Feinberg School of Medicine
Carlos Galvez, MD
Department of Medicine
Feinberg School of Medicine
Jeffrey A. Sosman, MD
Robert H. Lurie Comprehensive Cancer Center
The use of immune checkpoint inhibitors and targeted therapies prior to surgical resection is an active area of research that has not yet led to FDA approvals. Neoadjuvant therapies may be the next step forward to improve survival in patients with advanced stage III and resected stage IV disease who are at high risk of recurrence.
Despite the improvements in recurrence-free survival using adjuvant checkpoint inhibitors and targeted therapy over the last few years, up to half of patients still relapse within 24 months.1 Given the high response rates of patients to these new immunotherapies and the emerging preclinical models pointing to improved survival and immunologic responses to tumor antigens when treatment is administered prior to surgery, several groups have explored the use of single and combination neoadjuvant regimens.2 The theoretical benefits of neoadjuvant therapy include better exposure to tumor antigen, earlier treatment of micrometastases, decreased recurrence rates and improved overall survival. Additionally, initiating neoadjuvant regimens would allow physicians to assess patient response and tolerability to therapy earlier in the disease course and possibly modify postsurgical treatment plans accordingly.
The development of neoadjuvant therapy is still in its infancy, and use in patients is limited to small, early-phase clinical trials. Several phase 2 trials for neoadjuvant therapy have been reported in the literature, with at least seven active studies currently registered on the NIH clinicaltrials.gov database.3
Checkpoint Blockade Immunotherapies
Two studies have evaluated ipilimumab and nivolumab as neoadjuvants.4,5 Results from these small, exploratory studies suggest a potential clinical benefit for presurgical treatment with immunotherapy in high-risk patients.
The OpACIN trial randomized 20 stage IIIB and IIIC patients to 3 mg/kg ipilimumab and 1 mg/kg nivolumab at four postsurgical adjuvant doses (n=10, adjuvant arm) or two presurgical and two postsurgical doses (n = 10, neoadjuvant arm).4 All patients in the neoadjuvant arm received completion lymph node dissection as part of surgical management. Seven of 10 neoadjuvant arm subjects achieved pathologic response, with three demonstrating complete pathologic response. Two neoadjuvant and four adjuvant patients relapsed after two-year follow-up. Both treatment arms suffered from poor tolerability to the drug. Nine of 10 neoadjuvant and nine of 10 adjuvant randomized patients developed severe grade 3-4 adverse events, including colitis requiring immunosuppressive treatment, elevated liver enzymes, elevated lipase and Stevens Johnson syndrome.
Amaria et al. recently published a phase 2 study of stage III and oligometastatic stage IV patients randomized to neoadjuvant nivolumab (n =12) or ipilimumab-nivolumab combination therapy (n =11) followed by resection and adjuvant nivolumab monotherapy treatment for both arms.5 The combination immunotherapy treatment arm had a nonsignificant trend in improved relapse-free survival, distant metastasis-free survival and overall survival. Higher rates of grade 3-5 toxicities were reported in the combination therapy group (73 percent) compared to the monotherapy group (8 percent). The most commonly reported high-grade adverse events were transaminitis, colitis, pneumonia and electrolyte abnormalities.
These preliminary phase 2 trials suggest that dosing for combination immunotherapy should be adjusted in future studies. Direct comparison between these studies is limited by the inclusion of stage IV oligometastatic subjects in the Amaria et al. trial.5
Dabrafenib and trametinib are also being explored as a combination BRAF-MEK inhibitor in a neoadjuvant setting. The open-label Combi-Neo phase 2 study of stages IIIB, IIIC and oligometastatic stage IV BRAFV600E/K-mutant patients randomized the patients either to neoadjuvant dabrafenib-trametinib followed by surgical resection (n=14) and adjuvant therapy or to first-line surgery followed by standard of care adjuvant therapy (n=7). The study showed a significant improvement in event-free survival for the combination neoadjuvant group (HR 0.016; P <0.0001).6 Compared to other neoadjuvant trials, combination dabrafenib-trametinib was well tolerated, with a low rate of grade 3 or higher adverse events, including two instances of diarrhea and single occurrences of pyrexia and syncope. Five patients randomized to combination neoadjuvant therapy required a dose adjustment due to toxicity, and 12 patients had their regimen temporarily halted due to
episodes of fever.
The clinical benefit for neoadjuvant dabrafenib-trametinib currently remains unclear, especially in the context of recent data from large adjuvant therapy trials. The 10 percent relapse rates in the Combi-Neo study were similar to the rates reported in the phase 3 COMBI-AD adjuvant trial of dabrafenib-trametinib following resection.7.8
Other Neoadjuvant Trials
A recent interim analysis of a phase 2 study exploring neoadjuvant talimogene laherparepvec (T-VEC) was presented at the ASCO annual meeting last spring.9 T-VEC is a genetically modified type I herpes simplex virus that replicates in tumor cells and expresses GM-CSF to improve antigen loading onto MHC-I for tumor antigen presentation to circulating APCs.9 It is currently FDA-approved for advanced melanoma and is being explored for neoadjuvant use. Stages IIIB, IIIC and IVM1a patients were randomized to T-VEC followed by surgery (n=76) or surgery with standard of care treatment (n=74). Patients in the T-VEC-randomized arm who were then operated on had a 21 percent pathologic complete response rate and 56.1 percent negative margin resection rate compared to a 40.6 percent negative margin rate for standard of care; 89.5 percent of patients developed preoperative adverse events, including pyrexia (35 percent) in the T-VEC arm, compared to only 45 percent overall for the control arm.
Preliminary phase 2 studies indicate a possible role moving forward for checkpoint blockade immunotherapy, targeted therapy and T-VEC as neoadjuvant agents in stages III and IV melanoma. Additional evidence for clinical benefit and improved tolerability is required before implementation of these regimens in clinical practice outside of trials. Given the high rate of adverse events seen in combination neoadjuvant ipilimumab-nivolumab therapy, dosing of these agents will need to be adjusted in subsequent studies.
This is an exciting time for the field, as six ongoing phase 2 trials are studying combinations of targeted therapy agents and immunotherapy in the neoadjuvant setting, including one trial (NCT02858921) with an experimental arm for combination dabrafenib, trametinib and pembrolizumab triple therapy in stages IIIB and IIIC patients.3
- Weber JS, Mandalà M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: updated results from a phase III trial (CheckMate 238). J Clin Oncol 2018; 36 (15):9502. (15:doi:10.1200/JCO.2018.36.15_suppl.9502.)
- Liu J, Blake SJ, Yong MC, et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov 2016 Jan 1:CD-16. doi:10.1158/2159-8290.CD-16-0577.
- McKean MA, Amaria RN. Multidisciplinary treatment strategies in high-risk resectable melanoma: role of adjuvant and neoadjuvant therapy. Canc treat rev 2018; 70:144-153. doi: 10.1016/j.ctrv.2018.08.011. Epub 2018 Aug 29.
- Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018 Nov; 24(11):1655.
- Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 2018 Nov; 24(11):1649.
- Amaria RN, Prieto PA, Tetzlaff MT, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol 2018; 1:19(2):181-93.
- Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. NEJM 2017; 9:377(19):1813-23.
- Ascierto PA, Eggermont AM. Neoadjuvant therapy in melanoma: the next step? Lancet Oncol 2018; 1:19(2):151-3.
- Andtbacka RH, Dummer R, Gyorki DE, et al. Interim analysis of a randomized, open-label phase 2 study of talimogene laherparepvec (T-VEC) neoadjuvant treatment (neotx) plus surgery (surgx) vs surgx for resectable stage IIIB-IVM1a melanoma (MEL). ASCO Meeting Library, presented June 4, 2018. J Clin Oncol 2018; 36 suppl; abstr 9508. https://meetinglibrary.asco.org/record/161758/abstract