|LETTER TO EDITOR
|Year : 2022 | Volume
| Issue : 1 | Page : 182-183
Immunotherapy for triple-negative breast cancer: Time to pause?
Vamshi Krishna Muddu1, Nanditha Boindala2
1 Department of Medical Oncology, Institute of Oncology, AIG Hospitals, Hyderabad, Telangana, India, India
2 Department of Radiation Oncology, Institute of Oncology, AIG Hospitals, Hyderabad, Telangana, India, India
|Date of Submission||21-Jan-2022|
|Date of Decision||27-Jan-2022|
|Date of Acceptance||01-Feb-2022|
|Date of Web Publication||31-Mar-2022|
Vamshi Krishna Muddu
Department of Medical Oncology, AIG Hospitals, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Muddu VK, Boindala N. Immunotherapy for triple-negative breast cancer: Time to pause?. Cancer Res Stat Treat 2022;5:182-3
We read with interest the article by Sharma and Gogia, titled “Management of triple-negative breast cancer in the era of novel therapies: A narrative review.” The article succinctly outlines the changing landscape in the treatment of triple-negative breast cancer (TNBC) and highlights the newer treatment options, including immune checkpoint inhibitors (ICIs). While ICIs have resulted in better outcomes in lung, kidney, bladder cancers, and melanomas, we believe that their role in TNBC still needs to be defined. We would welcome the authors' opinion regarding the following concerns about the use of ICIs for breast cancer in the neoadjuvant and metastatic settings.
In the neoadjuvant setting in TNBC, two landmark randomized phase III trials, KEYNOTE-522 and IMpassion031 have tested the efficacy of pembrolizumab and atezolizumab, respectively, in combination with chemotherapy. Both these studies looked at pathological complete response (pCR) as the primary endpoint. The pCR rates from the addition of atezolizumab in the unselected population were 58% versus 41% (absolute difference of 17%) and in the programmed death-ligand 1 (PD-L1) positive subgroup, they were 69% versus 49% (absolute difference of 20%). Similar results were seen in the KEYNOTE-522 (64.8% vs. 51.2%, absolute difference of 13.6% in an unselected population). Both trials seemed to suggest that the benefit of immunotherapy occurred regardless of the PD-L1 status. However, conflicting results were reported from the neoadjuvant therapy in TNBC With anti-PDL1 (NeoTRIPaPDL1) study. This study looked at the pCR rates attained by adding atezolizumab to a combination of carboplatin and nab-paclitaxel. Overall, the pCR rate difference was only 2.6% in the intention-to-treat (ITT) population (odds ratio, 1.11, P = 0.66), with no significant benefit noted even in the PD-L1 positive subgroup. The GeparNuevo study, which looked at the efficacy of durvalumab in combination with chemotherapy in the neoadjuvant setting also failed to show a difference in pCR rates but surprisingly showed a benefit in overall survival (OS), distant disease-free survival, and invasive disease-free survival. A recent metanalysis in the British Medical Journal looking at individual patient data has shown that pCR after chemotherapy is only weakly correlated with event-free survival and OS. Considering the lack of clear benefit in the survival endpoints, conflicting results, cost of therapy, and lack of reliable predictive biomarkers, we can certainly question whether ICIs should, in fact, be considered as the standard of care for neoadjuvant therapy.
A similar pattern has been reported in metastatic breast cancer. The IMpassion130 study showed an OS benefit with the addition of atezolizumab to nab-paclitaxel (25 months vs. 15.5 months) in the PD-L1 positive group, but only a progression-free survival (PFS) benefit in the ITT population. Changing the chemotherapy backbone to paclitaxel in IMpassion131 surprisingly failed to result in either a PFS or OS benefit in both the ITT and the PD-L1 positive cohorts. In contrast, the final analysis of KEYNOTE-355 with pembrolizumab showed both OS and PFS benefits in the PD-L1 enriched group (CPS ≥10), 23 months versus 16.1 months (27% reduction in risk of death).,
Overall, the results of immunotherapy trials in TNBC raise several interesting questions: Are we looking at the right endpoints? Do we have the right biomarkers for testing sensitivity to immunotherapy?, Does altering the chemotherapy backbone change the way that immunotherapy works? The discordant results of these various studies should urge caution in pushing ICIs into routine use in TNBC. Longer follow-up is warranted before any final conclusions can be made.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sharma RK, Gogia A. Management of triple-negative breast cancer in the era of novel therapies: A narrative review. Cancer Res Stat Treat 2021;4:668-76. [Full text]
Menon N, Mailankody S. Immunotherapy protocols in lung cancer. Cancer Res Stat Treat 2018;1:139-62. [Full text]
Kapoor A. Current systemic therapy options in advanced clear cell renal cell cancer. Cancer Res Stat Treat 2021;4:124-6. [Full text]
Ravind R. Combinations will lead the way in immunotherapy for bladder cancer. Cancer Res Stat Treat 2020;3:603-7. [Full text]
Mittal A, Gupta A, Rastogi S. Melanoma at American society of clinical oncology 2020 – An update and its implications in the Indian setting. Cancer Res Stat Treat 2020;3:594-7. [Full text]
Gianni L, Huang C, Egle D, Bermejo B, Zamagni C, Thill M, et al
. Pathologic complete response to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 michelangelo randomized study. In: San Antonio Breast Cancer Symp. Cancer Res 2020;80: Abstract nr GS3-04.
Tarantino P, Gandini S, Trapani D, Criscitiello C, Curigliano G. Immunotherapy addition to neoadjuvant chemotherapy for early triple negative breast cancer: A systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 2021;159:103223.
Conforti F, Pala L, Sala I, Oriecuia C, De Pas T, Specchia C, et al.
Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomised clinical trials of early stage breast cancer: Systematic review and meta-analysis. BMJ 2021;375:e066381.
Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al.
Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): Updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:44-59.
Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al.
Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396:1817-28.
Khaddar S, Mishra BK. Biomarkers for response to immune checkpoint inhibitors: Where do we stand? Cancer Res Stat Treat 2021;4:363-4. [Full text]