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In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41–0.97, one-sided P= 0.04). Objective response rates were 28% (90% CI = 19–38%) and 9% (90% CI = 2–25%), respectively (one-sided P= 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576.

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AbstractAims:To assess healthcare costs during treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and following disease progression in patients with advanced non-small cell lung cancer (NSCLC).Methods:A retrospective analysis of medical records of US community oncology practices was conducted. Eligible patients had advanced NSCLC (stage IIIB/IV) diagnosed between January 1, 2008 and January 1, 2015, initiated treatment with erlotinib or afatinib (first-line or second-line), and had disease progression. Monthly Medicare-paid costs were evaluated during the TKI therapy period and following progression.Results:The study included 364 patients. The total mean monthly cost during TKI therapy was $20,106 (95% confidence interval [CI] = $16,836–$23,376), of which 47.0% and 42.4% represented hospitalization costs and anti-cancer therapy costs, respectively. Following progression on TKI therapy (data available for 316 patients), total mean monthly cost was $19,274 (95% CI = $15,329–$23,218), and was higher in the 76.3% of patients who received anti-cancer therapy following progression than in the 23.7% of those who did not ($20,490 vs $15,364; p < .001). Among patients who received it, anti-cancer therapy ($11,198; 95% CI = $7,102–$15,295) represented 54.7% of total mean monthly cost. Among patients who did not receive anti-cancer therapy, hospitalization ($13,829; 95% CI = $4,922–$22,736) represented 90.0% of total mean monthly cost. Impaired performance status and brain metastases were significant predictors of increased cost during TKI therapy.Limitations:The study design may limit the generalizability of findings.Conclusions:Healthcare costs during TKI treatment and following progression appeared to be similar and were largely attributed to hospitalization and anti-cancer therapy. Notably, almost one-quarter of patients did not receive anti-cancer therapy following progression, potentially indicating an unmet need; hospitalization was the largest cost contributor for these patients. Additional effective targeted therapies are needed that could prolong progression-free survival, leading to fewer hospitalizations for EGFR mutation-positive patients.

After falling from a roof, an older man lost neurological function below his face. In two days, the patient regained consciousness, but it was unclear whether he could communicate his preferences, whether due to injuries or difficulties with language. His family believed he could communicate with them, and that he was capable of making treatment decisions. The staff did not think to contact the hospital’s largely inactive ethics consultation service for assistance, and instead looked to the patient’s living will for guidance, even though the patient was not terminally ill, and his lack of capacity had not been determined.

alloHCT is offered with curative intent to patients with hematologic malignancies, and conventionally-computed survival estimates are offered for prognosticating outcomes. However, conventionally-computed survival estimates do not take into account elapsed time (and changing hazards with time survived); conditional survival overcomes these limitations, by calculating the probability of survival after having already survived a certain period of time – such data are unavailable for alloHCT recipients. We describe cause-specific (relapse-, GvHD-, treatment-related) conditional survival after alloHCT, providing clinically relevant information for patients who have survived 6 mos, 1, 2, and 5y after alloHCT.From 1976 to 2006, 2,427 consecutive patients received alloHCT for a hematologic malignancy at a single institution (median age: 34.7y [0.6–72.5]). Vital status and cause of death were determined using National Death Index, Social Security Death Index and medical records.As of 12/31/2007, a total of 1413 deaths (58% of the cohort) were observed; 39% attributed to recurrent disease; 34% to GvHD; 12% to infection; 5% to cardiopulmonary disease; 2% to subsequent malignant neoplasm (SMNs); and 8% to other causes. Conventionally-computed probability of survival was 44.6% at 5y and 41.2% at 10y from alloHCT. On the other hand, conditional on survival for 6 mo, 1, 2, and 5y after alloHCT, 5-y survival rates were 62%, 75%, 83%, and 93%, respectively (Figure A). The cohort was at a 40-fold increased risk of any death compared with the general population (95%CI=38.2–42.4); at a 25.6-fold increased risk of death due to pulmonary complications, 3.3-fold risk due to SMNs, and 2.3-fold risk due to cardiovascular complications. Among patients followed for 15+y after HCT, the risk of all-cause mortality was 2.6-fold that of the general population (95%CI=1.8–3.7). Standardized mortality ratios (SMR) and cause-specific conditional mortality rates by primary diagnosis are summarized in the Table.Individuals who survived the first 5y had negligible (≤5%) risk of relapse- and GvHD-related mortality over the subsequent 5y. Treatment-related mortality increased over time; among those who survived 5y, treatment-related mortality rates exceeded relapse-related mortality (Figure B). After adjustment for demographics, underlying diagnosis and treatment era, individuals with chronic GVHD (cGVHD) had a significantly lower risk of relapse-related mortality (RR=0.43, 95%CI=0.4–0.5) compared to those without cGVHD.The projected 5-y survival rates improve conditional on time survived from alloHCT; 5-y survival exceeds 93% for those who have already survived 5y. However, alloHCT recipients who have survived 15+y continue to remain at increased risk of death compared to the general population. cGVHD is associated with decreased risk of relapse-related mortality. Both relapse-related and GvHD-related mortality rates decline with time, such that, among those who have survived 5y, treatment-related mortality exceeds relapse-related mortality. Conditional survival estimates provide clinically relevant prognostic information, helping inform preventive and interventional strategies.No relevant conflicts of interest to declare.

HCT is a curative option for patients with hematologic malignancies. However, the procedure carries a high risk of death in the immediate post-HCT period in part due to disease recurrence (relapse-related mortality [RM]), but also due to treatment-related mortality (TRM) resulting from the following: i) toxicity due to high intensity treatment; ii) graft vs. host disease (GvHD) and its management; and iii) infections. Previous studies utilizing data from HCTs performed in 1980s and 1990s indicate that the 1-yr cumulative incidence of TRM exceeds 20% for related donor and 30% for unrelated donor HCTs. However, gaps in knowledge remain related to the cause-specific cumulative incidence of TRM and RM after autologous and allogeneic HCT performed in the more recent eras.Between 2005 and 2008, a total of 1,673 consecutive patients received HCT at City of Hope at a median age of 50 years for AML (n=433), NHL (n=428), MM (n=369), ALL (n=176), and HL (n=154); 913 patients received autologous HCT; 382 allogeneic related donor; and 378 unrelated donor HCT. Reduced intensity conditioning was used for 268 patients. Early mortality was defined as death in the first year after HCT due to disease (RM) or treatment (TRM). Information regarding vital status and cause of death were obtained from medical records, supplemented with Social Security Death Index. Overall survival (OS) and cumulative incidence of TRM and RM were calculated for 30 d, 6 mo and 1 yr after HCT for i) the entire cohort, and by ii) diagnosis and iii) type of HCT. Multivariable models identified predictors of TRM and RM.A total of 323 deaths (19.3% of the entire cohort) were observed within the first year after HCT; 55.5% attributed to TRM and 44.5% to RM. Among deaths due to TRM, 59% were attributed to infections, 12.9% to acute or chronic GvHD, and 9.5% to organ toxicity. Among autologous, related and unrelated donor HCT recipients, overall survival (OS) was 87.2%, 76.6% and 63.5% at 1 yr (p<0.001) (Figure 1A). Among autologous, related donor, and unrelated donor HCT recipients, 1-yr cumulative incidence of TRM was 1.6%, 12.1%, and 25.6% respectively (p<0.001) (Figure 1B), and cumulative incidence of RM was 8.2%, 6.9%, and 8.7% respectively (p=0.73) (Figure 1C). OS and cumulative incidence of TRM and RM by disease and type of HCT are summarized in Table. Predictors of increased RM included age at HCT 40–60 yr (HR: 1.6, p=0.04; referent group: <40 yr), and diagnosis of NHL (HR=2.0, p=0.008; referent group: AML); receipt of HCT in the later years was associated with decreased RM (2007: HR=0.5, p=0.02; 2008: HR=0.5, p=0.04; referent group: HCT in 2005). Of note, RM for NHL and AML did not differ by type of HCT (p=0.94). Predictors of TRM included allogeneic HCT (related: HR=4.3, p=0.0003; unrelated: HR=10.2, p<0.0001; referent group: autologous HCT). Among related and unrelated HCT recipients, use of reduced intensity conditioning did not have a significant impact on TRM (HR=1.2, p=0.6) or RM (HR=1.2, p=0.7).For patients with NHL and AML, cumulative incidence of RM does not differ by HCT type. Unrelated donor HCT continues to be associated with the highest risk of TRM. Infection is the most frequent cause of TRM, accounting for 62% of deaths due to TRM in unrelated donor, 52% in related donor, and 46% in autologous HCT recipients – reinforcing the need for aggressive measures for prevention and treatment of infections in this immune compromised population.No relevant conflicts of interest to declare.