Neoadjuvant immunotherapy: Results in melanoma show promise and pave the way for other solid tumors

It is astonishing to consider that it was only 10 years ago that the first immune checkpoint blockade inhibitor garnered Food and Drug Administration approval. Modern immunotherapy began as single-agent therapy in patients with widely metastatic disease in just a few types of cancer, whereas today, hundreds of different agents targeting various aspects of the anti-tumor immune response are being tested in all phases of clinical trials across different cancer histologies.¹ Immunotherapy has evolved from the treatment of widely metastatic disease to adjuvant treatment following surgical resection and more recently to neoadjuvant therapy for resectable disease.

TABLE 1. SELECTED EXAMPLES OF RESULTS FOR NEOADJUVANT IMMUNOTHERAPY TRIALS

More than 100 clinical trials are now investigating neoadjuvant immunotherapeutic strategies alone in diverse malignancies, including melanoma, non-small cell lung cancer (NSCLC), breast cancer, head and neck squamous cell carcinoma (HNSCC), sarcoma, and others (see Table 1). These neoadjuvant trials include both true neoadjuvant studies (typically a longer course of treatment with the goal of a measurable pathologic or clinical response) and window-of-opportunity trials, where agents are administered in the window between cancer diagnosis and planned definitive surgical therapy, allowing for short-term assessment of therapeutic efficacy.

Rationale for neoadjuvant immunotherapy

The overarching goal of administering immunotherapy in the neoadjuvant setting is to incite the most robust systemic anti-tumor immune response possible while the tumor remains in situ. The hope is that this immune response will persist long after the tumor is resected. Preclinical studies and early-stage clinical trials do, indeed, suggest an improved anti-tumor immune response to neoadjuvant versus adjuvant administration of immune checkpoint blockade.^2,3 Neoadjuvant strategies also can provide insight into the therapeutic efficacy of these relatively novel agents upon evaluation of the treated surgical specimen. Longitudinal biopsies (diagnostic biopsy, early on-treatment biopsy, and surgical specimen) are critical for translational research; specimens collected during neoadjuvant immunotherapy trials have provided key insights into our understanding of the anti-tumor immune response, resulting in improvement in current therapies, as well as development of novel therapeutics.

Successful use of neoadjuvant immunotherapy trials in melanoma

The rollout of clinical trials for neoadjuvant immunotherapy in advanced melanoma is a story of incremental progress built on international collaboration and thoughtful trial design. These trials are rapidly changing clinical practice and have become a model for others.

Early neoadjuvant trials in melanoma were small and used agents with little to no prior proven efficacy; thus, interest was limited, and most patients with advanced or oligometastatic disease proceeded immediately to surgical resection. The development of effective immune checkpoint blockade therapies reignited interest in neoadjuvant strategies, and initial studies were conducted using anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4) in combination with high-dose interferon.⁴ More recent trials have used anti-PD-1 or PD-L1 therapies alone or combined with anti-CTLA-4 agents.

The Phase 1b OpACIN (Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients) trial compared neoadjuvant and adjuvant administration of combined anti-PD-1 and anti-CTLA-4 therapies with adjuvant administration alone.³ A concurrent study compared neoadjuvant administration of anti-PD-1 alone with a combination of anti-PD-1 and anti-CTLA-4 therapy; both groups received adjuvant anti-PD-1 therapy.⁵ Both studies had an excellent response rate (33 percent to 45 percent pathologic complete response [pCR]) but were hindered by concerningly high toxicity in the most efficacious combination treatment groups (up to 70 percent to 90 percent Grade 3 or higher).^3,5 A follow-up study (OpACIN-neo; Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab) identified a dosing strategy for combination anti-PD1 and anti-CTLA-4 therapy that maintained efficacy (pCR of 57 percent) with markedly lower toxicity rates (20 percent Grade 3 adverse events).⁶

The durability of the response in patients exhibiting pCR in these studies (96 percent 24-month relapse-free survival) has been impressive.⁷ This finding has called into question the need for adjuvant therapy or even surgical resection when a pCR is obtained and has led to an intriguing ongoing trial, which tailors additional therapy based on pathologic response to neoadjuvant treatment (PRADO extension cohort of OpACIN-neo).⁸

The success of these trials has spurred interest in developing similar early-phase clinical trials in melanoma, including those combining immunotherapy with targeted therapies (NeoTrio NCT02858921, NeoACTIVATE NCT03554083, NeoPeLe NCT04207086) or other therapeutic modalities including radiation and intratumoral oncolytic viral therapies (Neo-NivoHF10 NCT03259425), concentrated cytokines (NCT04526730), and additional immunomodulators (NCT04708418), among others. Many of the clinicians and researchers involved in these studies have united to form the International Neoadjuvant Melanoma Consortium to establish standardized protocols and trial design platforms that have been made widely available.⁹ This group also has established common criteria for the pathologic evaluation of surgical specimens following neoadjuvant immunotherapy and has taken a concerted look at potential biomarkers of response/survival across trials.^10,11

Early promise across multiple solid tumor types

Results from neoadjuvant trials using immune checkpoint blockade in other solid-tumor malignancies are similarly encouraging. These trials have confirmed both the safety and efficacy of this treatment strategy (see Table 1). In NSCLC, neoadjuvant immune checkpoint blockade used in early-stage resectable NSCLC led to a 43 percent major pathologic response (MPR) and 14 percent pCR rate at time of resection.¹² In soft-tissue sarcoma, MPR was seen in 89 percent of patients with extremity/trunk undifferentiated pleomorphic sarcoma treated with immune checkpoint blockade and radiation.¹³ Although no pCRs were observed in a trial investigating anti-PD-1 agents in resectable HPV-unrelated HNSCC, 44 percent of patients exhibited a pathologic response in the tumor.¹⁴ Grade 3 or higher adverse event rates have generally been much lower than those complications observed in the early melanoma trials discussed earlier, as low as 8 percent in the HNSCC trial using a single anti-PD-1 agent.¹⁴

These studies have generally enrolled small numbers of patients, but larger studies are beginning to mature. A Phase 3 study involving 1,174 patients with treatment-naive triple-negative breast cancer showed that combining an anti-PD-1 agent with chemotherapy (n = 784) led to a significant increase in pCR rates at the time of surgical resection compared with patients receiving chemotherapy alone (n = 390) (64.8 percent versus 51.2 percent).¹⁵ Additional ongoing Phase 3 studies and longer follow-up from some of the initial investigations will ultimately provide the data needed to determine how to best incorporate these strategies into multidisciplinary care.

Unanswered questions

Not unlike the integration of radiation and/or chemotherapeutic strategies, the use of immunotherapeutic agents is transforming the operative management of patients with solid tumors. Although the long-term outcomes in patients achieving a complete response to these therapies are remarkable, this still represents only a minority of patients.

Furthermore, these agents often have significant adverse effects, which may be severe and include colitis, myocarditis, hepatitis, renal injury, pneumonitis, and endocrinopathies such as hypopituitarism, among others. Moreover, many of the endocrinopathies associated with immune checkpoint blockade, including thyroiditis and type 1 diabetes, have lifelong effects and can significantly affect the patient’s quality of life.¹⁶

There is a dire need for identification of biomarkers of treatment response to guide patient selection and minimize the potential toxicity of these agents, as well as the continued development of novel therapeutic agents. However, the sheer magnitude of progress in this realm in a short amount of time and translation across disease groups has provided much hope for patients.

References

1. Upadhaya S, Hubbard-Lucey VM, Yu JX. Immuno-oncology drug development forges on despite COVID-19. Nat Rev Drug Discov. 2020;19(11):751-752.
2. Liu J, Blake SJ, Yong MC, et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 2016;6(12):1382-1399.
3. Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med. 2018;24(11):1655-1661.
4. Tarhini A, Lin Y, Lin H, et al. Neoadjuvant ipilimumab (3 mg/kg or 10 mg/kg) and high dose IFN-alpha2b in locally/regionally advanced melanoma: Safety, efficacy and impact on T-cell repertoire. J Immunother Cancer. 2018;6(1):112.
5. Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med. 2018;24(11):1649-1654.
6. Rozeman EA, Menzies AM, van Akkooi ACJ, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): A multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 2019;20(7):948-960.
7. Menzies AM, Amaria RN, Rozeman EA, et al. Pathological response and survival with neoadjuvant therapy in melanoma: A pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nat Med. February 8, 2021 [Epub ahead of print].
8. Blank CUR, Reijers ILM, Pennington T, et al. First safety and efficacy results of PRADO: A phase II study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma. J Clin Onc. 2020;38(15_suppl):10002.
9. Amaria RN, Menzies AM, Burton EM, et al. Neoadjuvant systemic therapy in melanoma: Recommendations of the International Neoadjuvant Melanoma Consortium. Lancet Oncol. 2019;20(7):e378-e389.
10. Tetzlaff MT, Messina JL, Stein JE, et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann Oncol. 2018;29(8):1861-1868.
11. Rozeman EA, Hoefsmit EP, Reijers ILM, et al. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat Med. February 8, 2021 [Epub ahead of print].
12. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378(21):1976-1986.
13. Roland CL, Keung EZ, Lazar AJ, et al. Preliminary results of a phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). J Clin Onc. 2020;38(15_suppl):11505.
14. Uppaluri R, Campbell KM, Egloff AM, et al. Neoadjuvant and adjuvant pembrolizumab in resectable locally advanced, human papillomavirus-unrelated head and neck cancer: A multicenter, phase II trial. Clin Cancer Res. 2020;26(19):5140-5152.
15. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821.
16. Helmink BA, Roland CL, Kiernan CM, et al. Toxicity of immune checkpoint inhibitors: Considerations for the surgeon. Ann Surg Oncol. 2020;27(5):1533-1545.