Discussion
tumor, SD, osteosarcoma, deaths, primary bone tumors, ASPS
OSTEOSARCOMAS, TUMOR, SOFT TISSUE SARCOMAS, T(X;17)(P11;Q25), OSTEOSARCOMA, SECONDARY, RECURRENT OSTEOSARCOMA
Although in this study, the ORR of TQB2858 did not meet prespecified efficacy criteria of more than 20% for osteosarcoma or more than 40% for ASPS, there are still several key takeaways. First, there remains a tremendous need for novel therapies, especially for immunotherapy in patients with recurrent osteosarcoma and ASPS, as demonstrated by the faster-than-expected accrual in our study, even with concurrent trials for the same patient population. Second, our current Phase 1b trial design using a benchmark approach remains a highly effective and efficient mechanism to discern the signal of the activity of novel agents in patients. Using this approach, we confirmed that the efficacy of anti-PD-L1/TGF-β is promising for inducing more immunogenic responses in ASPS. More than 45% of patients showed clinical benefits at 12 weeks. The safety profile of TQB2858 was consistent with those reported in previous studies. No unexpected safety signs or treatment-related deaths were observed. To the best of our knowledge, this is the first study to demonstrate the activity and safety toward PD-L1 and TGF-β dual antibody therapy for osteosarcoma and ASPS.ASPS, accounting for less than 1% of all soft tissue sarcomas and occurring preferentially in young adults, is characterized by the t(X;17)(p11;q25) translocation, which codes for a chimeric ASPSCR1-TFE3 transcription factor, and is known for its sensitivity to TKI therapy with a response rate of approximately 30% [One case in the osteosarcoma cohort (1/5, 20%) had SD lasting for almost 7 months and then progressed with one new subcutaneous lesion. Osteosarcomas, which are classified as “complex genomics,” are the most frequent form of primary bone tumors and mainly affect children, adolescents, and young adults, and determining the signaling pathways that might be targeted by specific therapies is extremely difficult [TGF-β is a diverse regulatory and fibrogenic protein with three isoforms: TGF-β1 (the most common; we performed IHC for this isoform), TGF-β2, and TGF-β3 [This study had some limitations. First, and most importantly, it was a typical early phase trial with a small sample size. These two clinical-expansion cohorts need larger sample sizes with longer follow-up times to obtain a clear conclusion regarding the efficacy of this dual antibody, as well as future directions. Second, because of the rarity of ASPS, we had insufficient numbers to expand our observations, such as overcoming secondary resistance to anti-PD-1 monotherapy, which could have reduced the statistical power. By the way, patients included in the trial did not all get the same anti PD-L1 antibody before enrolled into this trial, which made the deduction mot so well-grounded. More observation with larger sample size should be obtained for the conclusion. Third, the lack of a control arm made it difficult to contextualize the findings in these two cohorts relative to the historical comparator. In addition, we performed IHC of the FFPE only for TGF-β1, which was mostly expressed in extracellular matrix other than the tumor cell membrane and made the manual interpretation difficult. Studies have reported the use of phosphorylation of SMAD2 or SMAD3, which are downstream transcription factors critical in the TGF-β pathway, to demonstrate the activation of this pathway. The effects of TQB2858 on TGF-β2 and TGF-β3 trapping require further investigation.