A Food and Drug Administration analysis of survival outcomes comparing the Adjuvant Paclitaxel and Trastuzumab trial with an external control from historical clinical trials.

BACKGROUND: Although the Adjuvant Paclitaxel and Trastuzumab (APT) trial has been adopted clinically, single-arm trials have limitations, and interest remains whether these patients with small node-negative human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) would benefit from more intensive chemotherapy. This analysis explored whether external controls can contextualize single-arm studies to add to clinical decision making in the use of de-escalated therapy in patients with low-risk HER2-positive EBC. PATIENTS AND METHODS: Patient-level data from five randomized trials supporting drug approval in adjuvant HER2-positive EBC were pooled, and patients with low-risk EBC were selected (n = 1770). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane/trastuzumab (ACTH) or taxane/carboplatin/trastuzumab (TCH; n = 1366) were matched (1:1) to patients treated with paclitaxel and trastuzumab (TH) in the APT trial (n = 406) using propensity scores. Patients treated with anthracycline/cyclophosphamide/taxane (ACT; n = 374) were also matched (1:1) to those treated with TH. Propensity scores were estimated using covariates of age, tumor stage, estrogen receptor status, progesterone receptor status, and histological grade. RESULTS: After matching, the estimated probabilities of invasive disease-free survival (iDFS) at 3 and 5 years were 98.6% and 96.5% in the TH arm, and 96.6% and 92.9% in the ACTH/TCH arm, respectively. The estimated probabilities of overall survival (OS) at 3 and 5 years were 99.7% and 99.3% in the TH arm, and 99.0% and 97.4% in the ACTH/TCH arm, respectively. Comparing the TH arm with the ACT arm in the matched sample, the estimated difference in iDFS was 7.5% (TH 98.8% and ACT 91.3%) at 3 years and 12.6% (TH 96.1% and ACT 83.5%) at 5 years. The estimated difference in OS was 2.6% (TH 100% and ACT 97.4%) at 3 years, and 5.3% (TH 99.3% and ACT 94.0%) at 5 years. CONCLUSIONS: Our analyses suggest that patients' outcomes in both arms were in general similar, thus providing additional reassurance regarding de-escalation of therapy.

Age-related differences in patient-reported outcomes in patients with advanced lung cancer receiving anti-PD-1/PD-L1 therapy.

BACKGROUND: Older adults with lung cancer often have comorbidities that may increase risk of symptomatic adverse events (AEs) and physical function decline. The objective of this study was to examine age-related differences in patient-reported symptoms and functional domains in patients with advanced lung cancer receiving immunotherapy drugs. METHODS: Three randomized controlled trials of anti-programmed death receptor-1/programmed death-ligand 1 therapy in patients with advanced non-small cell lung cancer that included patient-reported outcomes (PROs) were identified. Baseline PRO data were pooled for treatment arms from 2 trials that included the same PRO tools. Age-related differences in baseline mean scores for each of the health-related quality of life functional and symptom scales were assessed for patients ≥70 years and <70 years. Mean change from Baseline at 3 months was also calculated and plotted for each age group. The adequacy of PRO assessments was assessed by comparing clinician-reported AE data in the 3 trials to the item content of the PRO tools included. RESULTS: Across the 3 trials, 75 of patients were under 70 and 26% patients were 70 and older. Comparing baseline scores in the 2 trials with the same PRO tool, older adults reported small differences including lower physical functioning, less pain, insomnia and financial difficulties, and higher social functioning than younger patients at baseline. No large differences in the distributions of mean change from baseline in function or symptom were identified. Several common clinician-reported symptomatic AEs were not assessed by the PRO strategy employed in the 3 trials. Three clinician-reported symptomatic AEs (rash, fever, and pruritus) that were commonly reported in the safety data (9%-19%) were not assessed using the PRO tools employed. CONCLUSION: While several small differences were seen, there did not appear to be large differences at baseline or in the distributions of change from baseline in PRO functional domains between younger and older patients with lung cancer undergoing anti-programmed death receptor -1/programmed death-ligand 1 therapy. Relevant symptomatic side effects were not assessed by PRO measures in these trials, and this is a limitation of current PRO assessment strategies.

The future of interleukin-2: enhancing therapeutic anticancer vaccines.

PURPOSE: The purpose of our efforts is to trigger the immune destruction of established cancer. Interleukin (IL)-2 can mediate the regression of tumors in patients with melanoma and renal cell carcinoma. In animal models, the antitumor effects of IL-2 are mediated by T lymphocytes. Stimulation with specific antigen can enhance the ability of T cells to respond to IL-2 by triggering the rapid upregulation of the high-affinity IL-2 receptor. We are seeking to design recombinant and synthetic vaccines capable of preferentially priming T cells with specificity for tumor cells. METHODS: The antitumor activity of experimental vaccines is being studied preclinically using recently developed murine models that employ the mouse homologues of human tumor-associated antigens. Once the most effective experimental vaccines are optimized in experimental animals, clinical trials can be conducted. Vaccines are being evaluated for their ability to mediate the regression of established tumors, and a variety of immunologic correlates are being measured. RESULTS: In animal models, vaccines based on molecularly defined tumor-associated antigens expressed in viral vectors or delivered as "naked" DNA stimulate the expansion of CD4+ and CD8+ tumor-specific T lymphocytes. Coadministration of IL-2 with these vaccines dramatically enhances their ability to mediate the regression of established cancer. In the clinic, treatment of melanoma patients with peptide vaccine and IL-2 resulted in objective responses in approximately 40% of patients, a response rate more than twice that typically achieved with IL-2 alone. Paradoxically, tumor-specific CD8+ T-cell levels were not increased in these patients. CONCLUSION: The addition of recombinant and synthetic cancer vaccines to a regimen of IL-2 can result in improved antitumor responses in both animal models and melanoma patients. Vaccine-primed, tumor-specific T cells may preferentially proliferate upon administration of IL-2. The apparent lack of increase in CD8+ T-cell numbers in this setting suggests that the vaccine-primed T cells functionally disappear after a transient period of activation. Preventing the disappearance of activated T cells upon IL-2 administration-for example, by blocking proapoptotic signals-may enhance the therapeutic effectiveness of anticancer vaccines.