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Adjuvant T-DM1 in stage 1 HER2-positive breast cancer (June 2021)
A recent noncomparative randomized trial examined adjuvant ado-trastuzumab emtansine (T-DM1) or paclitaxel-trastuzumab (TH) among almost 500 patients with stage I HER2-positive breast cancer treated with initial surgery [1]. Although three-year disease-free survival was favorable with T-DM1 (98 percent), clinically relevant toxicities occurred in nearly half of patients, and the rate of treatment discontinuation for adverse events was higher with T-DM1 than TH (17 versus 6 percent). Because of concerns over tolerability and the limited follow-up of patients in this single trial, T-DM1 is not a standard adjuvant regimen for small, HER2-positive tumors treated with initial surgery.
Pembrolizumab in the initial treatment of advanced HER2-positive gastric and EGJ adenocarcinoma (May 2021)
The US Food and Drug Administration (FDA) has approved pembrolizumab, in combination with trastuzumab and fluoropyrimidine plus platinum-containing chemotherapy, for the treatment of HER2-overexpressing locally advanced or metastatic gastric or esophagogastric junction (EGJ) adenocarcinoma that is not amenable to surgical resection or definitive chemoradiation [2]. Approval was based on a preplanned interim analysis of the first 264 patients enrolled on the phase III KEYNOTE-811 trial, in which the addition of pembrolizumab to trastuzumab and fluoropyrimidine plus platinum-containing chemotherapy improved the objective response rate (74 versus 52 percent), complete response rate (11 versus 3 percent), and proportion of patients with an ongoing response at >=6 months (65 versus 53 percent) compared with placebo [3]. We now suggest adding pembrolizumab to trastuzumab plus a fluoropyrimidine and platinum-containing chemotherapy regimen for patients with previously untreated advanced HER2-overexpressing gastric or EGJ adenocarcinoma.
Adjuvant pembrolizumab in localized renal cell carcinoma (June 2021)
In patients with localized renal cell carcinoma (RCC) treated with nephrectomy, the use of adjuvant therapy to reduce the risk of metastatic or recurrent disease is an active area of investigation. In a double-blind, randomized phase III trial (KEYNOTE-564) of approximately 1000 patients with histologically confirmed clear cell RCC treated with nephrectomy, one year of adjuvant pembrolizumab improved disease-free survival compared with placebo (two-year DFS 77 versus 68 percent), and was well-tolerated [4]. For patients with localized RCC status post nephrectomy, we await regulatory approval of adjuvant immunotherapy, or introduction into consensus guidelines, prior to incorporating this strategy into routine clinical practice.
No benefit for adjuvant chemotherapy following chemoradiation for locally advanced cervical cancer (June 2021)
Standard treatment for locally advanced cervical cancer is concurrent chemoradiation, but further treatment is being investigated to improve outcomes. In a randomized trial including over 900 patients with locally advanced cervical cancer, those assigned to standard cisplatin-based chemoradiation, followed by four cycles of adjuvant carboplatin and paclitaxel, experienced similar five-year overall survival as those assigned to concurrent chemoradiation only (72 versus 71 percent) [5]. We continue to suggest concurrent chemoradiation alone for patients with locally advanced cervical cancer.
Duration of thromboprophylaxis in inpatients with cancer (May 2021)
Individuals with active cancer have a hypercoagulable state that puts them at increased risk of venous thromboembolism, and the risk is further increased by hospitalization. A new meta-analysis has addressed the optimal duration of venous thromboembolism (VTE) prophylaxis in individuals with cancer who are hospitalized with an acute medical illness [6]. The study included four randomized trials comparing extended-duration versus standard-duration thromboprophylaxis in the general population and evaluated outcomes in over 3600 individuals with active cancer or a history of cancer. The risk of VTE was not substantially lower in the extended prophylaxis patients, but the risk of bleeding was approximately twofold higher. These results support our practice of using standard duration thromboprophylaxis during hospitalization in most patients with cancer.
1. Tolaney SM, Tayob N, Dang C, et al. Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT): A Randomized Clinical Trial. J Clin Oncol. 2021; doi: 10.1200/JCO.20.03398.
2. Updated United States Food and Drug Administration-approved prescribing information for pembrolizumab available online at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s097lbl.pdf
3. Janjigian YY, Kawazoe A, Yanez PE, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: Initial findings of the global phase 3 KEYNOTE-811 study (abstract). J Clin Oncol. 39, 2021 (suppl 15; abstr 4013).
4. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study. J Clin Oncol. 2021;39;15S
5. Mileshkin LR, Moore KN, Barnes E, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK trial (ANZGOG 0902, RTOG 1174, NRG 0274). J Clin Oncol. 2021;39S:ASCO #LBA3.
6. Osataphan S, Patell R, Chiasakul T, et al. Extended thromboprophylaxis for medically ill patients with cancer: a systemic review and meta-analysis. Blood Adv. 2021;5(8):2055.
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