June 2020 Edition Vol.11, Issue 6

ASCO 2020: Top Studies at the Virtual Scientific Program

By Christina Bennett, MS

The virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting featured data from several potentially practice-changing trials, including CheckMate 9LA, KEYNOTE-204, BOSTON, and RAPIDO.

Another possible win for combination therapy in NSCLC?

In the CheckMate 9LA study presented at this year’s virtual ASCO, the addition of nivolumab plus ipilimumab to a limited two-cycle platinum-based chemotherapy regimen showed clinical improvement for patients with advanced non-small cell lung cancer (NCLCL) with no EGFR or ALK aberrations over patients receiving a four-cycle platinum-based regimen alone (Abstract 9501).

Although results of CheckMate 9LA led to the FDA approval of the immunotherapy combination with two cycles of chemotherapy as a first-line treatment for patients with metastatic or recurrent NSCLC with no EGFR or ALK aberrations, it’s unclear exactly how these results will play out in practice.

This is because the upfront nivolumab-ipilimumab combination—without platinum-based chemotherapy—was recently FDA approved in a similar NSCLC patient population based on results from the CheckMate 227 study. This approval is limited to patients whose tumors have PD-L1 expression of at least 1%.

For CheckMate 9LA, the overall survival (OS) interim analysis, which had a minimum follow-up of 8.1 months, showed benefit for patients who received the combination plus two cycles of platinum-based chemotherapy (n=361) compared with patients who received only four cycles of platinum-based chemotherapy (n=358; HR=0.69; 95% CI, 0.55 – 0.87; P=0.0006).

Similar to CheckMate 227, the OS benefit in CheckMate 9LA was seen across all PD-L1 subgroups, including patients whose tumors had PD-L1 expression less than 1% (HR=0.62; 95% CI, 0.45 – 0.85) (Figure 1).

Follow-up of 12.7 months continued to show an OS advantage for the dual immunotherapy/chemotherapy combination arm vs the chemotherapy-alone arm (HR=0.66; 95% CI, 0.55 – 0.80), with a median gain of nearly 5 months (15.6 vs 10.9 months).

Progression-free survival (PFS) also favored the combination arm over the chemotherapy-alone arm (HR=0.68; 95% CI, 0.57 – 0.82), as did the overall response rate (38% vs 25%). The improvement in response rate was largely attributed to an increase in the partial response rate (36% vs 24), given that the complete response rate between the two arms was similar (2% vs 1%). The duration of response was also longer in the combination arm compared with the chemotherapy-alone arm (median 11.3 vs 5.6 months).

A higher rate of treatment-related adverse events (TRAEs) that led to treatment discontinuation was seen with the combination arm compared with the chemotherapy-alone arm (19% vs 7%); both arms had 2% of patients die from treatment.

Regarding the toxicity of the combination arm, Alex Spira, MD, PhD, medical oncologist at Virginia Cancer Specialists (VCS) and chair of the US Oncology Research Executive Committee, said it’s “hard” to distinguish the contribution of the ipilimumab component based on the current standard of care, which is chemotherapy plus pembrolizumab.

“While [the results] may change practice for some [patients], the concerns of expense and possibly increased side effects are real, albeit mild for the latter.”

“In the end, it will fall to physician’s judgement and none of this is truly practice altering as the field has evolved since these studies were first designed,” said Dr. Spira, who was not involved in either trial. “Nevertheless, it’s good to have options.”

Pembrolizumab reduced disease progression in Hodgkin lymphoma

Compared with brentuximab vedotin (BV), pembrolizumab led to improved clinical outcomes for patients with relapsed or refractory (R/R) classic Hodgkin lymphoma (HL) whose disease had relapsed after autologous stem cell transplant or were ineligible for transplant and had tried one prior line of therapy (Abstract 8005).

The phase 3 KEYNOTE-204 trial met its primary endpoint, showing a 35% reduced risk of disease progression for patients who received pembrolizumab (n=148) compared with patients who received BV (n=152; HR=0.65; 95% CI, 0.48 – 0.88; P=0.00271). A nearly 5-month difference in median PFS was seen, favoring the pembrolizumab arm (13.2 vs 8.3 months), which also had a nearly 7-month longer median duration of response compared with the BV arm (20.7 vs 13.8 months).

Although the overall response rate was higher for the pembrolizumab arm compared with the BV arm (65.6% vs 54.2%), the difference was not statistically significant (P=0.0225). With about a 24% complete response rate in each arm, the numerical gain in responses for the pembrolizumab arm was largely due to a higher partial response rate (41.1% vs 30.1%).

“This trial shows that immediate outcomes are superior with pembrolizumab instead of BV and suggests that this should probably be moved up in the treatment algorithm for patients with R/R HL,” said Matthew Mei, MD, assistant clinical professor, City of Hope Department of Hematology and Hematopoietic Cell Transplantation. He was not involved in the trial.

The frequency of TRAEs was similar between the pembrolizumab arm and the BV arm (74.3% vs 77.0%), as was the rate of stopping treatment due to TRAEs (12.8% vs 16.4%).

The pembrolizumab arm had a higher rate of hypothyroidism, pyrexia, and pruritus, but lower rate of nausea, peripheral neuropathy, and peripheral sensory neuropathy (Figure 2).

“The safety data are largely what we expect,” said Dr. Mei. Regarding the one patient on the pembrolizumab arm who died from pneumonia as a result of treatment, he said it highlights that toxicity with checkpoint inhibitors can be “very severe” and require “ongoing vigilance.”

Dr. Mei believes that the data are practice changing and are most applicable in the community setting for patients with R/R HL for whom BV would otherwise have been given.

Addition of selinexor delays neuropathy in MM

The addition of selinexor to bortezomib and low-dose dexamethasone delayed disease progression and frequency of peripheral neuropathy in patients with R/R multiple myeloma (MM), according to the results of the randomized phase 3 BOSTON trial (Abstract 8501).

Selinexor, an oral XPO1 inhibitor, is currently approved in combination with dexamethasone as a later line therapy for patients with R/R MM.

“Overall the data are quite encouraging,” commented Joshua Richter, MD, assistant professor of medicine, Hematology and Oncology at The Tisch Cancer Institute at Mount Sinai. Not involved in the trial, he explained that before this, much of the data on the use of selinexor was in the “triple-refractory” setting in patients with more advanced disease.

“We now have evidence of the efficacy and tolerability in a less heavily pre-treated patient,” he said. Among the 402 patients enrolled in the trial, approximately half had one prior line and one-third two prior lines; the remaining had three prior lines.

Patients who received weekly selinexor, bortezomib, and low-dose dexamethasone (SVd; n=195) had a 30% reduced risk of disease progression or death compared with patients who received twice weekly bortezomib and low-dose dexamethasone (Vd; n=204; HR=0.70; P=0.0075). The median PFS was approximately 4.5 months longer for the SVd arm compared with the Vd arm (13.93 vs 9.46 months).

The SVd arm also had a significantly higher overall response rate (76.4% vs 62.3%; P=0.0012) and responses appeared deeper, with 45% of patients on the SVd arm achieving a stringent complete response, complete response, or very good partial response compared with 32% on the Vd arm.

The median time to next treatment was prolonged for the SVd arm (16.1 vs 10.8 months). However, whether there is a difference in OS is unclear, as the median OS is 25 months in the Vd arm and not reached in the SVd arm.

SVd may have a better safety profile than Vd, given that the overall frequency of peripheral neuropathy was significantly lower for SVd compared with Vd (32.3% vs 47.1%; P=0.0010). The severity of peripheral neuropathy also seemed improved, with less frequent grade 2 or higher events and grade 3 or 4 events for SVd (Figure 3).

Peripheral neuropathy remained the most common adverse event leading to treatment discontinuation for both the SVd arm and Vd arm (4.6% vs 7.4%).

SVd was associated with more hematologic TRAEs, with thrombocytopenia being the most common (60%) followed by anemia (36.4%) and neutropenia (14.9%). The SVd arm also had a higher rate of non-hematologic TRAEs, like nausea, fatigue, and diarrhea, but most were low-grade.

“The safety profile of this regimen is improved over what we saw in the STORM trial,” said Dr. Richter. “This is due to the improved tolerability of selinexor when dosed in a weekly fashion as opposed to a twice weekly fashion.”

View an OBR interview with Dr. Usmani on the BOSTON study:

Short-course radiotherapy doubles pCR in rectal cancer

Short-course radiotherapy followed by neoadjuvant chemotherapy improved outcomes for patients with locally advanced rectal cancer without compromising safety (Abstract 4006).

The international phase 3 RAPIDO trial included 920 patients from several countries who were randomized to receive either an experimental treatment or the standard approach, which consisted of chemoradiotherapy followed by surgery and optional adjuvant chemotherapy. The experimental treatment consisted of short-course radiotherapy over five days followed by neoadjuvant chemotherapy (6 courses of CAPOX or 9 cycles of FOLFOX4) and surgery.

One of the potential advantages of this new approach is that it only requires five radiation treatments as opposed to twenty-five with the standard approach.

This approach makes this a very COVID-19 friendly treatment option, “especially in regions of the US that are still affected by the COVID-19 pandemic,” said Edward Chu, MD, chief of the division of Hematology-Oncology at UPMC Hillman Cancer Center. He was not involved in the trial.

The trial met its primary endpoint, showing a 25% decreased risk of disease-related treatment failure (DrTF) for the experimental arm compared with the standard arm (HR=0.75; 95% CI, 0.60 – 0.96; P=0.019). (DrTF defined events as distant metastasis, local regional failure, new primary colorectal cancer, and treatment-related death.)

Study presenter Geke Hospers, MD, PhD, University of Groningen, University Medical Center Groningen, Department of Medical Oncology, Groningen, Netherlands, attributed the difference in DrTF largely to the decrease in distant metastases: Patients on the experimental arm had a 31% decreased risk (HR=0.69; 95% CI, 0.54 – 0.90; P=0.005).

The experimental treatment also led to a doubling in pathologic complete response (pCR) rate, with 28% of patients in the experimental arm achieving a pCR compared with 14% in the standard of care arm (P<0.001), which Dr. Chu said was “particularly impressive.”

“However, these positive elements of the study did not translate to a difference in overall survival at three years. Moreover, the local relapse rate was slightly higher with the short-course experimental treatment arm,” he said.

Both arms had an overall survival rate at three years of 89%, and while the experimental arm had a numerically higher locoregional failure rate at three years compared with the standard arm (8.7% vs 6.0%), the difference was not statistically significant (P=0.09).

As for safety, the treatment arms had no significant difference in surgical complications (P=0.67), which included wound complication, bleeding, and intra-abdominal infection, and no significant difference in overall quality of life at three years (P=0.11). The number of patients without stroma who developed low anterior resection syndrome was also not different (P=0.19).

Without an OS benefit and a potentially higher incidence of local failure associated with short-course radiation therapy, Dr. Chu said, it is “unlikely” that there will be a “major shift” in clinical practice in the United States.

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