Having covered adjuvant therapy yesterday, today I turn to NEOadjuvant treatments. In 2018 I wrote -
"Adjuvant therapy, is when a treatment is given AFTER signs of obvious disease have been removed, usually with surgery. And we have very good data that adjuvant treatments, both with targeted and immunotherapy, work in melanoma to prevent progression in many of those patients. After all, that is what the NED Stage IV ratties in my nivo trial proved from 2010 - 2013!!!! NEO-adjuvant therapy, is when a treatment is given BEFORE melanoma has been removed. "
Here are a zillion Neoadjuvant reports. Now, there are these:
Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Menzies, Amaria, Rozeman, et al. Nat Med. Feb 2021.
The association among pathological response, recurrence-free
survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma
remains unclear. In this study, we pooled data from six clinical trials of
anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192
patients were included; 141 received immunotherapy (104, combination of
ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted
therapy. A pathological complete response (pCR) occurred in 40% of patients:
47% with targeted therapy and 33% with immunotherapy (43% combination and 20%
monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR
50%) and OS (pCR 2-year OS 95% versus no pCR 83%). In patients
with pCR, near pCR or partial pathological response with immunotherapy, very
few relapses were seen (2-year RFS 96%), and, at this writing, no patient has
died from melanoma, whereas, even with pCR from targeted therapy, the 2-year
RFS was only 79%, and OS was only 91%. Pathological response should be an early
surrogate endpoint for clinical trials and a new benchmark for development and
approval in melanoma.
Hmmm.... While targeted therapy is almost magical in BRAF positive melanoma peeps for melting away tumors and those responses have proven at times to be durable, that durability can be fickle. This report (while not necessarily about neoadjuvant administration) is similarly illuminating:
First-line immunotherapy versus targeted therapy in patients with BRAF-mutant advanced melanoma: a real-world analysis. Pavlick, Zhao, Lee, et al. Future Oncol. Feb 2021.
Aim: To compare effectiveness of nivolumab + ipilimumab (NIVO + IPI) versus BRAF + MEK inhibitors (BRAFi + MEKi) in patients with BRAF-mutant advanced melanoma in the real-world setting.
Materials & methods: This study used the Flatiron Health electronic medical record database. Results: After adjusting for differences in baseline characteristics, NIVO + IPI was associated with a 32% reduction in risk of death versus BRAFi + MEKi. At a mean follow-up of 15-16 months, 64% of NIVO + IPI patients and 43% of BRAFi + MEKi patients were alive; subsequent therapy was administered to 33 and 41% of patients, respectively. After first-line NIVO + IPI, 20% of patients died before subsequent therapy, whereas 32% died after first-line BRAFi + MEKi.
Conclusion: In this real-world study, patients treated with first-line NIVO + IPI showed significant survival benefit versus those receiving first-line BRAFi + MEKi.
Then there's this, from ASCO....
Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma. Amaria, Postow, Tetzlaff, et al. ASCO 2021
Background: Neoadjuvant therapy (NT) for pts with clinical stage III melanoma remains an active area of research interest. Recent NT trial data demonstrates that achieving a pathologic complete response (pCR) correlates with improved relapse-free (RFS) and overall survival (OS). Checkpoint inhibitor (CPI) NT with either high or low dose ipilimumab and nivolumab regimens produces a high pCR rate of 30-45% but with grade 3-4 toxicity rate of 20-90%. In metastatic melanoma (MM), the combination of nivo with rela (anti Lymphocyte Activation Gene-3 antibody) has demonstrated a favorable toxicity profile and responses in both CPI-naïve and refractory MM. We hypothesized that NT with nivo + rela will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen.
Methods: We conducted a multi-institutional, investigator-initiated single arm study (NCT02519322) enrolling pts with clinical stage III or oligometastatic stage IV melanoma with RECIST 1.1 measurable, surgically-resectable disease. Pts were enrolled at 2 sites and received nivo 480mg IV with rela 160mg IV on wks 1 and 5. Radiographic response was assessed after completion of NT; surgery was conducted at wk 9 and specimens were assessed for pathologic response per established criteria. Pts received up to 10 additional doses of nivo and rela after surgery, with scans every 3 mo to assess for recurrence. The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST 1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses.
Results: A total of 30 pts (19 males, median age 60) were enrolled with clinical stage IIIB/IIIC/IIID/IV (M1a) in 18/8/2/2 pts, respectively. 29 pts underwent surgery; 1 pt developed distant metastatic disease while on NT. pCR rate was 59% and near pCR ( less than10% viable tumor) was 7% for a major pathologic response (MPR, pCR + near pCR) of 66%. 7% of pts achieved a pPR (10-50% viable tumor) and 27% pNR (greater than/= to 50% viable tumor). RECIST ORR was 57%. With a median follow up of 16.2 mos, the 1-year EFS was 90%, RFS was 93%, and OS was 95%. 1-year RFS for MPR was 100% compared to 80% for non-MPR pts. There were no treatment related gr 3/4 AEs that arose during NT; 26% of pts had a gr 3/4 AE that began during adjuvant treatment.
Conclusions: Neoadjuvant and adjuvant treatment with nivo and rela achieved high pCR and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings. Pts with MPR had improved outcomes compared to non-MPR pts. Translational studies to discern mechanisms of response and resistance to this combination are underway. Clinical trial information: NCT02519322.
Perhaps neoadjuvant care will become the way of the future. Thanks ratties.
best - c
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