Avelumab Continues to Show Value in JAVELIN Merkel 200 Analyses

Sandra P. D'Angelo, MD

In an analysis of patient-reported outcomes (PROs) of the JAVELIN Merkel 200 trial (NCT02155647) of avelumab (Bavencio), investigators found that there was a similarity in proportion of responders with metastatic Merkel cell carcinoma based on clinical and PRO endpoints.¹

Moreover, an additional analysis of this study showed that avelumab was a cost-effective end-of-life treatment option for patients with metastatic Merkel cell carcinoma compared with standard of care in the United Kingdom.²

JAVELIN Merkel 200 was the basis for the FDA’s accelerated approval of avelumab for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma, including those who have not received prior chemotherapy.

In the open-label, phase II trial, the objective response rate (ORR) with avelumab was 33% (95% CI, 23.3-43.8), which included an 11.4% (95% CI, 6.6-19.9) complete response rate and a 21.6% (95% CI, 13.5-31.7) partial response rate.^3,4 Additionally, the duration of response was at least 6 months in 86% of patients; 45% of patients had a DOR of 12 months or more.

The clinical outcomes and PROs of patients with metastatic Merkel cell carcinoma enrolled on JAVELIN Merkel 200 who were chemotherapy-refractory were analyzed in an effort to better understand the impact of avelumab. The proportion of patients categorized as responders were reported in a poster presentation during the 2018 ESMO Congress.

PROs were evaluated at baseline. From there, PROs were assessed at week 7, and then every 6 weeks until progression. PROs were evaluated a final time at the end of treatment using a generic health-related quality of life (HRQoL) tool called EQ-5D, as well as a cancer-specific HRQoL tool, FACT-M.

In the analysis population, 88 patients were recruited and followed for a median follow-up of 29.2 months. At the data cutoff of September 26, 2017, baseline EQ-5D assessments were available for 72 patients, while baseline FACT-M assessments were available for 70 patients.

After assessment, patients were categorized as meaningfully improved/stable or meaningfully worsened. PROs that established responders as meaningfully improved/stable, as well as the deterioration-free survival (QFS) analyses, were accompanied by best overall response (BOR) and progression-free survival (PFS). These factors were assessed by the Independent Endpoint Review Committee per RECIST v1.1 criteria.

Data showed that HRQoL QFS rates were slightly higher than the PFS rates, which was expected, according to the investigators. QFS was defined as the time from baseline to a meaningful worsening from baseline with no improvement in HRQoL or death. Two-year, PRO-based rates of improved/stable endpoint were shown to be higher than the BOR rate, which was 33%. At the end of the 2-year follow-up, at least 25% of patients still responded to avelumab, regardless of the endpoint considered.

“The findings show consistency across effectiveness in clinical and PRO endpoints,” principal investigator Sandra P. D’Angelo, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, and co-investigators wrote. “This study further establishes the relevance of using PRO endpoints in oncology trials to contribute to the interpretation of objective clinical endpoints.”

Investigators concluded the analysis by stating that the magnitude of avelumab effects on PROs was higher compared with clinical endpoints in this analysis. The similarity observed in the proportion of response based on clinical and PRO endpoints echoed the previously suspected association between these outcomes in patients with metastatic Merkel cell carcinoma treated with avelumab. Additionally, these findings support the idea of using PROs in clinical trials as a contributing factor to the interpretation of objective clinical endpoints.

A second analysis of the JAVELIN Merkel 200 trial was also presented at the 2018 ESMO Congress, evaluating the cost-effectiveness of avelumab compared with standard of care for patients with metastatic Merkel cell carcinoma.

Findings showed that avelumab was associated with an incremental cost-effectiveness ratio (ICER) of £32,612 ($41,560.94) and £36,635 ($46,686.78) per quality-adjusted life-year (QALY) gained for treatment-experienced (TE) patients and for treatment-naïve (TN) patients, respectively. Additionally, investigators reported that the PD-L1 inhibitor was associated with 93.3% and 76.4% probability of being cost-effective for TE and TN respectively, at a willingness-to-pay threshold of £50,000 [$63,694.25] per QALY gained.

Investigators noted that while TE patients had a minimum follow-up of 24 months, those who were categorized as TN were extrapolated from hazard ratios due to immature data.

These data were found via a 3-state partitioned-survival model, which was created from a UK National Health Services (NHS) perspective to assess the lifetime costs and effects of both avelumab and the standard of care. In order to calculate life-years and QALYs, survival and HRQoL data were taken from the JAVELIN Merkel 200 trial, as well as other observational studies.

From there, QALYs and overall costs collected referenced by the NHS were used to discern the ICER.

Principal investigator Murtuza Bharmal, of Merck Group Darmstadt, and co-investigators, concluded that this analysis demonstrates that avelumab is a cost-effective end-of-life treatment for patients with mMCC in the United Kingdom.

“Following assessment by NICE and the Scottish Medicines Consortium, avelumab was recommended for TE and TN patients; hence, a clinically effective treatment is now available to all English, Welsh, and Scottish patients with mMCC,” Bharmal et al, added.

Once mature TN data become available, there will be a confirmatory analysis.

References

1. D'Angelo SP, Fofana F, Schlichting M, et al. Responder analysis based on patient-reported outcomes (PROs) and clinical endpoints (CEPs) in patients (pts) with metastatic Merkel cell carcinoma treated with avelumab [published online ahead of print October 23, 2018]. Ann Oncol. doi: 10.1093/annonc/mdy289.038.
2. Bharmal M, Amin A, Stapelkamp C, et al. Cost-effectiveness (CE) of avelumab vs standard care (SC) for the treatment of patients (pts) with metastatic Merkel cell carcinoma (mMCC) [published online ahead of print October 23, 2018]. Ann Oncol. doi: https://doi.org/10.1093/annonc/mdy289.047.
3. Kaufman H, Russell JS, Hamid O, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: Results of the phase 2 JAVELIN Merkel 200 trial. J Clin Oncol. 2016;34(suppl; abstr 9508).
4. Kaufman H, Russell JS, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374-1385.