Allison Schepers, PharmD BCOP
Clinical Pharmacist Specialist, Medical Oncology
University of Michigan Medicine
Ann Arbor, MI
Instead of converging in Chicago for the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, the oncology community gathered remotely May 29–31 for the ASCO Virtual Scientific Program. Selected content was broadcast throughout the weekend, and all content— including plenary session presentations, the keynote address (“Chasing My Cure”) by Dr. David Fajgenbaum, oral abstracts, and posters—is currently available on demand for ASCO members and meeting registrants. The following notable abstracts may change clinical practice.
The current standard of care for microsatellite instability–high (MSI-H) or deficient mismatch repair (dMMR) metastatic colorectal cancer is 5-FU-based doublet or triplet chemotherapy followed by an immune checkpoint inhibitor in the second- or third-line setting. KEYNOTE-177 examined the role of pembrolizumab in the front line for this population.1 Patients with previously untreated MSI-H/dMMR metastatic colorectal cancer were randomized to receive physician’s choice of chemotherapy (n = 154) or pembrolizumab 200 mg every 3 weeks (n = 153). Allowed chemotherapy regimens were mFOLFOX6 or FOLFIRI, with or without bevacizumab or cetuximab. The combinations mFOLFOX6 + bevacizumab (44.8%) and FOLFIRI + bevacizumab (25.2%) were the most common chemotherapy regimens. BRAF V600E mutations were present in 22% and 28% of patients in the pembrolizumab and chemotherapy arms, as well as KRAS or NRAS mutations in 22% and 27%, respectively. Though the progression-free survival (PFS) curves initially favored chemotherapy, the curves crossed at the 6-month mark, and median PFS was 16.5 months with pembrolizumab compared to 8.2 months with chemotherapy (hazard ratio [HR] 0.60; 95% confidence interval [CI], 0.45–0.80; p = .0002). In patients with BRAF V600E mutations, PFS appeared similar to the overall population (BRAF V600E HR 0.48, 95% CI 0.27–0.86). However, patients with KRAS or NRAS mutations showed no benefit for pembrolizumab over chemotherapy (HR 1.19, 95% CI 0.68–2.07). Overall survival (OS) data are not mature and were not reported. Grades 3–5 adverse effects occurred in 22% of pembrolizumab patients and in 66% of chemotherapy patients, including one death due to intestinal perforation in the chemotherapy arm. Nine percent of pembrolizumab patients experienced Grade 3/4 immunotherapy-related adverse events. The use of post-protocol PD-1/PD-L1 inhibitors in the chemotherapy arm was 59%, which may be lower than routine clinical practice for MSI-H/dMMR patients. Although the PFS data are encouraging, we await OS data to confirm pembrolizumab as the preferred frontline treatment for this patient population. The COMMIT trial of frontline chemotherapy in combination with atezolizumab is also ongoing for the treatment of MSI-H/dMMR colorectal cancer.2
ESPAC-5F and SWOG S1505
Two trials explored the role of neoadjuvant chemotherapy for localized pancreatic cancer.3,4 ESPAC-5F randomized patients with borderline resectable pancreatic cancer to neoadjuvant FOLFIRINOX (n = 11), neoadjuvant gemcitabine and capecitabine (n = 12), neoadjuvant gemcitabine with radiotherapy (n = 8), or upfront surgery with investigator’s choice adjuvant treatment (n = 21).3 The primary outcome of resection rate did not differ between the combined neoadjuvant arms and the immediate-surgery arm (55% vs. 62%, p = .668). Twelve-month OS, however, was improved in the neoadjuvant group compared to the immediate-surgery arm (77% vs. 42%, HR 0.28, 95% CI 0.14–0.57, p < .001). Twelve-month OS was 84% with FOLFIRINOX, 79% with gemcitabine/capecitabine, and 64% with gemcitabine/radiotherapy, though the neoadjuvant regimens were not directly compared. SWOG S1505 randomized patients to receive perioperative mFOLFIRINOX (n = 55) or gemcitabine/nab-paclitaxel (n = 47).4 Both arms received 12 weeks of neoadjuvant chemotherapy and 12 weeks of adjuvant chemotherapy, and all patients were Eastern Cooperative Oncology Group performance status 0–1. In both arms, approximately 80% of patients completed neoadjuvant chemotherapy, 70% underwent resection, 55% started adjuvant chemotherapy, and 40%–50% completed adjuvant chemotherapy. The most common reasons that patients did not undergo resection were disease progression and deterioration or refusal. Median OS was nearly identical between arms: 22.4 months with mFOLFIRINOX and 23.6 months with gemcitabine/nab-paclitaxel. This trial suggested that patients who participate in neoadjuvant trials may be a less preselected, less robust population than those in adjuvant trials, because neither arm met the trial’s predicted OS endpoint. These trials suggest that neoadjuvant therapy is associated with high resection rates in resectable pancreatic cancer and may identify patients with aggressive disease biology who would not benefit from a large surgery. A standard-of-care perioperative or total neoadjuvant treatment approach has not yet emerged.
JAVELIN Bladder 100
JAVELIN Bladder 100 compared current frontline treatment for metastatic urothelial carcinoma (platinum doublet followed by observation) to a switch maintenance strategy of platinum doublet followed by avelumab.5 Patients with unresectable or metastatic urothelial carcinoma whose disease had not progressed after 4–6 cycles of gemcitabine and cisplatin or carboplatin were randomized to receive avelumab 10 mg/kg every 2 weeks with best supportive care (n = 350) or best supportive care alone (n = 350). Median OS in the avelumab arm was 21.4 months compared to 14.3 months in the supportive-care arm (HR 0.69, 95% CI 0.56–0.86, p < .001). Three hundred fifty-eight patients were PD-L1-positive (PD-L1 ≥25% in tumor cells or ≥25%–100% in tumor-associated immune cells), and median OS was not reached with avelumab compared to 17.1 months with best supportive care in this subgroup (HR 0.56, 95% CI 0.4–0.79, p < .001). OS did not differ in the subgroup of patients who were PD-L1-negative (HR 0.86, 95% CI 0.62–1.18). Grade 3/4 adverse effects occurred in 47.4% of patients on avelumab and in 25.2% of patients on supportive care. In the avelumab group, 11.9% of patients discontinued taking the drug because of adverse effects. Although no grade 4 or 5 immunotherapy-related adverse effects occurred, two treatment-related deaths occurred in the avelumab arm (due to sepsis and ischemic stroke). In the supportive-care arm, 43.7% of patients received an immune checkpoint inhibitor in the second-line setting, which may be a lower crossover rate than expected because checkpoint inhibitors are the preferred second-line treatment for metastatic urothelial carcinoma. The OS benefit observed in the JAVELIN Bladder 100 results differs from the results of the HCRN GU14-182 trial, which found no OS benefit with pembrolizumab maintenance compared to placebo following frontline platinum-based chemotherapy.6 The OS advantage of avelumab maintenance in patients who would otherwise receive immunotherapy in the second-line setting remains unclear. In settings where receipt of second-line immunotherapy is not assured, maintenance avelumab will likely become the standard of care.
The optimal frontline treatment for newly diagnosed multiple myeloma is controversial, with some providers preferring newer carfilzomib-based regimens over bortezomib, lenalidomide, and dexamethasone (VRd). In the ENDURANCE trial, patients without intent for upfront hematopoietic stem cell transplant (HSCT) were randomized to receive 36 weeks of carfilzomib, lenalidomide, and dexamethasone (KRd) or VRd.7 PFS was 34.6 months for KRd and 34.4 months for VRd (HR 1.04, 95% CI 0.83–1.31). OS also did not differ between arms. Rates of HSCT were similar between KRd and VRd patients (26.8% and 28%, respectively). Grades 3–5 adverse effects and grades 3–5 nonhematologic adverse effects occurred more frequently in the KRd arm (grades 3–5 adverse effects 65.6% vs. 59.4%, p = .038, nonhematologic 48.3% vs. 41.4%, p =.024). As expected because of the toxicity profiles of the proteasome inhibitors, bortezomib patients experienced a higher rate of peripheral neuropathy, and carfilzomib patients experienced higher rates of dyspnea, hypertension, heart failure, and acute kidney injury. The estimated cost for 36 weeks of KRd is $315,000, compared to $217,000 for VRd. Additional data are needed for high-risk multiple myeloma patients (t(14:20), t(14:16), del17p, LDH >2 times upper limit of normal, or plasma cell leukemia), who were excluded from this trial. However, because of the lack of overall survival, quality of life, or financial benefit with KRd, VRd remains the standard of care for treating newly diagnosed multiple myeloma.
Perhaps the most eagerly anticipated data presented at the ASCO 2020 meeting were from the ADAURA trial, which examined the role of EGFR-directed therapy in the adjuvant setting.8 Though mutation-directed therapy has drastically changed the non-small-cell lung cancer (NSCLC) landscape, these advances are currently limited to metastatic disease. ADAURA included patients with completely resected Stage 1B-3A epidermal growth factor receptor–mutated (EGFRm) non-small-cell lung cancer who were randomized to receive 3 years of adjuvant osimertinib 80 mg once daily (n = 339) or placebo (n = 343). Patients with or without adjuvant cytotoxic chemotherapy were included. The study was unblinded earlier than expected because of efficacy benefit in the osimertinib arm. Patients were stratified by stage, with approximately 30% stage 1B disease, 35% stage 2, and 35% stage 3A. Fifty-five percent of patients had received adjuvant chemotherapy. The primary endpoint was disease-free survival (DFS) in stage 2/3A patients. At 33% data maturity, median DFS was not reached with osimertinib compared to 20.4 months with placebo (HR 0.17, 95% CI, 0.12–0.23, p < .001). In patients of all stages, DFS was also increased with osimertinib (median DFS not reached vs. 28.1 months, HR 0.21, 95% CI 0.16–0.28, p < .001). DFS was significantly improved in all subgroups reported, including all stages, exon19del and L858R mutations, and patients with or without adjuvant chemotherapy. OS data are currently 5% mature, with median OS not reached in either arm and an early hazard ratio of 0.4 (95% CI 0.18–0.9). Eighteen percent of patients discontinued osimertinib or required a dose reduction because of adverse effects. Diarrhea was the most common all-grade adverse effect (46% in osimertinib compared to 19% placebo), followed by paronychia and dry skin. Though the early DFS data are exciting, the role of adjuvant osimertinib is controversial. Seventy percent of patients in ADAURA had stage 2/3B disease, but only 55% of the total study population received adjuvant chemotherapy, raising concern that ADAURA patients did not receive appropriate standard of care prior to randomization. DFS is not a proven surrogate for OS in EGFRm lung cancer, and OS data for this trial will likely require years to mature. In addition, it is unclear how adjuvant osimertinib would affect characteristics of recurrent disease or optimal treatment at recurrence, because osimertinib is also the preferred treatment for metastatic EGFRm NSCLC based on the FLAURA trial.9 The postprotocol treatment of patients on the ADAURA trial has not yet been reported. In addition, the $175,000 annual cost of osimertinib raises concerns about financial toxicity and value of care. Patients with early-stage NSCLC are not routinely tested for EGFR or other mutations, so even the identification of EGFRm patients would represent a paradigm shift. The decision to use osimertinib in the adjuvant setting will likely rely on individual provider and patient assessments of DFS benefit, toxicity over 3 years of adjuvant treatment, financial impact, and unknown OS benefit.
Chemotherapy Remote Care Monitoring Program
The work of pharmacists continues to be recognized by ASCO. Shannon Hough, PharmD BCOP, presented an oral abstract summarizing a pharmacist-driven remote care monitoring program for patients at high risk of experiencing chemotherapy-induced nausea and vomiting (CINV), as identified by the receipt of a neurokinin-1 antagonist.10 The program used text messages to assess patients’ symptoms for 7 days following chemotherapy. Responses indicating poor CINV control were automatically triaged to a clinic-based oncology pharmacist for review and optimization of the patient’s home CINV regimen. Participants in this program displayed a significantly lower rate of healthcare utilization (urgent care, emergency department, or inpatient visits) compared to an institutional historical control (4.53% vs. 6.68%, p = .02). This work highlights the potential of technology to assess patient-reported outcomes in real time and the value of oncology pharmacists in the outpatient setting.
The educational programming for the 2020 ASCO meeting will take place virtually August 8–10. Complete information about ASCO 2020 can be accessed at https://meetings.asco.org/am/virtual-welcome.
The 2021 ASCO Annual Meeting is currently planned for June 4–8, 2021, in Chicago, IL.
- Andre T, Shiu K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. J Clin Oncol. 2020;18(suppl; abstr LBA4).
- Lee JJ, Yothers G, Jacobs SA, et al. Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) study (NRG-GI004/SWOG-S1610): A randomized phase III study of mFOLFOX6/bevacizumab combination chemotherapy with or without atezolizumab or atezolizumab monotherapy in the first-line treatment of patients with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer. J Clin Oncol. 2018;36:15_suppl, TPS3615-TPS3615.
- Ghaneh P, Palmer DH, Cicconi S, et al. ESPAC-5F: Four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer. J Clin Oncol. 2020;38(suppl; abstr 4505).
- Sohal D, Duong MT, Ahmad SA, et al. SWOG S1505: Results of perioperative chemotherapy (peri-op CTx) with mFOLFIRINOX versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA). J Clin Oncol. 2020;38(suppl; abstr 4504).
- Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol. 2020;38(suppl; abstr LBA1).
- Galsky MD, Mortazavi A, Milowsky MI, et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol. 2020;38(16):1797-1806.
- Kuma S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial. J Clin Oncol. 2020;38(suppl; abstr LBA3).
- Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl; abstr LBA5).
- Soria J, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378:113-125.
- Hough S, McDevitt R, Nachar V, et al. Chemotherapy remote care monitoring program (CRCMP): integration of an SMS text patient-reported outcome (PRO) in the electronic health record (EHR) to identify patients needing pharmacist intervention for chemotherapy-induced nausea and vomiting (CINV). J Clin Oncol. 2020;38(suppl; abstr 2001).