Cancer. 2023 Mar;24(2):89–97. doi: 10.1016/j.cllc.2022.11.004
  2. U.S. Food and Drug Administration. FDA approves lazertinib with amivantamab-vmjw for NSCLC. 2024 [cited 2024 Dec 10]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer
  3. Cho BC, Lu S, Felip E, Spira AI, Girard N, Lee JS, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR -Mutated Advanced NSCLC. New England Journal of Medicine. 2024 Jun 26;391(16):1486–98. doi: 10.1056/nejmoa2403614
  4. Leighl NB, Akamatsu H, Sun Min Lim, Cheng Y, Minchom AR, Marmarelis ME, et al. Subcutaneous versus Intravenous Amivantamab, both in Combination with Lazertinib, in Refractory EGFR-mutated NSCLC: Primary Results from the Phase 3 PALOMA-3 Study. Journal of Clinical Oncology. 2024 Jun 10; doi: 10.1200/JCO.24.01001
  5. Alexander M, Cheng Y, Lee SH, Passaro A, Spira AI, Cho BC, et al. OA09.05 Subcutaneous vs Intravenous Amivantamab: Patient Satisfaction and Resource Utilization Results from the PALOMA-3 Study. Journal of Thoracic Oncology. 2024 Oct 1;19(10):S29–9. doi: 10.1016/j.jtho.2024.09.05
  6. Astra Zeneca. Imfinzi granted Priority Review in the US for patients with muscle-invasive bladder cancer [Internet]. 2024 [cited 2024 Dec 10]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2024/imfinzi-granted-priority-review-in-the-us-for-patients-with-muscle-invasive-bladder-cancer.html
  7. Cathomas R, Rothschild SI, Hayoz S, Bubendorf L, Özdemir BC, Kiss B, et al. Perioperative chemoimmunotherapy with Durvalumab for Muscle-Invasive urothelial carcinoma: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/17. Journal of Clinical Oncology. 2023 Aug 17;41(33):5131–9. doi: https://doi.org/10.1200/jco.23.00363
  8. Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncology. 2017;3(9):e172411. doi: https://www.ncbi.nlm.nih.gov/pubmed/28817753
  9. Powles T, Catto JWF, Galsky MD, Al-Ahmadie H, Meeks JJ, Nishiyama H, et al. Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. New England Journal of Medicine. 2024 Sep 15;391:1773-1786. doi: 10.1056/nejmoa2408154
  10. Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. New England Journal of Medicine. 2022 Jul 20;387(3):217–26. doi: 10.1056/nejmoa2202809
  11. U.S. Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. 2021 Jun 11[cited 2024 Dec 10]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-locally-recurrent-unresectable-or-metastatic-triple
  12.  Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kümmel S, et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. New England Journal of Medicine. 2022 Feb 9;386(6):556–67. doi: 10.1056/nejmoa2112651
  13. Schmid P, Cortes J, Dent R, McArthur H, Pusztai L, Kümmel S, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. New England Journal of Medicine. 2024 Sep 15; doi: https://doi.org/10.1056/nejmoa2409932
  14. U.S. Food and Drug Administration. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. 2021 Aug 11[cited 2024 Dec 18]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer
  15. Blank CU, Lucas MW, Scolyer RA, Van De Wiel BA, Menzies AM, Lopez-Yurda M, et al. Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma. New England Journal of Medicine. 2024 Jun 2; 391:1696-1708. doi: https://doi.org/10.1056/nejmoa2402604
  16. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. New England Journal of Medicine. 2019 Sep 28;381(16):1535–46. doi: https://doi.org/10.1056/nejmoa1910836
  17. Patel SP, Othus M, Chen Y, Wright GP, Yost KJ, Hyngstrom JR, et al. Neoadjuvant–Adjuvant or Adjuvant-Only pembrolizumab in advanced melanoma. New England Journal of Medicine. 2023 Mar 1;388(9):813–23. doi: https://doi.org/10.1056/nejmoa2211437

Written by Rachana Vashisht

Edited by Simon Ng

The content of VJOncology is intended for healthcare professionals