Immunotherapy with nivolumab (Opdivo, Bristol-Myers Squibb) holds promise for improving outcomes in patients with refractory metastatic anal cancer, including those who are HIV positive, researchers say.
Results from a single-arm, multicenter phase 2 trial show that in 37 previously treated patients with metastatic squamous cell carcinoma of the anal canal (SCCA) treated with at least one dose of nivolumab, 9 (24%) had radiographic responses with limited toxicity.
Two of the patients had complete responses and 7 had partial responses, note the authors, led by Cathy Eng, MD, from the University of Texas-MD Anderson Cancer Center in Houston.
Initial results were presented at last year's annual meeting of the American Society of Clinical Oncology, as reported at the time by Medscape Medical News. The final results were published online February 17 in Lancet Oncology.
Median progression-free survival was 4.1 months, and median overall survival was 11.5 months, with an estimated 1-year overall survival of 48%. The study authors also note that almost 1 year after the start of the study, 6 of the 9 responders were continuing to receive treatment after the data cutoff date.
"Given the paucity of treatment options available for this population, novel effective therapies are greatly needed. … Based on these results, we remain optimistic that immune checkpoint blockade drugs represent the next step towards improving clinical outcomes for patients with this disease," the authors comment.
In an accompanying commentary, Stefano Cascinu, MD, from the Università di Modena e Reggio Emilia, Italy, acknowledges that these findings provide hope. "For the first time in 20 years there is something new in the treatment of SCCA."
Still, much remains to be known about the use of immunotherapy in SCCA, Dr Cascinu says, noting that 75% to 80% of study participants didn't benefit from nivolumab therapy. He asks how patients who are potentially responsive to nivolumab can be identified and how others might be sensitized to therapy.
Orphan Disease; Nothing New in 20 Years
SCCA is an orphan disease, accounting for only 2% of all gastrointestinal cancers. It can be cured at early stages by using a combination of radiotherapy and chemotherapy with fluouracil (Adrucil, Teva) and mytomicin (Mutamycin, Bristol-Myers Squibb), Dr Eng and colleagues point out. Patients who experience local or regional recurrence are usually treated with salvage surgery.
However, 25% of patients with SCCA develop local extension or metastatic disease and relapse within 3 years of local treatment. "Such patients are treated with fluorouracil and cisplatin [Platinol, Bristol-Myers Squibb]," Dr Cascinu notes, adding that "even though median survival is less than 1 year, this regimen has not changed for 20 years because of a lack of randomised trials."
This trial may be the first completed study to treat metastatic SCCA with an immune checkpoint inhibitor, they say. It may also be the first to include high-risk HIV-positive patients. Up to 90% of SCCA cases are linked to previous infection with the human papillomavirus (HPV), the researchers point out.
"Provided that HIV-positive patients maintain adequate CD4+ T-cell counts under careful clinical observation with an infectious diseases specialist, we recommend that HIV-positive patients be considered for participation in future clinical trials with immune checkpoint inhibitors so that the safety and activity of these drugs can be studied further in a larger series," they write.
The study, carried out at 10 academic centers in the United States, enrolled patients who had undergone at least one previous systemic therapy for surgically unresectable or metastatic SCCA between May 14, 2015, and November 11, 2015. All had a life expectancy of at least 6 months and an Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients with adenocarcinoma of the anal canal, active autoimmune disease or a history of autoimmune disease, or any other concomitant condition requiring systemic corticosteroids were excluded.
Nivolumab was administered intravenously every 2 weeks at a dose of 3 mg/kg. Patients received a median of six doses over the 10-month median follow-up period.
Toxicity was assessed at baseline and every 2 weeks before patients received their next dose of nivolumab. In addition, optional tumor biopsy samples were collected at baseline and after two doses of nivolumab.
Radiographic studies consisted of computed tomography or MRI at baseline and repeated at 6-week intervals. The study's primary endpoint, radiographic response, was assessed by using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
No serious adverse events were reported, no patients with HIV developed grade 3 or 4 adverse events, and no patients dropped out of the study because of toxic effects related to treatment. Grade 3 anemia was reported in one patient. Other grade 3 adverse events included rash in one patient and fatigue in one patient.
One patient developed treatment-related autoimmune hypothyroidism, which resolved after a short course of corticosteroids. Another patient developed treatment-related grade 2 pneumonitis but was successfully treated with steroids after temporarily discontinuing nivolumab.
In 30 patients, serial blood samples collected before treatment and before the second, fourth, and sixth doses of nivolumab showed that responders had higher concentrations of programmed cell death-1 (PD-1) relative to nonresponders.
Analysis of pretreatment biopsy by flow cytometry revealed PD-1 expression on more than 40% of tumour cells in four patients who responded to nivolumab. This was significantly higher than PD ligand 1 expression observed in five nonresponders, the researchers report.
At the data cutoff date of May 16, 2016, 24 of the 37 patients (24%) had progression of disease and 16 had died, although there were no treatment-related deaths.
Dr Eng and colleagues point out that the study's median overall survival of 11.5 months was lower than that reported by the Centers for Disease Control and Prevention in a case series of HPV-associated cancers between 2008 and 2012. That series showed a median overall survival of 17 months.
However, the researchers also note that patients in their study were heavily pretreated, and they write that their results "suggest that immune checkpoint blockade agents might extend overall survival beyond currently available therapies, especially if provided early in the disease treatment course." More research is needed to confirm this, they add.
Dr Cascinu agrees. Future studies should look at the use of nivolumab before metastasis, and a combination of nivolumab and radiotherapy "might also be worthy of investigation," he says.
The dose of nivolumab used in the study didn't follow the 2016 US Food and Drug Administration recommendation of a fixed dose of 240 mg every 2 weeks, Dr Eng and colleagues say. This is one of the study's limitations, they admit, adding that they "support fixed dosing as a consideration for future trials for this population."
The study authors also note that the small number of tumor samples didn't allow them to quantitatively identify responders and nonresponders based on immune response and biomarker expression. Nevertheless, the findings "are consistent with data from other solid tumors such as melanoma," they say.
In an upcoming trial looking at the efficacy and safety of nivolumab plus ipilimumab (Yervoy, Bristol-Myers Squibb) for patients with metastatic SCCA, Dr Eng and colleagues say they plan to analyze paired biopsy samples for changes in the tumor microenvironment associated with treatment response.
This study was funded by the National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the EB Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor. Dr Eng reports a financial relationship with Daiichi, Keryx, Bayer, Sirtex, Genentech, and Roche/Genentech. Several coauthors also report financial relationships with pharmaceutical companies. Dr Cascinu has disclosed no relevant financial relationships.
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Cite this: Nivolumab Shows Promise in Advanced Metastatic Anal Cancer - Medscape - Mar 01, 2017.