BENEFIT OF PEMBROLIZUMAB IN MSI-H CANCERS SUSTAINED
1174O: Pembrolizumab in microsatellite instability high cancers: updated analysis of the phase 2 KEYNOTE-164 and KEYNOTE-158 studies
Luis A. Diaz
Dr. Luis A. Diaz (Memorial Sloan Kettering Cancer Center, New York, NY) discussed an updated report from KEYNOTE-164 and KEYNOTE-158, investigating pembrolizumab treatment of microsatellite instability high (MSI-H) cancers, both colorectal (CRC) and non-CRC. The primary endpoint of these studies was ORR, and, for this report, median follow-up of all patients was 18 months.
Among both CRC and non-CRC cohorts, the confirmed ORR was 34% (95% CI 29-39%), including 8% of patients with complete responses. Those patients who responded enjoyed prolonged remission, as the median duration of response was not reached, and 54% of patients had a DOR of at least 18 months. The median OS across the studies was 27.8 months (21.3 to not reached), and the mPFS was 4.0 months (2.5-4.3). No new safety signals were noted in the extended follow-up. Therefore, treatment of cancer patients with MSI-H disease with pembrolizumab continues to show substantial benefit.
RECHALLENGE A POSSIBILITY AFTER DURVALUMAB TREATMENT INTERRUPTION
1175O: Durvalumab activity in previously treated patients who stopped durvalumab without disease progression
Siddharth Sheth
Re-treatment with durvalumab was discussed by Dr. Siddharth Sheth (University of North Carolina, Chapel Hill, NC) in the setting of patients who discontinued durvalumab treatment initially without disease progression (DP). In this trial, patients who had benefit from durvalumab but stopped treatment were eligible for rechallenge if they experienced DP off-therapy. Out of the 1022 patients in the entire NCT01693562 trial, 160 stopped durvalumab treatment without DP, and 70/160 were subsequently rechallenged.
During first treatment with durvalumab, 5.7% of patients experienced CR and 50% had PR; once off-treatment, the median time to progression was 266 days. When rechallenged with durvalumab, best overall responses were as follows: 0% CR, 11.4% PR, 60% PR, and 22.9% DP. Among these patients, the median duration of response was 16.5 months, with a 12-month PFS of 34.2%. While 14 primary tumor types were included in this study, no outcomes were found to significantly vary across tumor type. This study consequently lends support to rechallenge of patients with immune checkpoint inhibitors after initial benefit and subsequent off-treatment disease progression.
POTENTIAL OF SUNITINIB AND NIVOLUMAB IN SARCOMAS IDENTIFIED
1669O: IMMUNOSARC: A collaborative Spanish (GEIS) and Italian (ISG) sarcoma groups phase I/II trial of sunitinib plus nivolumab in advanced soft tissue and bone sarcomas: Results of the phase II-soft-tissue sarcoma cohort
Javier Martin Broto
Dr. Javier Martin Broto (Hospital Universitario Virgen del Rocío, Sevilla, Spain) presented the results from the soft tissue sarcoma (STS) cohort of the IMMUNOSARC study. Therein, pretreated progressing patients were administered sunitinib and nivolumab until progression or intolerance. The primary endpoint of this study was progression-free survival at six months, while overall survival, objective response rate, and safety were also explored.
After a median 6.1 month follow-up, 23/50 patients had progressed on-treatment with a median PFS of 5.9 months. While nine patients had died, the median overall survival had not yet been reached. In the 43 patients evaluable by central radiologic review, there were 1 CR, 3 PR, 26 SD, and 4 PD. The most common relevant grade 3 or 4 toxicities observed included liver enzyme level increases (AST increase in 11.8%, and ALT increase in 9.8%). Since 50% of patients were progression-free at this 6-month point, the combination of sunitinib and nivolumab merits continued exploration in sarcomas.
B-CELL EXPRESSION SIGNATURES CORRELATE WITH OUTCOMES ON HER2-TARGETED THERAPY
174O: Predictive and prognostic value of B-cell gene-expression signatures and B-cell receptor (BCR) repertoire in HER2+ breast cancer: A correlative analysis of the CALGB 40601 clinical trial (Alliance)
Aranzazu Fernandez-Martinez
The importance of the immune system in responses to all types of cancer therapies is being realized; therefore, Dr. Aranzazu Fernandez-Martinez (University of North Carolina, Chapel Hill, NC) investigated the correlation of B-cell gene expression with patient outcomes on the CALGB 40601 trial. This neoadjuvant study of single vs dual HER2 targeting (using trastuzumab + lapatinib) in combination with paclitaxel enrolled patients with HER2+ breast cancer. Pre-treatment samples were analyzed for gene expression profiling by mRNA sequencing, and results were correlated with pathologic complete response and event-free survival.
While over 600 expression signatures were evaluated, ten were found to significantly associate with pCR and EFS, and five of these with improved outcomes. Among the five were one T-helper signature, two IgG signatures, and two B-cell signatures. In particular, patients with a high IgG signature demonstrated best responses when treated with a trastuzumab combination (pCR 58% vs 34%, p = 0.001). Lower pCR rates were associated with the absence of assembled Ig heavy chain gamma or a high evenness, while patients with high Ig heavy chain gamma counts experienced prolonged EFS. Therefore, the B cell profile of breast cancers may help predict responders to HER2 combination treatments.
EXTENDED PFS IN MUC WITH ATEZOLIZUMAB AND CHEMOTHERAPY REGIMEN
LBA14: IMvigor130: Efficacy and safety from a phase 3 study of atezolizumab (atezo) as monotherapy or combined with platinum-based chemotherapy (PBC) vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC)
Enrique Grande
Atezolizumab as a monotherapy or in combination with chemotherapy for first-line treatment of metastatic urothelial carcinoma was presented by Dr. Enrique Grande (MD Anderson Cancer Center Madrid, Madrid, Spain). Three treatment cohorts were investigated in this phase 3 study: Arm A – atezolizumab + platinum-based chemotherapy; Arm B – atezolizumab alone; and Arm C – placebo + chemotherapy. The primary endpoints were investigator-assessed PFS and OS between Arms A and C, and OS between Arms B and C.
A significant difference in PFS was noted between Arms A and C after a median follow-up of 11.8 months, at 8.2 months and 6.3 months, respectively (P=0.007). However, OS between the two groups did not meet the prespecified efficacy boundary, as the mOS values were 16.0 months and 13.4 months (P=0.027). Median overall survival was also similar between patients treated in Arms B and C, with a HR of 1.02. Within Arm B, patients with high immune cell PD-L1 expression (IC2/3) had a mOS that was not estimable, compared to 17.8 months for PD-L1+ patients in Arm C. Thus, while encouraging PFS trends were noted with combination chemotherapy and atezolizumab, the true benefit of this combination in metastatic urothelial carcinoma will be seen only after a more extended follow-up.