Attached is an article below demonstrating the efficacy of avelumab for the treatment for merkel cell carcinoma (MCC). I want you to extract all the findings for the paper that talk about the efficacy of this treatment process with avelumab: 

1) does the treatment regime help reduce by size? if it does, then what quantitative data is there? does the size of the MCC tumor matter in regards to the treatment regime given?
2) Does the reduction vary by location? Does avelumab work more efficiently in certain areas of the body?
3) How well does it work with immunosuppressed patients? Give all data showing efficacy of avelumab for patients with and without immunosuppression status.
4) Can you also discuss the PDL1 mechanism that caused the treatment for MCC? is the PD L1 status efficacious?

Aim: To assess clinical outcomes in patients with locally advanced (la) or metastatic (m) Merkel cell carci- noma (MCC) initiating first-line (1L) avelumab in a USA community oncology setting. Materials & meth- ods: Adults with laMCC or mMCC initiating 1L avelumab were identified from The US Oncology Network electronic health record database and chart review. Results: Median overall survival and progression-free survival were not reached in laMCC (n = 9) vs 20.2 and 10.0 months in mMCC (n = 19); response rates were similar (66.7% vs 63.2%). Conclusion: This is the first study to show clinical benefit in patients with laMCC receiving 1L avelumab in a US real-world setting. Response rates in patients with mMCC were consistent with pivotal trials.
Lay abstract: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Because MCC progresses quickly, many patients have a poor prognosis. Avelumab is a type of drug that helps the patient’s im- mune system to fight cancer. Avelumab was the first such drug approved by the US FDA for treating metastatic MCC based on the results of the JAVELIN Merkel 200 clinical trial. In SPEAR-Merkel, we studied how MCC patients with locally advanced as well as metastatic disease responded when they were treated with first-line avelumab in a real-world setting. These patients were from oncology practices in commu- nities throughout the USA. Overall response rates in SPEAR-Merkel were comparable between patients with locally advanced and metastatic MCC. Importantly, we found that these patients experienced survival benefit similar to patients in the JAVELIN Merkel 200 (part B) study and other real-world studies.
First draft submitted: 10 December 2020; Accepted for publication: 16 February 2021; Published online: 12 March 2021
Keywords: avelumab • community oncology • immunotherapy • Merkel cell carcinoma • real-world clinical outcomes
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer that can metastasize early on, leading to a poor prognosis for many patients [1–3]. Patients with locoregional MCC have recurrence rates ranging from 43 to 48% [4,5]. MCC has a 5-year survival rate of 78% for localized disease, 52% for regional disease and 19% for advanced or metastatic disease [6]. Approximately a third of patients with MCC die of the disease within 5 years, and it is associated with the highest mortality rate among skin cancers, including melanoma [6]. MCC is more common in immunocompromised patients: specifically, those who have undergone an organ transplant, those with HIV infection or lymphoproliferative malignancies and those receiving immunosuppressant medications [2,3,7].
Until the US FDA approval of avelumab in March 2017 for patients with metastatic MCC (mMCC), the main first-line (1L) therapy for mMCC was chemotherapy. However, although the objective response rate is high (52–61%) with 1L chemotherapy, the duration of response is low (2–4 months) and toxicities occur such as myelosuppression and neutropenia [8–11]. Such adverse events are of particular concern in the mMCC population, which includes a large number of patients aged ≥65 years as well as already immunocompromised patients [8,12]. Immunosuppression has been observed to play a role in the pathogenesis of MCC, which provides a rationale for the use of therapies that stimulate antitumor immune responses: specifically, antibodies that target PD-L1 and its receptor PD-1. PD-L1 binding to PD-1 inhibits the T-cell signaling pathways that play roles in T-cell survival, proliferation and cytotoxic activity [10].
FDA approval of avelumab for mMCC was based on part A of the JAVELIN Merkel 200 trial (ClinicalTrials.gov: NCT02155647). Part A investigated 88 patients who progressed on prior chemotherapy for mMCC. After 1 year of follow-up, the objective response rate was 33.0%, with 74% of responses lasting over a year, and the median overall survival (OS) was 12.9 months [13]. Part B of JAVELIN Merkel 200 investigated patients who received no prior systemic therapy for mMCC. In an analysis of data that included ≥15 months of follow-up for 116 patients, an objective response rate of ≥6 months was seen in 39.7%, the median duration of response (DOR) was 18.2 months, the median OS was 20.3 months and the 12-month OS rate was 60% [14]. Grade ≥3 adverse events were observed in 21 patients, and no treatment-related deaths occurred. Since 2018, the National Comprehensive Cancer Network (NCCN) guidelines have recommended avelumab as 1L treatment for mMCC [15,16].
Following availability of data from the JAVELIN Merkel 200 trial, an expanded access program (EAP) was initiated across 38 countries so that patients with mMCC could receive avelumab on a compassionate-use basis. The objective response rate was 46.7% among 240 patients evaluable for response, 46.7% among those receiving only 1L treatment (n = 15) and 37.5% among immunocompromised patients (n = 16). The median duration of treatment was 7.9 months in all 240 patients, 4.5 months in those receiving only 1L avelumab and 5.2 months in immunocompromised patients. The most common reason for treatment discontinuation was radiographically or clinically assessed disease progression [12].
Few studies have examined treatment patterns and clinical and economic outcomes in patients with locally advanced MCC (laMCC) as well as those with mMCC outside of clinical trials, due to the rarity of the disease [12]. The goal of the Study Informing Treatment Pathway Decisions in Merkel Cell Carcinoma (SPEAR-Merkel) was to assess current treatment patterns, clinical outcomes and healthcare utilization among patients with laMCC or mMCC who initiated avelumab in the 1L setting within a large network of community-based oncology practices. An understanding of the utilization of and outcomes with 1L avelumab in a nonclinical trial, community- based population with laMCC or mMCC could expand real-world knowledge beyond pivotal trials or published prospective trials and provide further practical information to aid clinicians actively treating this disease in the USA.
Materials & methods
Study design, data source & patient population
This was a retrospective, observational, descriptive study of patients with laMCC or mMCC initiating 1L avelumab between 1 March 2017, and 31 March 2019 (patient identification period), in The US Oncology Network (USON). Eligible patients were followed through 30 September 2019. Patients were identified using the iKnowMed (iKM) electronic health record (EHR) system. iKM is an oncology-specific EHR system that captures outpatient practice encounter history in USON community oncology practices. The USON includes 1200 affiliated physicians practicing in over 470 sites of care across 25 states and provides care for nearly 1 million patients with cancer annually. Data were obtained via programmatic database abstraction and chart review from the iKM EHR system, with supplemental vital status provided by the Social Security Administration’s Limited Access Death Master File (LADMF). All data were handled in compliance with the Health Insurance Portability and Accountability Act and the Health Information Technology for Economic and Clinical Health Act. The study protocol was granted an exception and waiver of informed consent by the US Oncology Institutional Review Board, IRB no. 19-024E.
Eligible patients had a diagnosis of laMCC or mMCC, had received avelumab as 1L therapy for laMCC or mMCC at a USON practice with full iKM EHR capabilities over the study period, and were aged ≥18 years at the initial recorded diagnosis of MCC. Patients were characterized as having either laMCC or mMCC based on disease status prior to the initiation of 1L avelumab. Prior to 1L initiation, patients with laMCC had nonmetastatic disease and had evidence of nodal involvement in the same region as the primary tumor, locally recurrent disease, high-risk locally advanced disease or unresectable disease. Patients with evidence of distant metastases or disseminated disease to the initial/primary site of diagnosis prior to the initiation of 1L were considered to have mMCC. Baseline variables were assessed for the 90-day period before and following 1L avelumab initiation. Baseline values were reported for the closest value to time of treatment initiation, with priority given to values before initiation. All study variables and outcomes were assessed regardless of maximum follow-up, using data available until the end of the study observation period (30 September 2019). All study patients were required to have ≥6 months of follow-up or evidence of death prior to the end of the study observation period.
Patient chart data were captured for hospitalizations, emergency department (ED) visits and reasons for these utilizations occurring during and within 30 days of initiation of 1L avelumab. Patient chart data were also captured for reasons for treatment discontinuation; each patient could have ≥1 reason reported.
Statistics
Descriptive analyses were conducted to assess demographic, clinical and treatment characteristics and healthcare utilization. Categorical variables (e.g., sex, Eastern Cooperative Oncology Group performance status [ECOG PS], ED visits and hospitalizations) were reported as frequencies and percentages. Continuous variables (e.g., age) were reported as mean (standard deviation) and median (range).
Kaplan–Meier curves were constructed to illustrate time-to-event outcomes, including OS, time to treatment discontinuation (TTD), DOR and physician-assessed progression-free survival (PFS) with medians and 95% CIs, stratified to present results overall and by laMCC or mMCC status. OS was defined as the interval (in months) between treatment initiation and date of death (any cause) as documented in the LADMF or the iKM EHR database. TTD was defined as the interval (in months) between 1L avelumab treatment initiation and discontinuation. DOR was defined as the interval (in months) from the first documented complete response (CR) or response not otherwise specified (R-NOS) until the earliest date of physician-assessed progression, start of a new treatment or death. Physician-assessed PFS was defined as the interval (in months) from treatment initiation until date of physician-assessed disease progression or death. For all Kaplan–Meier time-to-event analyses, patients who did not experience an event were censored at study end date or last visit date available in the data set, whichever occurred first.
Results
Patient population
A total of 148 adult patients initiated systemic treatment for MCC from 1 March 2017 to 31 March 2019, and were identified in iKM (Figure 1). Of these, 36 patients initiated treatment with avelumab in a 1L or second-line setting during the study identification period (1 March 2017–31 March 2019). Twenty-eight patients initiated 1L avelumab (9 [32.1%] with laMCC, 19 [67.9%] with mMCC) as confirmed through chart review.
Patient characteristics
In the overall 1L avelumab population, the median age was 78 years (range: 52–90+ years) and 64.3% were aged ≥75 years (Table 1). Most patients were male (overall: 85.7%; laMCC: 100%; mMCC: 78.9%) and White (overall: 82.1%; laMCC: 77.8%; mMCC: 84.2%).
Treatment patterns
In the 1L avelumab population, the median (range) time from diagnosis of laMCC or mMCC to initiation of 1L avelumab was 6.0 weeks (0.1–161.7 weeks) overall, 6.1 weeks (0.1–97.6 weeks) in patients with laMCC and 6.0 weeks (1.4–161.7 weeks) in patients with mMCC. The median TTD in patients receiving 1L avelumab was 10.5 months (95% CI: 5.3–14.3 months) overall, 11.8 months (95% CI: 2.3 months–not reached [NR]) in patients with laMCC, and 10.5 months (95% CI: 5.3 months–NR) in patients with mMCC (Table 2, Figure 2).
Two-thirds of the overall 1L avelumab population (64.3%) discontinued 1L avelumab during the study period: 66.7% with laMCC and 63.2% with mMCC (Table 2). The most commonly reported reasons were disease progression (33.3%), physician preference (27.8%) and toxicity or not documented (11.1% each). Death was recorded as the reason for discontinuation in three patients with mMCC and none with laMCC.
Most patients (85.7%) received no systemic treatment after discontinuation of 1L avelumab; 10.7% received platinum doublet chemotherapies (11.1 and 10.5% in the laMCC and mMCC cohorts, respectively) and one patient with laMCC (11.1%) received pembrolizumab. CI: 7.5 months–NR) in the overall 1L avelumab population, NR in patients with laMCC and 9.6 months (95% CI: 2.6–15.5 months) in patients with mMCC (Figure 2). In the overall 1L avelumab population, the median PFS was 11.4 months (95% CI: 5.3 months–NR) and the median OS was 20.2 months (95% CI: 11.1 months–NR) (Figure 3). Neither the median PFS nor the median OS was reached in patients with laMCC. In patients with mMCC, the median PFS was 10.0 months (95% CI: 2.8 months–NR) and the median OS was 20.2 months (95% CI: 10.0 months–NR).
Hospitalizations & ED visits
During 1L avelumab treatment, 32.1% of patients had ≥1 ED visit and 42.9% had ≥1 hospitalization; 3.6% (n = 1) and 10.7% (n = 3), respectively, were treatment related (Table 4). The most common reasons for ED visits in the overall 1L avelumab population were pain (14.3%), gastrointestinal (diarrhea, nausea and vomiting) and dyspnea (10.7% each). The most common reasons for hospitalizations included infection-related (17.9%), gastrointestinal (10.7%) and cardiovascular (7.1%) adverse events.
Discussion
To our knowledge, SPEAR-Merkel is the first study to evaluate real-world clinical outcomes in patients with laMCC or mMCC in the USA treated with 1L avelumab. In this study, use of 1L avelumab in patients with laMCC accounted for 32% of patients. The inclusion and analysis of patients with laMCC distinguish our study from the EAP, another real-world study of avelumab in MCC, as the EAP examined only patients with mMCC. Results in this study indicate that in real-world practice, clinicians in the community setting in the USA are using avelumab as 1L treatment in patients with mMCC and, in addition, in patients with laMCC. Notably, we observed avelumab-associated clinical benefit among the latter. Specifically, outcomes in patients with laMCC appeared similar to if not better than those in patients with mMCC. SPEAR-Merkel further adds to the current knowledge, which can help clinicians make treatment decisions for their patients with laMCC.
In the combined laMCC and mMCC cohorts, baseline demographic characteristics were similar to those of patients with advanced MCC in clinical trials and in other real-world studies. In our study, most patients receiving 1L avelumab were male and aged ≥65 years. Nearly all (96.4%) in our study were immunocompetent, as were patients in clinical trials [8,12,17,18]. However, proportions of patients with immunocompromised status have ranged from 6 to 30% across other real-world studies [8,9,11,12,19–21]. Two of these studies investigated patients treated with avelumab. It is not clear whether avelumab was preferentially given to immunocompetent patients, given the small sample size of immunocompromised patients in nonavelumab as well as avelumab studies [12,21].
Outcomes in SPEAR-Merkel also bear certain similarities to data from clinical trials and other real-world studies. The median OS and PFS in SPEAR-Merkel were 20.2 and 11.4 months, respectively, among patients receiving avelumab as 1L treatment, and 66.4% were still alive at 12 months. The rwORR was 64.3% at a median follow-up of 11.2 months, with a median DOR of 15.5 months. In JAVELIN Merkel 200 part B, the median OS and PFS in patients with mMCC receiving 1L avelumab were 20.3 and 4.1 months, respectively, after 15 months of follow-up, with a 12-month survival rate of 60% [14]. The median DOR was 18.2 months (95% CI: 11.3 months– not estimable) [14]. In SPEAR-Merkel, 85.7% received no systemic treatment after 1L avelumab discontinuation; 67.8% of the study population showed a response (i.e., CR, R-NOS, mixed). In JAVELIN part B, 22.4% were still on treatment at last follow-up.
In SPEAR-Merkel, although 32.1% of patients had ≥1 ED visit and 42.9% had ≥1 hospitalization during treatment due to toxicity, one ED visit and three hospitalizations were determined to be treatment related. In SPEAR-Merkel, 7.1% of the overall patient population discontinued 1L avelumab treatment due to toxicity, whereas in JAVELIN Merkel 200 part B, 12.1% of those who received 1L avelumab discontinued treatment due to toxicity [14].
With regard to real-world data, the objective response rate in EAP was 46.7% and the median duration of therapy was 4.5 months among patients receiving 1L avelumab [12]. However, it is important to note that the EAP data are limited by missing data, lack of follow-up and oncologist-reported response (no central imaging review was obtained) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. In patients with advanced MCC treated with 1L avelumab at four referral centers in the Netherlands (n = 40; 8 laMCC, 32 mMCC), the median OS was 25.8 months, the median PFS was 14.6 months and 28% (n = 11) had a complete response [21].
The results of SPEAR-Merkel supplement findings from the clinical trial setting, as patients who are typically ineligible for clinical trials were included. For example, patients with an ECOG PS of ≥2 were excluded from the JAVELIN Merkel 200 study, and most patients in that study had an ECOG PS of 0. In our study, 10.7% of patients overall had an ECOG PS of 2, although the status was ‘not documented’ for nearly a third. Treatment trends and clinical outcomes in SPEAR-Merkel, therefore, reflect how avelumab is being used in the community oncology setting in the USA, especially in patients with poor PS (i.e., ECOG PS = 2).
Several limitations of this study must be noted. First, as SPEAR-Merkel was a retrospective observational study, underlying clinical differences may have influenced outcomes. Second, because of the rarity of MCC, sample sizes were small, limiting the drawing of conclusions. Third, some variables of interest (e.g., ECOG PS, disease stage) may not have been as completely captured across the study population in real-world clinical practice as they are in the clinical trial setting. Fourth, The USON encourages the use of evidence-based guidelines, and so USON patients may receive different treatments than patients treated in other community oncology settings or in academic centers. Thus, the results of SPEAR-Merkel are most generalizable to community-based oncology clinics that adhere to best-practice guidelines. Finally, JAVELIN Merkel 200 part B defined response according to RECIST, as most oncology clinical trials do, whereas SPEAR-Merkel used physician-based assessments, which may be more subjective. As such, physician-assessed response rates may be more optimistic than response rates assessed using RECIST criteria in the clinical trials. Nonetheless, for the most part, SPEAR-Merkel results align with those of JAVELIN Merkel 200 part B and support the benefit of 1L avelumab in patients with MCC in clinical practice.
Current NCCN guidelines also recommend pembrolizumab and nivolumab as 1L treatment for advanced MCC [15,16]. Future studies should examine real-world clinical outcomes for all NCCN-recommended immuno- oncology therapies, including avelumab, for 1L treatment of advanced MCC in a changing treatment landscape.
Conclusion
In SPEAR-Merkel, clinical outcomes in patients with mMCC treated with 1L avelumab are consistent with those observed in pivotal trial data from the JAVELIN Merkel clinical trial program. In addition, SPEAR-Merkel shows clinical benefit beyond JAVELIN – namely in patients with laMCC in a real-world population – and outcomes in patients with laMCC appeared similar to those in patients with mMCC. SPEAR-Merkel further adds to the current knowledge of healthcare resource utilization in patients with laMCC or mMCC receiving avelumab in a real-world clinical setting.