Neoadjuvant Anti-PD-1 Strategy Prevails Over Adjuvant in Resectable Melanoma

PARIS -- The randomized trial data have spoken, and they favor neoadjuvant immunotherapy over adjuvant treatment for resectable melanoma.

Neoadjuvant pembrolizumab (Keytruda) followed by surgery and additional pembrolizumab led to a 2-year event-free survival (EFS) rate of 72% as compared with 49% for patients randomized to adjuvant therapy. A subgroup analysis showed a consistent advantage for neoadjuvant therapy.

The rate of grade ≥3 treatment-related adverse events (TRAEs) was low and did not differ between treatment groups, reported Sapna Patel, MD, of the University of Texas MD Anderson Cancer Center in Houston, at the European Society for Medical Oncology (ESMO) annual congress.

"Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab, followed by adjuvant pembrolizumab, improves event-free survival in resectable melanoma," she said.

The trial addressed a fundamental question about resectable cancer, said Patel. Does neoadjuvant immune checkpoint blockade before surgery enhance tumor response or merely delay curative surgery?

Multiple studies have documented that surgery followed by adjuvant anti-PD-1 therapy improves recurrence-free survival in high-risk melanoma. Surgery removes the majority of antitumor cells that reside in the tumor, and adjuvant therapy activates small populations of antitumor T cells at sites of systemic micrometastasis.

In contrast, anti-PD-1 therapy before surgery induces an immune response from a larger population of T cells in the bulk of the tumor, she continued. Inhibiting anti-PD-1/L1 before surgery induces a systemic antitumor response locally and at distant sites.

"This approach is hypothesized to leave behind larger numbers of antitumor T cells that can be activated and circulated systemically to recognize and attack micrometastatic melanoma tumors," said Patel.

She and her colleagues designed and conducted the SWOG S1801 trial to determine whether neoadjuvant anti-PD-1 therapy would lead to a better EFS as compared with adjuvant therapy. Patients in both arms received 18 cycles of pembrolizumab. Those randomized to the adjuvant arm received all 18 doses after surgery. Those in the neoadjuvant arm received three cycles of pembrolizumab before surgery and the remaining 15 afterward.

The primary analysis included 313 randomized patients. The analysis confirmed the superiority of the neoadjuvant strategy, as the 23% absolute difference in EFS at 2 years translated into a 42% reduction in the hazard ratio (95% CI 0.39-0.87, P=0.004). Overall survival did not differ significantly in an early analysis but yielded a trend favoring the neoadjuvant strategy (HR 0.63). A subgroup analysis showed a consistent benefit across all major groups.

Grade ≥3 TRAEs occurred infrequently during the neoadjuvant phase, during surgery, and during the adjuvant phase.

During neoadjuvant treatment three patients had grade ≥3 increases in alanine transaminase (ALT), and two patients each had increased aspartate transaminase (AST) and hyperglycemia. The most common TRAEs during surgery were wound infection, occurring in two patients in the adjuvant arm and three in the neoadjuvant arm. During the adjuvant treatment, grade ≥3 maculopapular rash occurred in four patients in the adjuvant arm, and two patients each in the adjuvant arm had increased ALT, increased AST, and nausea.

The trial added to previous support for a neoadjuvant strategy from preclinical, biological, and clinical studies, said Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Center in Melbourne, Australia, one of two ESMO-invited discussants for the session.

"I suspect [the neoadjuvant approach] should be considered for all cancers in the early-stage setting that are developing immunotherapy combinations or approaches," said Loi, who provided a translational perspective for SWOG 1801. "Validation of pathologic responses will be important for other tumor types, particularly their relationship to long-term outcomes. Additional biomarker work will be important for escalating and de-escalating adjuvant therapy and understanding who does really well," she said.

SWOG 1801 yielded a "pretty striking result," said James Larkin, MD, of the Royal Marsden Hospital in London, England, providing the oncologist perspective. Upon closer review of the results, he drew attention to a "few minor points": under-representation of patients with BRAF-mutant melanoma (~20%); seemingly greater benefit in certain subgroups (stages IIIC, IIID, and IV-NED, less in stage IIIB); and that men appeared to benefit more than women.

Larkin also noted that the control arm underperformed, as the trial design assumed a 2-year EFS rate of 64%, as compared with the 49% that was observed.

The trial left several unanswered questions, he said:

• What is the optimal duration of neoadjuvant therapy?

• Can treatment be individualized by use of imaging or noninvasive testing?

• How much postoperative treatment is needed?

• Can some patients avoid surgery?

"I think this was a nice trial with a simple but powerful design," said Larkin. "Of course, it's a randomized, phase II trial, not phase III."

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