Recent evidence suggests that neoadjuvant immunotherapy offers a unique opportunity to explore disease mechanisms and identify new biomarkers of immune checkpoint blockade response and resistance, according to the researchers.
Treatment with immune checkpoint blockades (ICBs) in the neoadjuvant setting is being explored in hundreds of clinical trials across several cancer types and has been approved in 2 disease settings in the past 2 years. In a recent review published in Cancer Cell, researchers examined the advances made in a selection of cancers, as well as their implications for neoadjuvant ICB use across other cancer types.1
Investigators at the Bloomberg~Kimmel Institute for Cancer Immunotherapy and Johns Hopkins Kimmel Cancer Center focused on clinical developments in non–small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), skin cancers, and gastrointestinal cancers, all of which have seen significant advances regarding immunotherapy in the neoadjuvant setting.
“We consider this approach to cancer immunotherapy to be a gold mine for advancing our scientific knowledge of how an immune checkpoint blockade is working, to define better biomarkers that predict clinical outcomes, and to help us design the next generation of more effective treatments with combination therapies,” said lead author Suzanne Topalian, MD, director of the Johns Hopkins Melanoma/Skin Cancer Program and associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, in a statement.2
While ICB use in the neoadjuvant is still investigational across most disease states, it is currently approved for patients with TNBC and in NSCLC, the authors noted. In the neoadjuvant setting, immunotherapy is given to treatment-naïve patients with the intent to cure.
“Beyond its potential to enhance surgical resectability of the primary tumor, neoadjuvant immunotherapy further seeks to utilize the primary tumor as a source of antigens recognized by the immune system, inducing or enhancing systemic anti-tumor immunity to target and eliminate distant micrometastases that would otherwise become the nidus of post-surgical relapse,” the authors explained.
The authors highlighted a plethora of data surrounding ICB use across diseases, with several notable main themes currently emerging among trials with median follow-ups longer than 2 years across tumor types.
The first is that neoadjuvant anti-PD-L1/PD-1 treatment and combinations containing anti-PD-L1/PD-1 agents, which have already shown effectiveness against unresectable tumors, seem to be effective when given before surgery.
“That said, it is impossible to directly compare pathologic responses in the neoadjuvant setting to clinical responses according to radiographic criteria typically used to assess tumor regression in unresectable cancers, since radiographic responses after ICB tend to underestimate pathologic responses,” the authors noted.
Another significant finding was that the depth of response to neoadjuvant ICBs correlated with the length of relapse-free survival following surgical resection. Particularly in trials exploring neoadjuvant ICBs in TNBC and NSCLC, few patients relapsed after experiencing pathologic complete responses (pCR) with no evidence of residual malignant cells at the time of surgery.
“In addition to more sophisticated analyses of resected tumors, improved serum/plasma [circulating tumor]DNA and proteomic technologies to detect minimal residual disease will likely emerge as important biomarkers, alone or in conjunction with pathologic response, to guide post-surgical treatment or observation,” the authors wrote.
Additionally, the review found that neoadjuvant ICBs may prime antitumor activity in the immune system and have potential to positively impact surgery by minimizing the size of tumors to make their removal less disfiguring, or even making surgery unnecessary altogether. This could improve both cosmetic and functional outcomes in tumors types where resection can be disfiguring, such as Merkel cell carcinoma and cutaneous squamous cell carcinoma.
Finally, the authors emphasized the importance of analyses of viable tumor cell specimens following resection in patients who received ICBs ahead of surgery. This type of research can provide insight into mechanisms of action and treatment resistance.
“With an explosion of scientific insights and clinical benefits emerging from neoadjuvant ICB and its combinations with targeted kinase inhibitors, chemotherapies, other immunotherapies and experimental agents, this field of translational investigation is still just scratching the surface of possibilities,” the authors concluded. “Hundreds of neoadjuvant ICB trials are now underway—they must be carefully designed to answer the most salient clinical and scientific questions in this new age of cancer immunotherapy.”
1. Topalian SL, Forde PM, Emens LA, Yarchoan M, Smith KN, Pardoll DM. Neoadjuvant immune checkpoint blockade: A window of opportunity to advance cancer immunotherapy. Cancer Cell. 2023;41(9):1551-1566. doi:10.1016/j.ccell.2023.07.011
2. Immune checkpoint blockade prior to surgery promising in multiple cancer types. News release. Johns Hopkins Medicine. September 28, 2023. Accessed September 29, 2023. https://www.newswise.com/articles/immune-checkpoint-blockade-prior-to-surgery-promising-in-multiple-cancer-types