Neoadjuvant T-VEC May Improve Survival in Advanced Melanoma

Author(s):

Talimogene laherparepvec (T-VEC; Imlygic) prior to surgery was associated with improved recurrence-free survival and overall survival compared with surgery alone in patients with resectable advanced melanoma.

John Hyngstrom, MD, an assistant professor of surgical oncology with the Huntsman Cancer Institute at the University of Utah

John Hyngstrom, MD

Talimogene laherparepvec (T-VEC; Imlygic) prior to surgery was associated with improved recurrence-free survival (RFS) and overall survival (OS) compared with surgery alone in patients with resectable advanced melanoma, according to results from an open-label, phase II trial.¹

Data presented in a poster at the 16th International Congress of the Society for Melanoma Research showed that at a median follow-up of 31.2 months, the 2-year OS rate in the T-VEC arm was 88.9% versus 77.4% for surgery alone (HR, 0.49; 80% CI, 0.30-0.79; P = .05).

The 2-year RFS rate was 29.5% with T-VEC plus surgery compared with 16.5% with T-VEC alone (P =.07). Further, patients in the T-VEC arm had better outcomes despite receiving less subsequent therapy with checkpoint inhibitors.

“There’s an absolute improvement of about 14% in terms of RFS compared with surgery alone,” said study co-author John Hyngstrom, MD, an assistant professor of surgical oncology with the Huntsman Cancer Institute at the University of Utah. “What was surprising was that there was an improvement in 2-year OS, which [we] were not necessarily looking for.”

Investigators recruited 150 patients with high-risk resectable stage IIIB-IVM1a melanoma at sites in 9 countries. Patients were then randomly assigned to immediate surgery (n = 74) or intralesional T-VEC followed by surgery at week 13 (n = 76).

Investigators previously presented 1-year results from the study at the 2019 ASCO Annual Meeting.² The efficacy analysis shared at ASCO included 57 patients who received at least 1 dose of T-VEC and had surgery and 69 patients who had immediate surgery.

In the T-VEC arm, 33.5% of patients remained recurrence-free compared with 21.9% of patients who had surgery only (HR, 0.73; 80% CI, 0.56-0.93; P = .048). A sensitivity analysis that excluded positive surgical margins as an RFS event produced a larger difference in favor of neoadjuvant therapy (HR, 0.63; 80% CI, 0.47-0.83; P = .024).

More patients randomized to T-VEC were alive at 1 year (95.9% vs 85.8%; HR, 0.47; 80% CI, 0.27-0.82; P = .076), but at the time of the analysis, the difference did not reach statistical significance.

Of the 57 patients in the T-VEC arm in the efficacy analysis, 13 (22.8%) had a pathologic complete response (pCR). The pCR rate was 17.1% (13 of 76) in the T-VEC arm in the intent-to-treat analysis.

Investigator-assessed clinical response in the T-VEC arm was 13.2% (10 of 76), including 5 of 13 patients who had pCR and 5 of the 63 who had less than pCR. The disease control rate (response plus stable disease) was 40.8% by ITT analysis, including 11 of 13 patients who had pCR and 20 of 63 patients who had less than pCR after T-VEC treatment.

The most commonly observed treatment-emergent adverse events (AEs) were flu-like symptoms.

Postoperative AE rates were 33.3% in the T-VEC group and 46.4% in the immediate-surgery group. Serious AEs (SAEs) occurred in 14.0% of the T-VEC group and 2.9% of the immediate-surgery arm. Grade 3 SAEs in the T-VEC group consisted of 2 cases of cellulitis and 1 case each of anembryonic gestation, cholecystitis, device occlusion, influenza, and wound infection. In the immediate-surgery group, grade 3 SAEs consisted of 1 case each of peripheral embolism and wound abscess.

Hyngstrom said the ongoing phase Ib/III MASTERKEY-265/KEYNOTE-034 trial (NCT02263508) is evaluating patients with unresectable stage III/IV disease assigned to pembrolizumab (Keytruda) plus T-VEC or placebo. That study has not reported data yet, but he said combining a checkpoint inhibitor with T-VEC in a neoadjuvant setting could result in improved pathologic complete response and RFS.

“There's some correlative evidence that would suggest that, certainly in patients where we can detect CD8+ cell density or PD-L1 expression, that there might be [synergy] with a PD-1 inhibitor,” he added. “That would be the natural thing to combine with a PD-1 inhibitor.”

References

Dummer R, Gyorki DE, Hyngstrom J, et al. Improved recurrence-free survival (RFS) from a randomized phase 2 study of neoadjuvant (neo) talimogene laherparepvec (T-VEC) plus surgery (surg) vs surg for resectable stage IIIB-IVM1a melanoma (MEL). Presented at: the 16th International Congress of the Society for Melanoma Research; November 20-23, 2019; Salt Lake City, UT.
Dummer R, Gyorki DE, Hyngstrom J, et al. One-year (yr) recurrence-free survival (RFS) from a randomized, open label phase II study of neoadjuvant (neo) talimogene laherparepvec (T-VEC) plus surgery (surgx) versus surgx for resectable stage IIIB-IVM1a melanoma (MEL). J Clin Oncol. 2019;37(suppl 15; abstr 9520). doi: 10.1200/JCO.2019.37.15_suppl.9520.