Steven A. Gilmore, PharmD BCOP
Clinical Oncology Pharmacy Specialist
The Johns Hopkins Hospital
Baltimore, MD

“Delivering Discoveries: Expanding the Reach of Precision Medicine” took center stage as the theme of the 2018 annual meeting of the American Society of Clinical Oncology (ASCO), which took place June 1–5 in Chicago, IL. Presentations and discussions over the course of 5 days provided educational opportunities to more than 39,000 conference attendees. Precision medicine and immunotherapy dominated the updates and new discoveries presented during plenary sessions, and oral abstract presentations focused on lung, breast, and kidney cancers, as well as hematologic malignancies and patient outcomes research.

The ASCO advance of 2018 is adoptive cell therapy using chimeric antigen receptor (CAR) T-cells that have been genetically modified to target a patient’s leukemia or lymphoma cells. More recently, CAR T-cells have been engineered to target B-cell maturation antigen (BCMA) expressed on multiple myeloma cells. Results from an ongoing classic phase 1 dose-escalation study (NCT02658929) using the CAR product currently named bb2121 were presented by Dr. Noopur Raje.¹ The study included 22 heavily pretreated patients with multiple myeloma (MM) and a median eight prior lines of therapy, and nearly half with high-risk cytogenetics, who received 50–800 x 10⁶ cells. Grade <3 cytokine release syndrome (CRS) occurred in 60%, with increasing incidence in patients who received >150 x 10⁶ cells.¹ The effective doses were higher than 150 x 10⁶ cells, where 96% of patients responded to the treatment, and 50% had a complete or stringent complete response. Responses occurred in patients with low or high tumor BCMA expression.¹ Overall, the progression-free survival (PFS) was 11.8 months for the patients who received greater than 150 x 10⁶ cells.¹

Following the work presented first at ASCO 2017 by Ethan Basch et al.,² Dr. Fabrice Denis presented on a randomized trial comparing a Web-based follow-up via patient-reported outcomes (PROs) vs. routine surveillance in lung cancer patients.³ The trial evaluated survival of patients monitored using a Web application named MoovCare. The study was a randomized phase 3 multicenter study that included patients with both small-cell lung cancer and non-small-cell lung cancer who had Internet access and a performance status of 0–2. The goal was to detect relapse using the Web application; after a preplanned interim analysis, the study was stopped for additional recruiting by the data monitoring committee, and 34 patients crossed over to the Web-mediated group. After 121 eligible patients were randomized and after 2 years of follow-up, the OS was 23 months in the Web-mediated follow-up group and 14.8 months in the routine monitoring group (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.39–0.995, p = .048), without adjustment for crossover.³ This study is the first multicenter study using PROs and assessing survival as the primary outcome.

In the Hematologic Malignancies Plasma Cell track, Dr. Luciano Costa presented a phase 2 study of venetoclax plus carfilzomib and dexamethasone in relapsed or refractory MM.⁴ Safety was the primary objective measured; secondary endpoints included overall response rate (ORR), time to progression (TTP), and incidence of minimal residual disease (MRD) negative CR. There were four dose-escalation cohorts receiving increasing doses of venetoclax (maximum dose 800 mg daily) and carfilzomib (maximum dose 56 mg/m² twice weekly dose and 70 mg/m² weekly dose) and dexamethasone (maximum dose 40 mg weekly).⁴ Through the accrual date of April 2018, 42 patients have been enrolled, and no dose-limiting toxicities have been identified. Half of all patients were refractory to a proteasome inhibitor, and 62% were refractory to an immunomodulating agent. The most common adverse events (AEs) included diarrhea, fatigue, and thrombocytopenia, with approximately 70% of patients having grade 3–4 toxicity (primarily asymptomatic cytopenias). Only one patient (with a heavy tumor burden) experienced tumor lysis syndrome, and this was managed without clinical consequences.⁴ The ORR was 83%, with 57% having at least a very good partial response (VGPR). Similar to prior studies of venetoclax in combination with bortezomib,⁵ all patients with t(11;14) responded, with 86% having a VGPR. This study concludes that adding venetoclax to carfilzomib shows promising efficacy in previously treated and multiply refractory patients.⁴

The plenary sessions began with Dr. Joseph Sparano’s presentation of results from TAILORx: a phase 3 trial of chemoendocrine therapy versus endocrine therapy alone in hormone-receptor-positive (estrogen-receptor-positive or progesterone-receptor-positive [ER/PR-positive]), human epidermal growth factor receptor 2 (HER2)-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score (Oncotype DX Recurrence Score [RS]).⁶ This prospective randomized trial included 10,253 women 18–75 years of age with ER/PR-positive, HER2-negative, axillary node–negative breast cancer of tumor size 1.1 cm–5 cm, and mid-range RS. These patients were randomized to receive either endocrine therapy (ET) or chemoendocrine therapy (CET). After 836 invasive disease-free survival (iDFS) events and a median follow-up of 90 months, ET was noninferior for iDFS compared to CET (HR 1.08, 95% CI 0.94–1.24, p = .26) among the intention-to-treat population. ET alone was also noninferior in the analysis for OS (HR 0.97, p = .8) and distant recurrence-free interval (HR 1.03, p = .8).⁶ Overall, the work concludes that ET is noninferior to CET in this breast cancer population, with an RS of 11–25. The study authors stated that more work is needed in patients with RS 25–100 because of the increase in recurrence event rates in this group despite use of CET.⁶

Dr. Mejean presented the results from “CARMENA: Cytoreductive Nephrectomy (CN) Followed by Sunitinib Versus Sunitinib Alone in Metastatic Renal Cell Carcinoma (RCC)—Results of a Phase III Noninferiority Trial.”⁷ This trial included 450 adults enrolled with metastatic (without symptomatic brain metastasis) clear-cell RCC between September 2009 and September 2017, who were eligible for sunitinib and had not had prior systemic therapy for RCC. Patients were randomized 1:1 to CN followed by sunitinib or sunitinib alone. Patients in the sunitinib arm were given 50 mg per day for 4 weeks followed by 2 weeks off, with dose reductions and interruptions allowed per routine practice to manage AEs.⁷ The primary endpoint of the study was OS, with secondary endpoints including PFS, ORR, clinical benefit, and safety. Patients who received sunitinib alone without nephrectomy experienced a median OS of 18.4 months (95% CI, 14.7–23) versus 13.9 months (95% CI, 11.8–18.3) in the CN-sunitinib group. The HR for death between the two groups was 0.89 (95% CI, 0.71–1.1) in favor of sunitinib alone and did not exceed the prespecified limit of 1.2, thus showing noninferiority to the adjuvant arm. Additionally, ORR was similar between the two groups (29.1% for the sunitinib-alone arm and 27.4% for the nephrectomy arm), and clinical benefit was higher in the sunitinib-alone arm (47.9% vs. 36.6%, p = .02).⁷ The analysis concludes that sunitinib alone is not inferior to CN followed by sunitinib for OS in the treatment of intermediate- and poor-risk metastatic RCC.⁷

Dr. Gilberto Lopes also presented results from the KEYNOTE-042 study of pembrolizumab versus platinum-based chemotherapy as first-line therapy for advanced or metastatic non-small-cell lung cancer with a PD-L1 tumor proportion score (TPS) of 1% or greater.⁸ In this open-label phase 3 study, patients with squamous or nonsquamous histologies were included. Patients were excluded if they had EGFR mutations or ALK translocations. Patients were randomized to pembrolizumab 200 mg every 3 weeks for up to 35 cycles, or to chemotherapy for up to 6 cycles with pemetrexed maintenance (encouraged, but optional), for patients with nonsquamous histology. Among 1,274 patients who were randomized, 637 patients were enrolled into each arm. The primary outcome of OS was met and was improved in subgroups with TPS of 50% or greater, 20% or greater, and 1% or greater. After a median follow-up of 12.8 months, pembrolizumab improved the median OS compared to chemotherapy (20 months vs. 12.2 months for TPS ≥50%, 17.7 months vs. 13 months for TPS ≥20%, and 16.7 months vs. 12.1 months for TPS ≥1%). In the TPS ≥50% group, the ORR was 39.5% with pembrolizumab compared to 32% with chemotherapy; 33.4% and 28.9% in patients with TPS ≥20%; and 27.3% and 26.5% in patients with TPS ≥1%. The duration of response in patients with TPS ≥1% was 20.2 months with pembrolizumab compared to 8.3 months with chemotherapy, and treatment-related toxicities were higher with chemotherapy compared to pembrolizumab (89.9% vs 62.7%). The study concluded that pembrolizumab is a safe and effective first-line treatment option that significantly improved OS over standard-of-care chemotherapy in patients with advanced or metastatic non-small-cell lung cancer who had PD-L1 expression of any level without an EGFR mutation or ALK translocation.⁸

For more information and for updates on ASCO’s next meeting in June 2019, visit https://www.asco.org/.

References

1. Raje N, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase 1 study. J Clin Oncol. 2018;36(suppl; abstr 8007).
2. Basch E, Deal AM, Kris MG, et al. Symptom monitoring with patient-reported outcomes during routine cancer treatment: a randomized controlled trial. J Clin Oncol. 2016;34:557.
3. Denis F, Basch EM, Lethrosne C, et al. Randomized trial comparing a web-mediated follow-up via patient-reported outcomes (PRO) vs. routine surveillance in lung cancer patients. J Clin Oncol. 2018;36(suppl; abstr 6500).
4. Costa LJ, Stadtmauer EA, Morgan GJ, et al. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2018;36(suppl; abstr 8004).
5. Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;130:2392-2400.
6. Sparano JA, Gray RJ, Wood WC, et al. TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. J Clin Oncol.2018;36:LBA1.
7. Mejean A, Escudier B, Thezenas S, et al. CARMENA: Cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—Results of a phase III noninferiority trial. J Clin Oncol. 2018;36:LBA3.
8. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36:LBA4.