ASCO’s 2020 Advance of the Year: Systemic therapies refine cancer surgical treatment

The American Society of Clinical Oncology (ASCO) has named the refinement of surgical treatment of cancer as 2020 Advance of the Year.

In its latest annual report, ASCO identified three cancers where systemic therapies have helped reshape the role of surgical treatment, making them some of the year’s most successful areas of research: melanoma, renal cell carcinoma (RCC) and pancreatic cancer. [J Clin Oncol 2020, doi: 10.1200/JCO.19.03141]

Advanced melanoma: Neoadjuvant combos reduce surgeries, allow more successful & less invasive surgery 

Two studies published last year that examined the efficacy and safety of neoadjuvant combinations of targeted agents and immunotherapies are changing practice, helping many patients with locally advanced melanoma avoid or have more successful and less invasive surgery.

The single-arm, open-label, single-centre, phase II NeoCombi trial evaluated the combination of two MAPK pathway inhibitors, dabrafenib and trametinib, given before surgery to patients with stage IIIC melanoma with the BRAF^V600mutation. At resection, 86 percent of patients achieved a response and 46 percent had a complete response (CR), which facilitated surgical removal of the tumour and the surrounding tissue. [Lancet Oncol 2019;20:961-971]

After resection, all patients achieved a pathological response, with 49 percent attaining CR. Toxicities were generally similar to those in patients treated with the dabrafenib-trametinib combination for metastatic disease.

“Neoadjuvant dabrafenib combined with trametinib was tolerable, with no relapses during the 12-week neoadjuvant period, and all patients were able to undergo surgery. This treatment could therefore be a feasible approach in a subset of patients not suitable for neoadjuvant anti–PD-1-based therapy,” concluded the study authors.

Another trial, the multicenter, phase II, randomized OpACIN-neo study, evaluated the optimal neoadjuvant dosing schedule for two immunotherapies, ipilimumab and nivolumab. Previous studies have demonstrated the superior efficacy of adjuvant ipilimumab plus nivolumab vs either agent alone in locally advanced melanoma; however, the tumour response rate, progression-free survival (PFS) and overall survival (OS) gains came at the cost of increased toxicity. [Lancet Oncol 2019;20:948-960]

OpACIN-neo identified a tolerable neoadjuvant dosing schedule of two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg, which was associated with a radiological objective response rate of 57 percent and a pathological response rate of 77 percent. Importantly, while this reduced dosing regimen was effective, patients experienced fewer grade 3/4 adverse events (AEs) in the first 12 weeks than standard dosing; each of the grade 3/4 AEs occurred in no more than one patient in the reduced dosing group. “Long-term outcomes are awaited to determine if this less toxic approach can be recommended as a standard of care [SoC],” wrote the ASCO report authors.

RCC: Targeted therapy as alternative to immediate surgery 

Cytoreductive nephrectomy (CN) has been the standard of care in metastatic RCC (mRCC) for 20 years, but the efficacy of targeted therapies has challenged this standard.

The phase III randomized CARMENA trial demonstrated that sunitinib alone offered noninferior OS vs CN followed by sunitinib in patients with mRCC with a poor or intermediate prognostic risk (median OS, 18.4 months vs 13.9 months; stratified hazard ratio [HR], 0.89; 95 percent confidence interval [CI], 0.71 to 1.10). [N Engl J Med 2018;379:417-427]

“Avoiding nephrectomy minimizes surgical complications involving blood transfusions, further operations, or intensive care. Initial nephrectomy can delay the start of targeted therapies that have shown a survival benefit, and patients may die before receiving such therapies,” commented the researchers.

The SURTIME trial, which randomized mRCC patients to receive sunitinib either before or after CN (deferred or immediate CN), found no difference in the primary endpoint of 28-week progression-free rate between the two groups, but yielded an intention-to-treat OS HR of 0.57 (95 percent CI, 0.34 to 0.95; p=0.03) for deferred vs immediate CN. The median OS was 32.4 months vs 15.0 months in the deferred vs immediate CN arm. “More patients received systemic therapy, and CN could be avoided in those with progressive disease,” added the researchers. [JAMA Oncol2019;5:164-170]

“Both studies highlight the evolving role of systemic treatment in patients with mRCC,” commented the ASCO report authors.

Pancreatic cancer: Neoadjuvant therapy allows surgery for more patients

Surgical resection offers the best chance of survival for patients with pancreatic cancer, but many pancreatic tumours are either difficult to remove entirely or cannot be removed at all.

Preclinical data show that manipulating the renin-angiotensin system (RAS) may have antitumour associations with pancreatic cancer, while retrospective observational cohort studies suggest that pancreatic cancer patients already taking RAS inhibitors such as losartan because of pre-existing cardiovascular disease had longer survival. [Clin Cancer Res 2017;23:5959-5969]

A single-arm phase II study evaluated the margin-negative (R0) resection rate of neoadjuvant FOLFORINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy in 49 patients with locally advanced pancreatic cancer. The R0 resection rate was 61 percent among all eligible participants. Overall, median PFS was 17.5 months and median OS was 31.4 months. Among patients who underwent resection, median PFS was 21.3 months and median OS was 33.0 months. Grade ≥3 AEs occurred in 51 percent of patients, all of which were reported during FOLFORINOX induction. No deaths were associated with AEs and 80 percent of patients were able to complete the preplanned eight cycles of FOLFORINOX and losartan. [JAMA Oncol 2019;5:1020-1027]

“The R0 resection rate was 88 percent among patients who underwent resection... While limited by relatively small numbers, this outcome represents a new benchmark in [pancreatic cancer]. Surgical resection was associated with PFS and OS rates that exceed historical data,” concluded the study authors.