Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial

Yamazaki, Tomoko; Gunderson, Andrew; Gilchrist, Miranda; Whiteford, Mark H.; Kiely, Maria X; Hayman, Amanda V.; O’Brien, David; Ahmad, Rehan; Manchio, Jeffrey V.; Fox, Nathaniel E.; McCarty, Kayla; Phillips, M.; Brosnan, Evelyn; Vaccaro, Gina M.; Li, Rui; Simon, M.; Bernstein, Eric; McCormick, Mary; Yamasaki, Lena; Wu, Yaping; Drokin, Ashley; Carnahan, Trevor; To, Yy; Redmond, William L.; Lee, Brian; Louie, Jeannie; Hansen, Eric K.; Solhjem, Matthew C.; Cramer, Julie; Urba, Walter J.; Gough, Michael; Crittenden, Marka R.; Young, Kristina H.

doi:10.1016/s1470-2045(22)00446-6

Cited by 71 publications

(32 citation statements)

References 28 publications

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“…In the AVERECTAL trial, 44 patients with pMMR/MSI-L and dMMR/MSI-H LARC were treated with short-course radiotherapy (SCRT) followed by 6 cycles of consolidation chemotherapy with FOLFOX plus avelumab and surgery, resulting in a promising 37% pCR rate [ 13 ]. An immunoscore assessing the density of CD3 + and CD8 + T-cells was implemented and found predictive of pathological response [ 30 ]. However, the actual proportion of pMMR/MSI-L patients out of the overall population is still unpublished.…”

Section: Proficient Mmr or Msi-low Localized Rectal Cancermentioning

confidence: 99%

“…No advantage in the pCR rate was observed, as well (29% versus 31% in experimental and control arm, respectively, p = 0.75) [ 14 ]. Immunotherapy in LARC has also moved beyond immune checkpoint blockade: in the recent single-arm phase 2 ExIST study ( n = 38), a TGF-β inhibitor, galunisertib, has been delivered before and during the last two weeks of neoadjuvant CRT before immediate surgery, in case of absence of cCR, or surgery/NOM with consolidation oxaliplatin-based fluoropyrimidine doublets, if a cCR had been achieved [ 30 ]. With a 32% complete response rate ( n = 12), a composite outcome of pCR plus cCR maintained one year after last treatment administration in patients who underwent a NOM protocol, the ExiST study met its primary endpoint, endorsing future investigations on galunisertib activity in a randomized setting [ 30 ].…”

Section: Proficient Mmr or Msi-low Localized Rectal Cancermentioning

confidence: 99%

“…Immunotherapy in LARC has also moved beyond immune checkpoint blockade: in the recent single-arm phase 2 ExIST study ( n = 38), a TGF-β inhibitor, galunisertib, has been delivered before and during the last two weeks of neoadjuvant CRT before immediate surgery, in case of absence of cCR, or surgery/NOM with consolidation oxaliplatin-based fluoropyrimidine doublets, if a cCR had been achieved [ 30 ]. With a 32% complete response rate ( n = 12), a composite outcome of pCR plus cCR maintained one year after last treatment administration in patients who underwent a NOM protocol, the ExiST study met its primary endpoint, endorsing future investigations on galunisertib activity in a randomized setting [ 30 ]. However, it should be noticed that 11% of the patients enrolled had stage IV rectal cancer, and that among the 12 patients achieving a complete response, a proved pCR to CRT plus galunisertib was achieved in only 5 out of 25 patients undergoing surgery (20%), the rest being addressed to NOM, where the relative contribution of galunisertib and chemotherapy to achieve at least 12 months of persistent cCR cannot be discerned, due to the non-randomized study design [ 30 ].…”

Section: Proficient Mmr or Msi-low Localized Rectal Cancermentioning

confidence: 99%

“…With a 32% complete response rate ( n = 12), a composite outcome of pCR plus cCR maintained one year after last treatment administration in patients who underwent a NOM protocol, the ExiST study met its primary endpoint, endorsing future investigations on galunisertib activity in a randomized setting [ 30 ]. However, it should be noticed that 11% of the patients enrolled had stage IV rectal cancer, and that among the 12 patients achieving a complete response, a proved pCR to CRT plus galunisertib was achieved in only 5 out of 25 patients undergoing surgery (20%), the rest being addressed to NOM, where the relative contribution of galunisertib and chemotherapy to achieve at least 12 months of persistent cCR cannot be discerned, due to the non-randomized study design [ 30 ]. Main findings on immunotherapy in LARC regardless of microsatellite status are summarized in Table 1 .…”

Section: Proficient Mmr or Msi-low Localized Rectal Cancermentioning

confidence: 99%

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The Evolving Landscape of Immunotherapy in Locally Advanced Rectal Cancer Patients

Germani

Carullo

Boccaccino

et al. 2022

Cancers

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Standard treatments of localized rectal cancer are surgery or the multimodal approach with neoadjuvant treatments (chemo-radiotherapy, short-course radiotherapy, induction, or consolidation chemotherapy) followed by surgery. In metastatic colorectal cancer (mCRC), immune checkpoint inhibitors (ICIs) are now the first choice in patients with a deficient mismatch repair system/microsatellite instability (dMMR/MSI-H) and are being explored in combination with chemotherapy to rewire the immune system against malignant cells in subjects with proficient mismatch repair system/microsatellite low (pMMR/MSI-L) cancers, with promising signals of efficacy. Recently, some efforts have been made to translate ICIs in earlier stages of CRC, including localized rectal cancer, with breakthrough efficacy and an organ preservation rate of mono-immunotherapy in dMMR/MSI-H patients and promising anti-tumor activity of immunotherapy plus neoadjuvant (chemo)radiotherapy in pMMR/MSI-L subjects. Here, we present the rationale, results, and limitations of the most remarkable trials assessing ICIs in dMMR/MSI-H and pMMR/MSI-L localized rectal cancer patients, at the same time highlighting the most promising research perspectives that have followed these studies.

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Section: Proficient Mmr or Msi-low Localized Rectal Cancermentioning

confidence: 99%

Section: Proficient Mmr or Msi-low Localized Rectal Cancermentioning

confidence: 99%

Section: Proficient Mmr or Msi-low Localized Rectal Cancermentioning

confidence: 99%

Section: Proficient Mmr or Msi-low Localized Rectal Cancermentioning

confidence: 99%

See 2 more Smart Citations

The Evolving Landscape of Immunotherapy in Locally Advanced Rectal Cancer Patients

Germani

Carullo

Boccaccino

et al. 2022

Cancers

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“…The proposed mechanisms of synergy observed with this approach include (a) the release of tumor antigens and damage-associated molecular patterns; (b) deletion of Tregs; (c) upregulation of antigen-processing machinery, MHC class I, and death receptors such as Fas and NKG2D; (d) cytokine and chemokine induction; and (e) enhanced immune cell trafficking ( 24 ). Relevant to the Redman et al study, the addition of Galunisertib, a TGF-β type I receptor inhibitor, to diminish the immunosuppressive effects of TGF-β in the TME, improved pathologic response rates to chemoradiation in a neoadjuvant clinical trial in patients with locally advanced rectal cancer ( 25 ). Changes in CXCR3 + CD8 + T cell tumor trafficking and activation status that correlated with response were suggested as possible mechanisms for the observed increase in clinical activity ( Figure 1 ).…”

Section: Translational Relevancementioning

confidence: 99%

Moving beyond the T cell synapse for combination neoadjuvant immunotherapy in head and neck cancer

Bell¹,

Gough²,

Crittenden³

et al. 2022

Journal of Clinical Investigation

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Patients with HPV-unrelated head and neck squamous cell carcinoma (HPV-unrelated HNSCC) show only modest benefit from treatment with PD-1 inhibitors (PD-1i). Targeting transforming growth factor β (TGF-β) may make PD-1i more effective by inducing T cell responses. In this issue of the JCI , Redman et al. performed a clinical trial in 14 patients with HPV-unrelated HNSCC using bintrafusp alfa, a bifunctional fusion protein that blocks PD-L1 and TGF-β. Primary tumors displayed pathologic responses with 5 of 14 patients having at least a partial response. While no primary tumor or metastatic lymph node demonstrated a complete pathologic response, the findings suggest that concurrent neoadjuvant inhibition of PD-L1 and TGF-β may provide a rational strategy to improve pathologic response and clinical outcome in patients with HPV-unrelated HNSCC.

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Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives

Fang

Meng

et al. 2022

Cancer Communications

101

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As a critical component of the tumor microenvironment (TME), cancer‐associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well‐known signaling pathways, including the transforming growth factor‐β (TGF‐β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa‐B (NF‐κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen‐activated protein kinase (MAPK), and phosphoinositide 3‐kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia‐inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma‐targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

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Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial

Cited by 71 publications

References 28 publications

The Evolving Landscape of Immunotherapy in Locally Advanced Rectal Cancer Patients

The Evolving Landscape of Immunotherapy in Locally Advanced Rectal Cancer Patients

Moving beyond the T cell synapse for combination neoadjuvant immunotherapy in head and neck cancer

Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives

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