Lisa Astor

The FDA has accepted a Biologics License Application (BLA) for retifanlimab, an investigational intravenous PD-1 inhibitor, as a potential treatment for adult patients with locally advanced or metastatic squamous cell carcinoma of the anal canal (SCAC) who have progressed on or who are intolerant of platinum-based chemotherapy and has granted the BLA a Priority Review.

A Prescription Drug User Fee Act target action date of July 25, 2021, was granted for review of the retifanlimab BLA.

“Patients with SCAC who have progressed after first-line chemotherapy treatment currently have no approved treatments available, and we are encouraged that the FDA’s acceptance of this BLA for Priority Review brings us one step closer to addressing this historically neglected, yet important, tumor,” said Lance Leopold, MD, group vice president, Immuno-Oncology Clinical Development, Incyte, in a statement. “Despite SCAC being a rare disease, its incidence is increasing, and its impact is profound. We look forward to working with the FDA to potentially fill an unmet need and advance progress in SCAC for patients.”

SCAC accounts for near 3% of digestive system cancers and is associated with human papillomavirus (HPV) and HIV infections. Currently, there are no FDA-approved treatments for patients who have progressed after frontline chemotherapy.

Data supporting the BLA come from the phase 2 POD1UM-202 trial (NCT03597295), in which retifanlimab induced durable responses in patients with previously treated patients with locally advanced or metastatic SCAC.

The single-arm, open-label, multicenter trial enrolled 94 patients with locally advanced or metastatic SCAC who had progressed on standard therapy. Patients with well-controlled HIV infection were eligible to enroll in the study if they had a CD4 count of ≥300/mcL, undetectable viral load, and if they were still receiving highly active antiretroviral therapy. Those with prior immunotherapy use, active autoimmune disease requiring systemic immunosuppression, known central nervous system metastases and/or carcinomatous meningitis, known active hepatitis, or active infections requiring systemic therapy were ineligible for enrollment. 

Retifanlimab was administered intravenously at 500 mg once every 4 weeks.

The primary end point was overall response rate (ORR) and secondary end points were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events, and pharmacokinetics.

Patients had a median age of 64 years and the majority of patients were female (64.9%), White (76.6%), and had an ECOG performance status of 1 (58.5%). About three-fourths (73.4%) had received prior chemoradiotherapy, 17% had received radiotherapy alone, and 97% had received prior platinum. Thirty-nine patients (41.5%) had liver metastases and 9 (9.6%) were HIV-positive.

The ORR by independent central review was 14% consisting of 1 complete response and 12 partial responses. An additional 35.1% had stable disease. The median DOR was 9.5 months (range, 5.6-not estimable). Responses were observed in patients regardless of PD-L1 expression, liver metastases, or HIV positivity.

The median PFS was 2.3 months (95% CI, 1.9-3.6) and the median OS was 10.1 months (95% CI, 7.9-not estimable). Responses were associated with a prolongation of PFS and OS.

Treatment with retifanlimab was well tolerated. Grade ≥3 treatment-related adverse events were reported in 11.7% of patients and grade ≥3 immune-related adverse events in 6.4%. The most common adverse events were fatigue and diarrhea. Only 2.1% of patients discontinued treatment due to an immune-related adverse event.

The FDA also granted retifanlimab an orphan drug designation for the treatment of anal cancer.

A phase 3 trial (POD1UM-303/InterAACT 2; NCT04472429) has been opened to explore the combination of retifanlimab with carboplatin and paclitaxel in patients with inoperable locally recurrent or metastatic SCAC.

Incyte Announces Acceptance and Priority Review of BLA for Retifanlimab as a potential treatment for patients with squamous cell carcinoma of the anal canal (SCAC). News release. January 21, 2021. Accessed January 22, 2021. https://bit.ly/3qN8LOT

Rao S, Capdevila J, Gilbert D, et al. LBA42 POD1UM-202: Phase II study of retifanlimab in patients (pts) with squamous carcinoma of the anal canal (SCAC) who progressed following platinum-based chemotherapy. 

 2020;31(suppl 4):S1170-S1171. doi:10.1016/j.annonc.2020.08.2272

Articles

The FDA has accepted a Biologics License Application for retifanlimab, an investigational intravenous PD-1 inhibitor, as a potential treatment for adult patients with locally advanced or metastatic squamous cell carcinoma of the anal canal  who have progressed on or who are intolerant of platinum-based chemotherapy and has granted the BLA a Priority Review. 

FDA Grants Priority Review for Retifanlimab for Advanced Squamous Cell Carcinoma of the Anal Canal

The frontline combination of trifluridine/tipiracil (TAS-102; Lonsurf) in combination with bevacizumab (Avastin) demonstrated an overall survival (OS) benefit compared with capecitabine and bevacizumab as treatment of patients with unresectable metastatic colorectal cancer (mCRC) who are not eligible for a standard chemotherapy regimen, resulting in a difference of almost 5 months, according to the final analysis of the phase 2 TASCO1 trial (NCT02743221).1

In results presented during the 2021 Gastrointestinal Cancers Symposium, the trifluridine/tipiracil and bevacizumab arm had a median OS of 22.31 months (95% CI, 18.00-23.69) compared with 17.67 months (95% CI, 12.58-19.81) in the capecitabine and bevacizumab arm (HR, 0.78; 95% CI, 0.55-1.10).

“This study was not comparative so no formal statistical analysis is presented and survival is a secondary end point,” clarified Eric Van Cutsem, MD, PhD, head of the Digestive Oncology Unit at the University Hospital Gashuisberg in Leuven, Belgium.

The multinational, open-label, randomized, noncomparative study included patients with colorectal cancer who had not received prior systemic chemotherapy for their unresectable metastatic disease. Additionally, they were ineligible for intensive therapy due to investigator judgment, for such reasons as advanced age, low tumor burden, ECOG performance status, and comorbidities.

Patients were randomized 1:1 between the 2 treatment arms based on 

status, ECOG performance status, and region. In the trifluridine/tipiracil and bevacizumab arm (n = 77), trifluridine/tipiracil was administered at 35 mg/m2 twice daily orally on days 1 through 5 and 8 through 12 every 4 weeks plus 5 mg/kg of intravenous bevacizumab on days 1 and 15 every 4 weeks. The capecitabine and bevacizumab arm (n = 76) consisted of 1250 or 1000 mg/m2capecitabine twice daily orally for 2 of every 3 weeks and 7.5 mg/kg of intravenous bevacizumab on day 1 of every 3-week cycle. Treatment continued until progression, unacceptable toxicity, or investigator/patient decision.

The primary end point was progression-free survival and secondary end points included OS, objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety.

For the primary analysis for PFS the cutoff date was January 15, 2018, and was based on 100 PFS events. The final analysis was conducted after the end of the study cutoff date of September 1, 2020.

The median age of all patients was 75 years (range, 33-91) with 43% over 75 years. The majority of patients were male (57%), White (97%), had an ECOG performance status of 1 (50%), 

wild-type disease (69%), left-sided tumors (68%), and had at least 3 metastatic sites (73%). Three-fourths of patients had not received prior adjuvant therapy. The most common reason for ineligibility for intensive therapy was advanced age (46%) followed by tumor burden (19%).2

In the primary analysis, the median PFS was 9.2 months (95% CI, 7.59-11.56) in the trifluridine/tipiracil and bevacizumab arm versus 7.8 months (95% CI, 5.55-10.15) in the capecitabine and bevacizumab arm (HR, 0.71; 95% CI, 0.48-1.06). At 12 months, the PFS rate was 40% with trifluridine/tipiracil versus 30% with capecitabine.

At the end of the study, 14.29% of patients in the trifluridine/tipiracil arm were still alive and 86.84% were dead whereas 13.16% were alive and 85.71% were dead in the capecitabine arm. Of the 21 patients not included, 4 were considered lost to follow-up and 17 were censored.1

Treatment discontinuation occurred due to adverse events (AEs) in 23.38%, due to progressive disease in 61.04%, and for other reasons in 11.84% in the trifluridine/tipiracil arm whereas 22.37%, 65.79%, and 15.59% discontinued from the capecitabine arm due to AEs, progressive disease, and other reasons, respectively.

At 6 months, the OS rate in the trifluridine/tipiracil arm was 85% versus 83% in the capecitabine arm, the rates were 76% and 67% at 12 months, respectively, 62% and 47% at 18 months, and 38% and 34% at 2 years.

Subgroup analyses favored the trifluridine/tipiracil arm with most variables, especially for patients with 

mutant disease (HR, 0.17), ECOG performance status as the reason for intensive therapy ineligibility (HR, 0.33), and female gender (HR, 0.44). Right-sided tumors, however, seemed to favor the capecitabine arm (HR, 1.49).

Sixty percent of patients in the trifluridine/tipiracil arm went on to receive at least 1 subsequent therapy versus 41% in the capecitabine arm. The most common subsequent therapies across the 2 arms were fluorouracil, capecitabine, irinotecan, oxaliplatin, and bevacizumab.

In the updated safety analysis, the safety profile was unchanged from the initial analysis, Van Cutsem noted. He said that patients had a good tolerance for trifluridine/tipiracil and bevacizumab.

The most common grade 3/4 hematologic AEs with trifluridine/tipiracil and bevacizumab were neutropenia (46.8%), anemia (13%), and neutrophil count decrease (19.5%). Common grade 3/4 non-hematologic AEs with trifluridine/tipiracil and bevacizumab were hypertension (13.0%) and vomiting (5.2%).

These 2 combinations will be examined further in the comparative, open-label, randomized phase 3 SOLSTICE trial (NCT03869892) in patients with mCRC who are not candidates for intensive therapy.

1. Van Cutsem E, Danielewicz I, Saunders MP, et al. Phase II study evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) patients who are noneligible for intensive therapy (TASCO1): Results of the final analysis on the overall survival. 

2. Van Cutsem E, Danielewicz I, Saunders MP, et al. Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study. 

2020;31(9):1160-1168. doi:10.1016/j.annonc.2020.05.024

The frontline combination of trifluridine/tipiracil in combination with bevacizumab demonstrated an overall survival benefit compared with capecitabine and bevacizumab as treatment of patients with unresectable metastatic colorectal cancer who are not eligible for a standard chemotherapy regimen, resulting in a difference of almost 5 months, according to the final analysis of the phase 2 TASCO1 trial.

TAS-102 Shows OS Benefit With Bevacizumab in mCRC Ineligible for Intensive Therapy

Neoadjuvant chemotherapy regimens were not found to increase the risk for perioperative complications in patients who have potentially resectable advanced thoracic esophageal cancer, according to data from the phase 3 JCOG 1109 trial that were virtually presented at the 2021 Gastrointestinal Cancers Symposium.

Moreover, neoadjuvant chemotherapy regimens of docetaxel, cisplatin, and 5-FU (fluorouracil) (DCF) and radiation with cisplatin and 5-FU (CF-RT) did not increase the risk of postoperative complications when compared with CF alone in these patients.

The 3-arm JCOG 1109 trial is evaluating the overall survival benefit of DCF and CF-RT compared with standard CF as preoperative therapy in patients with thoracic esophageal cancer. The primary analysis for the trial is planned for 2023. This analysis focused on the impact on perioperative complications and risk factors for these complications with the 3 neoadjuvant regimens as the impact of preoperative therapy for esophageal cancer has not been fully investigated yet.

The trial enrolled patients with histologically proven squamous cell carcinoma, adenosquamous carcinoma, or basaloid carcinoma who had lesions in the thoracic esophagus. Patients also had to be between 20 and 75 years of age and have an ECOG performance status of 0 or 1. No prior therapy for cancer except for resection was allowed.

A total of 601 patients with clinical stage IB/II/III thoracic esophageal cancer were randomized equally to one of the 3 arms to receive neoadjuvant chemotherapy prior to transthoracic esophagectomy with regional lymphadenectomy. Following chemotherapy, 546 patients went on to surgery.

In the control arm (arm A), patients received cisplatin 80 mg/m2 on day 1 plus 5-FU at 800 mg/m2 on days 1 to 5 of the 3-week cycle for 2 cycles. Patients in arm B received cisplatin 70 mg/m2 on day 1, 5-FU 700 mg/m2 on days 1 to 5, and docetaxel 70 mg/m2 on day 1 every 3 weeks for 3 cycles. Arm C received cisplatin 75 mg/m2 on day 1 with 5-FU 1000 mg/m2 days 1 through 4 every 4 weeks for 2 cycles in addition to radiation therapy at a total of 41.4 Gy.

Surgery consisted of total or subtotal thoracic esophagectomy and regional lymphadenectomy; transhiatal esophagectomy was not allowed but thoracoscopic esophagectomy and D2 or greater lymphadenectomy was allowed.

Of the patients who went on to undergo surgery, baseline characteristics were well balanced between the 3 neoadjuvant treatment arms. The median age of patients was 65 years (range, 30-75), the majority of patients were male, had an ECOG performance status of 0, had tumors in the middle of the esophagus, and had cT3 and stage III disease.

The approach to surgery and the time of surgery did not differ significantly between arms, nor did the extent of lymph node dissection nor residual tumor. The number of harvested lymph nodes, however, was significantly lower in the CF-RT arm.

The incidence of postoperative complications did not significantly increase with DCF or CF-RT. The rate of grade 3/4 pneumonia was 7.6% in arm A, 5.5% in arm B, and 6.2% in arm C. Grade 3/4 leakage was observed in 3.2% in arm A, 6.6% in arm B, and 7.3% in arm C. The rate of recurrent laryngeal nerve paralysis (RLNP) was 3.2%, 1.6%, and 1.7% in arms A, B, and C, respectively.

Perioperative complications were observed in 1 patient in the CF arm, 3 in the DCF arm, and 3 in the CF-RT arm.

Postoperative complications of any kind and of grade 2 or higher in severity were observed more in the CF arm (56.2%) compared with the DCF arm (43.7%; 

= .02) and compared with the CF-RT arm (47.8%; 

There was a significant difference, though, in the frequency of chylothorax in the investigational arms compared with the control CF arm (1.1%, 3.8%, and 5.1% for arms A, B, and C, respectively).

Presenter Kazuo Koyanagi, MD, PhD, of the National Cancer Center, Department of Gastrointestinal Oncology, Esophageal Surgery Division in Tokyo, Japan, noted that while the reason for the decrease in harvested lymph nodes and the increase in chylothorax in the CF-RT arm is unclear, the tissue fibrosis resulting from radiation therapy could be a possible reason for these effects.

Independent risk factors correlating with the incidence of grade 2 or higher postoperative complications by multivariate analysis included tumor location in the middle (risk ratio, 0.79; 

= .24) of the esophagus. Additional factors included neoadjuvant therapy approach, with a risk ratio of 0.79 (

= .12) with CF-RT, thoracoscopic surgical approach (risk ratio, 0.77; 

= .002), and operation time of more than 492 minutes (risk ratio, 1.26; 

“From these results we could at least say preoperative DCF or CF-RT didn’t increase the risk of postoperative complications,” Koyanagi said.

Surgical approach and extension of lymph node dissection did not differ as a result of the 3 neoadjuvant treatment regimens, nor did the rate of intra-hospital death. Preoperative chemotherapy with the DCF and CF-RT regimens were not associated with radicality or short-term outcomes.

The risk of postoperative complications was not increased with DCF or CF-RT when compared with standard CF for patients with esophageal cancer. A decrease in risk was observed with neoadjuvant DCF chemotherapy, but whether or not this is reflective of an improvement in prognosis will require further investigation. “Reduction of the risk for postoperative complications would be expected to improve the curability of surgery in the DCF group,” Koyanagi noted.

Koyanagi K, Kato K, Ito Y, et al. Impact of preoperative therapy for locally advanced thoracic esophageal cancer on the risk of perioperative complications: Results from multicenter phase III trial JCOG 1109. 

Neoadjuvant Chemo Does Not Impact Surgical Risk in Thoracic Esophageal Cancer

The FDA has approved fam-trastuzumab deruxtecan-nxki (DS-8201a; Enhertu) for the treatment of adult patients with HER2-positive locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab (Herceptin)-based regimen.

“The impact of this approval is great for our patients to be able to offer our patients HER2-directed therapy in the third-line setting is really game-changing, and to the patients, to their families, it offers hope that you can target HER2 and something important about tumor biology that is driving their tumor. And I think a more long-term impact is on the research field to be able to validate and for the first time say, targeting HER2 in later lines of therapy is important and has promise,” Yelena Y. Janjigian, MD, chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, told 

Trastuzumab deruxtecan is a HER2-targeted antibody-drug conjugate (ADC) with a humanized anti-HER2 antibody, a cleavable peptide-based linker, and a topoisomerase I inhibitor payload.

The approval is based on findings from the phase 2 DESTINY-Gastric01 trial (NCT03329690).

DESTINY-Gastric01 was an open-label randomized study that explored the use of trastuzumab deruxtecan versus chemotherapy in patients with HER2-positive advanced gastric cancer GEJ adenocarcinoma that had progressed on at least 2 prior therapies, including trastuzumab. Patients in the study (n = 188) were randomized 2:1 to the investigational or control arm.

In the trastuzumab deruxtecan arm, patients received intravenous treatment at 6.4 mg/kg every 3 weeks and in the control arm patients received physician’s choice of irinotecan at 150 mg/m2 every 2 weeks or paclitaxel at 80 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Treatment continued until disease progression, withdraw of consent, or unacceptable toxicity.

The primary end point was objective response rate (ORR) by RECIST criteria as assessed by independent central review. Secondary end points included overall survival (OS), duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), and safety.

Baseline characteristics were balanced between the 2 arms. The median age of patients was 65 (range, 34-82) in the trastuzumab deruxtecan arm and 66 (range, 28-82) in the chemotherapy arm. The majority of patients across both arms were male (76%), from Japan (80%), had intestinal histologic subtype (68%), and had immunohistochemistry (IHC) 3+ HER2 expression (77%). The primary site of disease was in the stomach in 87% and GEJ in 13%.

A majority of patients had received 2 prior systemic therapies for advanced or metastatic disease (56%) and 17% had received 4 or more prior regimens. These treatments included trastuzumab for all patients, taxane for 86%, ramucirumab (Cyramza) for 72%, immune checkpoint inhibition for 33%, and irinotecan or another topoisomerase I inhibitor for 7%.

The median duration of treatment was 4.6 months (range, 0.7-22.3) in the trastuzumab deruxtecan arm and 2.8 months (range, 0.5-13.1) in the control arm.

The ORR was 51% (95% CI, 42%-61%) with trastuzumab deruxtecan versus 14% (95% CI, 6%-26%) with physician’s choice of chemotherapy (

<.001). In the investigational arm, responses consisted of complete responses in 9% and partial responses in 42%, another 35% had stable disease. The confirmed ORR was 43% versus 12% in the ADC and chemotherapy arms, respectively. The confirmed DCR was 86% with trastuzumab deruxtecan and 62% with chemotherapy.

Median DOR was 11.3 months (95% CI, 5.6-not estimable [NE]) with trastuzumab deruxtecan versus 3.9 months (95% CI, 3.0-4.9) with chemotherapy. The median time to response was 1.5 and 1.6 months in the trastuzumab deruxtecan and chemotherapy arms, respectively.

OS was significantly longer with the ADC with a median of 12.5 months (95% CI, 9.6-14.3) versus 8.4 months (95% CI, 6.9-10.7) with chemotherapy (HR, 0.59; 95% CI, 0.39-0.88; 

.01). At 6 months, the OS rate was 80% with trastuzumab deruxtecan versus 66% with chemotherapy; the 1-year rates were 52% and 29%, respectively.

Median PFS was 5.6 months (95% CI, 4.3-6.9) with trastuzumab deruxtecan and 3.5 months (95% CI, 2.0-4.3) with chemotherapy (HR, 0.47; 95% CI, 0.31-0.71). The 6-month PFS rate was 43% in the investigational arm and 21% in the control arm, and the rates at 1 year were 30% versus 0%, respectively.

Adverse events (AEs) were reported in all of patients in the ADC arm versus in 98% of the chemotherapy arm. The most common grade ≥3 AEs were decreased neutrophil count (51% with trastuzumab deruxtecan vs 24% with chemotherapy), anemia (38% vs 23%), decreased white cell count (21% vs 11%), and decreased appetite (17% vs 13%). Febrile neutropenia was reported in 6 patients in the investigational arm (all of grade 3) versus in 2 in the control arm (1 grade 3, 1 grade 4).

Drug-related interstitial lung disease or pneumonitis was reported in 10% of the trastuzumab deruxtecan group, most of these were grade 1 or 2 in severity, but 2 were of grade 3 and 1 of grade 4. The median time to first onset was 84.5 days (range, 36-638) and the majority of cases resolved or were in the process of resolving at data cutoff.

Treatment discontinuation due to AEs were reported in 15% of the trastuzumab deruxtecan arm and 6% of the chemotherapy arm. Treatment interruption was reported in 62% and 37% of the ADC and chemotherapy arms, respectively, and dose reduction was needed in 32% and 34%. One death due to pneumonia was reported in the trastuzumab deruxtecan arm that was considered to be treatment related.

In a prior phase 1 dose-escalation study (NCT02564900) of patients with advanced solid tumors, patients received either 5.4 mg/kg or 6.4 mg/kg of trastuzumab deruxtecan every 3 weeks. In patients with gastric cancer, the dose of 6.4 mg/kg was selected for dose expansion.

Among the 44 patients with HER2-positive gastric or GEJ cancer from the phase 1 study, preliminary activity and a manageable safety profile was demonstrated. The ORR in these patients was 43.2% (95% CI, 28.3%-59.0%). Serious treatment-emergent AEs were observed in one-fourth of the patients and pneumonitis was reported in 4 patients, including 1 grade 3 case, but no drug-related deaths due to AEs were reported in this subgroup.

1. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA. January 15, 2021. Accessed January 15, 2021. https://bit.ly/3sxawRJ

2. Shitara K, Bang YJ, Iwasa S, et al; DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. 

. 2020;382:2419-2430. doi:10.1056/NEJMoa2004413

3. Shitara K, Iwata H, Takahashi S, et al; DESTINY-Gastric01 Investigators. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. 

2019;20(6):827-836. doi:10.1016/S1470-2045(19)30088-9

The FDA has approved fam-trastuzumab deruxtecan-nxki for the treatment of adult patients with HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

Lisa Astor | Authors

Articles

FDA Grants Priority Review for Retifanlimab for Advanced Squamous Cell Carcinoma of the Anal Canal

TAS-102 Shows OS Benefit With Bevacizumab in mCRC Ineligible for Intensive Therapy

Neoadjuvant Chemo Does Not Impact Surgical Risk in Thoracic Esophageal Cancer

FDA Approves Trastuzumab Deruxtecan for HER2+ Gastric/GEJ Cancer