"Hard-to-talk" cancer: an emerging standard for rare diseases

preface

cancer seems to be an "unspeakable" disease, and with the increase in the diagnosis rate of cancer diseases worldwide, people's awareness is also improving

cancer is a rare tumor with the predominant histological type being squamous cell carcinoma (SCCA) of the anus, along with adenocarcinoma, basal cell carcinoma, melanoma, and neuroendocrine tumors

It is estimated that 90% of anal cancer cases are caused by oncogenic human papillomavirus (HPV), particularly HPV16

cancer is unique, with the in-depth study of its pathogenesis and histopathology and the advancement of radiation therapy levels, radiotherapy and chemotherapy have gradually replaced traditional surgical treatment as the preferred treatment method

chemotherapy

In patients with resectable local recurrences, salvage surgery

Targeted therapy

Basic studies have found that the expression rate of EGFR gene in SCCA is high, and EGFR inhibitors theoretically have a certain therapeutic effect

Immunotherapy

Immune checkpoint inhibitors can also be used in the treatment

The NCI9673 study is the first prospective Phase II study
to be completed in refractory metastatic SCCA.

Studies have shown that the objective response rate (ORR) of treating refractory SCCA with navulijumab monotherapy was 24%, with 2 patients achieving complete remission and 7 patients achieving partial remission, median progression-free survival (PFS) of 4.
1 months, median OS of 11.
5 months, and patient
tolerability.

Based on this result, the NCI9673 study will continue to evaluate the efficacy
of navuliyumab ± ipicumab in refractory metastatic SCCA.

Keynote-028 studies have shown that after receiving pambolizumab treatment with SCCA patients (n=24/63) included in the study cohort, 4 patients (17%) achieved partial remission and 10 patients (42%) achieved disease stabilization
.

The median PFS was 3.
0 months and the median OS was 9.
83 months
.

Only 4 (6%) of all patients experienced severe toxicity
.

The multi-cohort Phase II KEYNOTE-158 study included 112 patients with SCCA, and the ORR of pambolizumab was 11.
6%, which did not reach the median duration
of remission.

14.
7% of patients with PD-L1≥1% and 6.
7% of patients with PD-L1 <1%<b12> achieved remission.

Among all patients, the median PFS was 2.
0 months and the median OS was 12.
0 months
.

Another phase II study of pambolizumab specifically targeting patients with metastatic SCCA is underway (NCT02919969
).

Another PD-1 inhibitor, retifanlimab, has also been evaluated in patients with refractory SCCA, with an ORR of 13.
8% for retifanlimab, regardless of PD-L1 expression; PFS is 2.
3 months; The median OS is 10.
1 months
.

SCCA is characterized by a low tumor mutation burden (TMB) with a median TMB of 2.
5 mutations/megabase (Mb)
reported according to all-exome sequencing.

The KEYNOTE-158 study showed no improvement in ORR (7% vs 11%)
in patients with high TMB SCCA compared with patients with non-high TMB.

Therefore, the role of TMB as a predictive biomarker for benefit from efficacy against PD-1 monotherapy has not been clarified
.

In 59 patients with advanced HPV-positive malignancy (8 cases with primary rectal squamous cell carcinoma), the ORR of the TGF-β/PD-L1 bifufusp alfa was 31%.


This highlights that TGF-β may help overcome tumor cells' resistance to immune checkpoint blockade
.

The CARACAS trial evaluated the PD-L1 inhibitor avelumab monotherapy or in combination with cetuximab in patients
with metastatic SCCA.

The trial was non-randomized and showed an ORR of 10% for avelumab monotherapy and 17%
for avelumab plus cetuximab ORR.

Avelumab plus cetuximab was slightly improved compared to avelumab median PFS alone (3.
8 months vs 2.
0 months), but the combination regimen should be validated
in larger prospective studies.

Although only a small percentage of SCCA patients benefit from immunotherapy, immunotherapy remains a well-tolerated and effective treatment in the management of metastatic cancer that has emerged
in recent years.

To further explore the efficacy of immunotherapy in patients with SCCA, a number of clinical studies have been initiated
.

Further exploration of SCCA can also help promote the research process
of other HPV-related malignancies such as cervical cancer, head and neck cancer, penile cancer, etc.

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References:

Anal Cancer: Emerging Standards in a Rare Disease.
J Clin Oncol.
2022 Aug 20; 40(24):2774-2788.
doi: 10.
1200/JCO.
21.
02566.

Editing/Typography: Jiang Zhou

Execution: Traveller