Brittany Lovely

According to updated data from a phase 2 trial (NCT03433469) of neoadjuvant osimertinib (Tagrisso), the third-generation EGFR tyrosine kinase inhibitor (TKI) induced a pathologic complete response (pCR) rate of 69% in patients with surgically resectable 

-mutant non– small cell lung cancer (NSCLC).

Additionally, the major pCR rate was 15%. The treatment was well tolerated with no serious or grade 3/4 adverse effects, unanticipated delays to surgery, tumors that became unresectable, or any increase in surgical complications reported. The average duration of treatment was 59 days, and the objective response rate was 46%.

“Neoadjuvant osimertinib may lead to a better mechanistic understanding of what drives incomplete response and residual disease [for patients with 

-mutant NSCLC],” wrote principal investigator Collin M. Blakely, MD, PhD, an associate professor of medicine at the University of California, San Francisco (UCSF), in a poster presentation of the data.

In the study, participants receive osimertinib 80 mg orally once daily for 28 days for a minimum of 1 cycle prior to surgical resection or until disease progression or unacceptable toxicity. Investigators may give a second cycle of osimertinib prior to surgery if clinically indicated and patients may receive up to 2 weeks of additional therapy while awaiting surgery.

The primary outcome is major pCR, defined as at least 10% residual viable tumor following neoadjuvant osimertinib. Additional efficacy end points include tumor downstaging, objective response, pCR rate, and 5-year disease-free and overall survival rates.

In a detailed analysis, investigators reported pathologic response for the 13 patients treated with osimertinib. Six patients had L858R substitutions, and 7 had exon 19 deletions (del19).

Among patients with L858R substitutions, a partial response was observed in 1. This patient remained on treatment for 82 days and the best radiographic response was –50%. The duration of treatment for the remaining 5 patients with stable disease was 64, 37, 62, 62, and 43 days; the corresponding best radiographic response rates for these patients were –29%, –9%, 0%, –25%, and –7%, respectively.

Among those with del19, 5 had a partial response. For responders, the duration of treatment was 58, 74, 60, 42, and 69 days; the corresponding best radiographic response rates were –40%, –35%, –42%, –33%, and –40%. For the 2 patients with stable disease, the duration of treatment was 57 and 59 days and the best radiographic response rates were 0% and –24%, respectively.

Investigators noted that a loss of function 

mutation was associated with tumors with a lack of pathologic response. Further, an analysis of immune cells for 3 patients revealed that those with residual disease following treatment with osimertinib had decreased macrophages and increased T-cell infiltration compared with the baseline analysis. Based on these results, the investigators hypothesized that T-cell infiltration may correlate with the degree of pathological response.

In an update of the trial’s progress, Blakely noted that 2 sites have joined UCSF and have begun enrollment—the University of California, Davis, and the University of Colorado Denver. Thus far, 30 patients have been screened and 15 of 27 planned patients have been enrolled in the study. Of those 15 patients, 14 have successfully undergone resection and 1 is receiving therapy. Recruitment is ongoing and the study has an estimated completion date of May 31, 2026.

There are no approved neoadjuvant EGFR TKIs for resectable NSCLC. Investigators have assessed various agents in this setting for patients with 

-mutant NSCLC, and results have demonstrated trends toward improvements in pathologic response rates. Both gefitinib (Iressa) and erlotinib (Tarceva) have induced pCRs of approximately 50% in phase 1 and 2 studies of patients with early-stage NSCLC; however, the patient populations are small.

Osimertinib is approved as an adjuvant therapy after tumor resection in patients with NSCLC whose tumors have 

exon del19 or exon 21 L858R mutations.3 The drug’s approval was based on findings from the phase 3 ADAURA trial (NCT02511106), which compared the third-generation EGFR TKI with placebo in patients with fully resected stage IB to IIIA 

In published data, the primary end point of disease-free survival for this patient population was not reached (95% CI, could not be calculated) in the experimental arm vs 27.5 months (95% CI, 22.0-35.0) in the placebo arm (HR, 0.20; 99.12% CI, 0.14-0.30; 

Building on the demonstrated efficacy of osimertinib in the adjuvant setting and the results of the phase 2 study, investigators commenced the phase 3 neoADAURA trial (NCT04351555).2 The trial is designed to compare the use of neoadjuvant osimertinib with or without chemotherapy to chemotherapy alone in patients with resectable, stage II to IIIB 

1. Blakely C. A phase II trial of neoadjuvant osimertinib for surgically resectable EGFR-mutant non-small cell lung cancer: updated results. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer. September 8-14, 2021; Denver, Colorado. Abstract P26.02.

2. Friedlaender A, Addeo A, Russo A, Gregorc V, Cortinovis D, Rolfo CD. Targeted therapies in early-stage NSCLC: hype or hope? 

. 2020;21(17):6329. doi:10.3390/ijms21176329

3. FDA approves osimertinib as adjuvant therapy for non–small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed September 9, 2021. bit.ly/3hipZB9

4. Wu YL, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected 

. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071

Articles

Neoadjuvant osimertinib may lead to a better mechanistic understanding of what drives incomplete response and residual disease for patients with EGFR-mutant NSCLC. according to Collin M. Blakely, MD, PhD.

High pCR Rate Shows Potential for Neoadjuvant Osimertinib in EGFR+ NSCLC

-mutant non–small cell lung cancer (NSCLC) had pathologic complete responses (pCRs) to treatment with neoadjuvant osimertinib (Tagrisso) in a phase 2 study (NCT03433469), signaling a role for the strategy in this patients population.

Specifically, the pCR rate among 13 patients was 69%; the major pCR rate was 15%. The treatment was well tolerated with no serious or grade 3/4 adverse effects, unanticipated delays to surgery, tumors that became unresectable, or an increase in surgical complications reported. The average duration of treatment was 59 days, and the objective response rate was 46%.

-mutant NSCLC],” wrote Collin M. Blakely, MD, PhD, associate professor of medicine and principal investigator of the study at the University of California, San Francisco, in poster of the data.

Participants receive osimertinib 80 mg orally, once daily for 28 days for a minimum of 1 cycle prior to surgical resection or until disease progression or unacceptable toxicity. Investigators may give a second cycle of osimertinib prior to surgery if clinically indicated and patients may receive up to 2 weeks of additional therapy while awaiting surgery.

The primary outcome is major pCR, defined as at least 10% residual viable tumor following neoadjuvant osimertinib. Additional efficacy end points include tumor downstaging, objective response, pCR rate, and 5-year disease-free and overall survival.

In a detailed analysis of pathologic response was reported for the 13 patients treated with osimertinib. Six patients had L858R substitutions, and 7 patients had exon 19 deletions (del19).

For patients with L858R substitutions, a partial response was observed in 1 patient. This patient remained on treatment for 82 days and the best radiographic response was –50%. The durations of treatment for the remaining 5 patients with stable disease were 64, 37, 62, 62, and 43 days; the corresponding best radiographic responses for these patients were –29%, –9%, 0%, –25%, and –7%, respectively.

For patients del19, 5 patients had a partial response. For responders the durations of treatment were 58, 74, 60, 42, and 69 days; the corresponding best radiographic response rates were –40%, –35%, –42%, –33%, and –40%. For the 2 patients with stable disease the durations of treatment were 57 and 59 days, respectively, and the best radiographic response rates were 0% and –24%, respectively.

 mutations was associated with tumors with lack of pathologic response. Further, an analysis of immune cells for 3 patients revealed that in patients with residual disease following treatment with osimertinib demonstrated decreased macrophages and increased T-cell infiltration, compared with baseline analysis. Based on these results, investigators hypothesized that T-cell infiltration may correlate with the degree of pathological response.

In an update of the trial progress, Blakely noted that 2 sites joined UCSF and have begun enrollment—the University of California, Davis, and the University of Colorado, in Denver. Thus far, 30 patients have been screened and 15 of 27 planned patients have enrolled on the study. Of the 15 patients, 14 have successfully undergone resection and 1 patient is on therapy. Recruitment is ongoing and the study has an estimated completion date of May 31, 2026.

There are no approved neoadjuvant EGFR-TKIs for resectable NSCLC. Investigators have assessed various agents in this setting for patients with 

-mutant NSCLC, and results have demonstrated trends towards improvements in pathologic response rates. Both gefitinib (Iressa) and erlotinib (Tarceva) have induced pCRs of approximately 50% in phase 1 and 2 studies; however, patient populations are small.

Osimertinib is approved as for adjuvant therapy after tumor resection in patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations.

The approval was based on findings from the phase 3 ADAURA trial (NCT02511106), which compared the third-generation EGFR TKI, with placebo in patients with fully resected stage IB to IIIA 

Building on the demonstrated efficacy of osimertinib in the adjuvant setting and the results of the phase 2 study, investigators commenced the phase 3 neoADAURA trial (NCT04351555).2 The trial is designed to compare the neoadjuvant osimertinib with or without chemotherapy to chemotherapy alone in patients with resectable, stage II-IIIB 

1. Blakely C. A phase II trial of neoadjuvant osimertinib for surgically resectable EGFR-mutant non-small cell lung cancer: updated results. Presented at: 2021 World Conference on Lung Cancer. September 8-14, 2021; Denver, Colorado. Abstract P26.02.

2. Friedlaender A, Addeo A, Russo A, Gregorc V, Cortinovis D, Rolfo CD. Targeted therapies in early stage NSCLC: hype or hope? 

3. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed September 9, 2021. bit.ly/3hipZB9

4. Wu YL, Tsuboi M, John T, et al; ADAURA Investigators. Osimertinib in resected 

Phase 2 study results signal benefit of neoadjuvant osimertinib in patients with surgically resectable EGFR-mutant non–small cell lung cancer.

Neoadjuvant Osimertinib May Have a Role in EGFR-Positive NSCLC

In patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) regardless of PD-L1 expression, the addition of toripalimab to platinum-based chemotherapy demonstrated significantly improved survival outcomes, according to data of an interim analysis from the phase 3 JUPITER06 study (NCT03829969) that were presented at the ESMO Virtual Congress 2021.

Toripalimab plus chemotherapy reduced the risk of progression by 42% compared with placebo (HR, 0.58; 95% CI, 0.461-0.738; 

 < .00001). Specifically, the median progression-free survival in the toripalimab arm (n = 257) was 5.7 months (95% CI, 5.6-7.0) vs 5.5 months (95% CI, 5.2-5.6) in the placebo arm (n = 257).

The median overall survival (OS) for patients treated with the combination was 17.0 months (95% CI, 14.0-not estimable [NE]) compared with 11.0 months (95% CI, 10.4-12.6) for those who received placebo (HR, 0.58; 95% CI, 0.425-0.783; 

“These results from JUPITER06 support the use of toripalimab in combination with [paclitaxel and cisplatin] as a new standard of care for the first-line treatment for advanced or metastatic ESCC,” said Feng Wang, MD, PhD, professor and vice director in the Department of Medical Oncology at Sun Yet-Sen University Cancer Center in Guangzhou, China.

Investigators enrolled 514 patients with treatment-naïve advanced or metastatic ESCC who had not received prior chemotherapy to receive paclitaxel and cisplatin with either toripalimab or placebo. Individuals were randomized 1:1 to receive 240 mg toripalimab or placebo

in combination with paclitaxel (175 mg/m2) plus cisplatin (75 mg/m2) once every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance. Patients were treated until progressive disease, intolerable toxicity, or withdrawal of consent/investigator judgement for up to 2 years.

Patients were stratified by prior radiation (yes vs no) and ECOG performance status (0 vs 1).

The coprimary end points were PFS by independent central review per RECIST v1.1 and OS. Secondary end points included PFS by investigator analysis, objective response rate, duration of response, disease control rate, 1- and 2-year PFS and OS rates, safety, and health-related quality of life.

Baseline characteristics were well balanced between the cohorts. The median age in the toripalimab arm was 63.0 years (range, 20-75), 74.3% of patients had an ECOG performance status of 1, and a majority of patients had metastatic disease (80.2%). In the placebo cohort, the median age was 62.0 years (range, 40-74), 74.7% had an ECOG performance status of 1, and 77.0% had metastatic disease. Recurrent or unresectable disease was observed in 19.5% and 23.0% of patients in the toripalimab and placebo arms at baseline, respectively.

In terms of PD-L1 expression, most patients had a combined positive score (CPS) greater than or equal to 1. Specifically, for those in the toripalimab arm, 16.7% had CPS less than 1, 78.2% had CPS of at least 1, 50.2% had CPS less than 10, and 44.7% had CPS of at least 10. These rates were 17.1%, 77.8%, 57.2%, and 37.7% in the placebo arm, respectively. CPS was not available for 5.1% of patients in each arm.

Wang presented additional available efficacy data for the anti–PD-1 monoclonal antibody in the intention-to-treat population. Specifically, the 1-year PFS rate for patients in the toripalimab arm was 27.8% (95% CI, 20.4%-35.8%) vs 6.1% (95% CI, 2.2%-12.6%) in the placebo arm.

The 1-year OS rate in the toripalimab arm was 66.0% (95% CI, 57.5%-73.2%) vs 43.7% (95% CI, 34.4%-52.6%) in the placebo arm. Notably, the 2-year OS rate was NE (NE-NE) for those in the experimental arm compared with 17.5% (95% CI, 8.7%-28.9%) in the placebo arm.

In terms of PD-L1 expression, OS and PFS benefits were maintained in the stratified analysis. Specifically, in the PD-L1–high cohort (CPS ≥ 1), the median PFS was 5.7 months in the toripalimab arm (n = 201) vs 5.5 months in the placebo arm (n = 200; HR, 0.58; 95% CI, 0.444-0.751). In the PD-L1–low cohort (CPS < 1), the median PFS was 5.7 months vs 5.6 months with toripalimab (n = 43) and placebo (n = 44), respectively (HR, 0.66; 95% CI, 0.370-1.189).

The median OS for patients treated with toripalimab plus chemotherapy who had high PD-L1 expression was 15.2 months vs 10.9 months (HR, 0.61; 95% CI, 0.435-0.870). For those with low PD-L1 expression, the median OS was NE in the experimental arm vs 11.6 months in the placebo arm (HR, 0.61; 95% CI, 0.297-1.247).

“The incidence of treatment-related AEs [adverse effects] and fatal AEs were similar between the 2 groups,” Wang said. Specifically, the incidence of grade 3 or higher AEs was 64.6% with the addition of toripalimab to chemotherapy vs 56.0% with placebo; any grade AEs were reported for 97.3% of patients in each arm.

All-grade infusion-related reactions were similar between the 2 arms (3.5% and 3.1%, respectively). Two patients in the toripalimab arm experienced a grade 3 or higher infusion-related AE.

Any-grade AEs leading to treatment discontinuation occurred in 3.5% of patients in the toripalimab arm, 2.7% of which were grade 3 or higher. Two patients in the placebo arm discontinued because of AEs (0.8%), one of whom stopped treatment because of a grade 3 or higher AE.

Fatal AEs were reported for 1 patient in the toripalimab arm vs 3 patients in the placebo arm.

The incidence of immune-related AEs was higher in the toripalimab vs placebo (37.0%

vs 26.5%); grade 3 or higher immune-related AEs were 7.0% vs 1.6%, respectively. “The higher incidence of immune-related AEs in the toripalimab arm were expected,” Wang said, adding that they were manageable for immunotherapy.

“The most common AEs were hematologic toxicity,” Wang noted. In the safety analysis, the most common reported AEs (incidence ≥ 30%) were anemia, leukopenia, neutropenia, nausea, peripheral neuropathy, fatigue, decreased appetite, alopecia, and vomiting.

In July 2021, Junshi Bioscience, the developer of toripalimab, announced that the National Medical Products Administration of China accepted a supplemental new drug application based on data from the JUPITER06 study.2 In the United States, Junshi Biosciences and Coherus, the US-based developer, plan to submit a supplemental biologics license application in 2022 for the treatment of ESCC.

Xu RH, Wang F, Cui C, et al. JUPITER-06: a randomized, double-blind, phase 3 study of toripalimab versus placebo in combination with first-line chemotherapy for treatment naive advanced or metastatic esophageal squamous cell carcinoma (ESCC). Presented at: European Society for Medical Oncology Annual Congress 2021; September 16-21, 2021; virtual. Abstract 1373MO.

Junshi Biosciences announces acceptance by NMPA of supplemental new drug application for toripalimab plus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma. News release. Junshi Biosciences; July 31, 2021. Accessed September 17, 2021. bit.ly/3CjgxFJ

Coherus and Junshi Biosciences to present positive progression free survival and overall survival results from JUPITER-06, a phase 3 clinical trial evaluating toripalimab in combination with chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma. News release. Junshi Biosciences and Coherus; September 16, 2021. Accessed September 17, 2021. bit.ly/3hIUL6C

In patients with advanced or metastatic esophageal squamous cell carcinoma regardless of PD-L1 expression, the addition of toripalimab to platinum-based chemotherapy demonstrated significantly improved survival outcomes. 

 Survival Benefit in Frontline Esophageal Squamous Cell Carcinoma Seen With Toripalimab/Chemo Combo

In a phase 2 study of patients with BCG-unresponsive non–muscle invasive bladder cancer (NIMBC), treatment with recombinant pox-viral vector vaccine Panvac™ plus bacillus Calmette-Guérin (BCG) did not significantly improve clinical outcomes, according to a presented at the American Urologic Association 2021 Annual Meeting.

Patients with high-grade NMIBC who did not respond to 1 or more induction courses of intravesical BCG were randomized to receive BCG (n = 15) or BCG plus Panvac (n = 15). The 12-month recurrence-free survival (RFS) rate was 42.9% (95% CI, 22.9%-80.0%) for those who received BCG alone compared with 44.4% (95% CI, 24.8%-79.9%) for those who received the combination (

The median time to recurrence 11.7 months vs 9.9 months, respectively (

 = .77). The RFS rate for entire population was 43.3% (95% CI, 27.9%-66.8%).

The 12-month progression-free survival rates were 79.6% (95% CI, 56.9%-100%) and 78.6% (95% CI, 59.8%-100%) for patients treated with BCG alone and BCG plus Panvac, respectively.

Four patients from the BCG alone arm and 5 patients from the combination arm sought radical cystectomy following treatment.

In terms of baseline histologic characteristics, 14 patients had Ta, 7 had T1, 6 patients had carcinoma in situ alone, 2 had carcinoma in situ with Ta, and 1 had carcinoma in situ with T1. Additionally, 33% of patients (n = 10/30) had at least 2 prior induction courses of BCG.

The vaccine is designed to enhance the presentation of CEA and MUC-1, which are overexpressed in certain cancers, and activate cytotoxic T-lymphocyte response. The therapy consists of a recombinant vaccinia viral vector, a modified vaccinia Ankara-Bavarian Nordic, and a recombinant fowlpox vector. It is administered via a vaccinia priming dose, followed by multiple boosting doses of the fowlpox vector.

Participants enrolled to the phase 2 trial received BCG in 6 weekly injections; those in the Panvac arm received the vaccine in 5 injections over 15 weeks.

In the inclusion criteria for the study, investigators noted that all subclassifications for BCG failure would be considered for inclusion into the study, including BCG-refractory, -resistant, and -relapsing.

Investigators noted in the abstract that the trial was “unique” stating, “It originated prior to the definition of BCG-unresponsive disease and at least a third of the patients on this trial were already BCG unresponsive upon enrollment and received more BCG.”

In a guidance for developing drugs and biologics for treatment, the FDA defined BCG-unresponsive disease as having at least 1 of the following characteristics: persistent or recurrent carcinoma in situ with or without recurrent Ta/T1 disease within 12 months of the completion of adequate BCG therapy, recurrent high-grade Ta/T1 disease within 6 months of the completion of adequate BCG therapy, and/or T1 high-grade disease at the first evaluation after a BCG induction course.

Further, the FDA defined adequate BCG is defined as at least 5 of 6 doses of an induction course plus at least 2 of 3 doses of maintenance therapy, or at least 5 of 6 doses of an induction course plus at least 2 of 6 doses of a second induction course.

“Unlike [ongoing] trials, this trial had a comparison group of BCG alone and, despite the heavy pretreatment in up to a third of patients, the RFS in both arms was still comparable to what has been seen in current BCG unresponsive trials,” the investigators concluded.

The abstract was presented by Ragheed Saoud, MD, a urologist at Northwell Health in Riverside, New York.

1. Saoud R, Telfer S, Marfur M, et al. Clinical outcomes of a randomized, prospective, phase II study to determine the efficacy of bacillus Calmette-Guerin (BCG) given in combination with Panvac versus BCG given alone in adults with high grade BCG-refractory non-muscle invasive bladder cancer. 

. 2021;206(suppl3):e302. doi:10.1097/JU.0000000000002001.14

2. CEA-MUC-1-TRICOM vaccine CV301. National Cancer Institute. Accessed September 13, 2021. 

https://www.cancer.gov/publications/dictionaries/cancer-drug/def/cea-muc-1-tricom-vaccine-cv301

3. Study of bacillus Calmette-Guerin (BCG) combined with Panvac versus BCG alone in adults with high grade non-muscle invasive bladder cancer who failed at least 1 course of BCG. ClinicalTrials.gov. Updated January 22, 2020. Accessed September 13, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02015104

4. BCG-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. FDA. 2018. Accessed September 13, 2021. 

https://www.fda.gov/media/101468/download

n a phase 2 study of patients with BCG-unresponsive non–muscle invasive bladder cancer, treatment with recombinant pox-viral vector vaccine Panvac plus bacillus Calmette-Guérin did not significantly improve clinical outcomes.

Disease Recurrence Not Significantly Delayed With Panvac Plus BCG in Advanced NMIBC

Phase 3 study research signals that antibody titers and fold changes are possibly predictive of nadofaragene firadenovec efficacy in patients with bacillus Calmette-Guérun (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC). The secondary analysis results were presented by Anirban P. Mitra, MD, PhD, during the 2021 American Urological Association Annual Meeting.

Specifically, investigators hypothesized that anti-adenoviral antibody levels and fold change metrics could be as novel predictors of durable response to nadofaragene firadenovec. Based on response to the intravesical gene therapy, patients with peak titer levels that were greater than 800 and peak fold changes greater than 8 were determined to be favorable for response. Patients who did not meet both criteria were designated as unfavorable.

At month 12 following the first treatment with nadofaragene firadenovec, 47 patients were responsive to treatment and a total of 44 patients were nonresponders. On-treatment peak titer levels greater than 800 were reached in 89.4% of responders compared with 59.1% of nonresponders (

= .001). Regarding peak fold change, 51.1% of responders had a peak fold change of at least 8 compared with 27.3% of nonresponders (

Further, the combination of markers was noted in 46.8% and 18.2% of responders and nonresponders, respectively (

“[Peak titer levels] were associated with the highest sensitivity, accuracy, and negative predictive value,” said Mita, a urologic oncology fellow at The University of Texas MD Anderson Cancer Center in Houston. “In addition, when we looked at peak fold changes with a cutoff of 8 this was also able to significantly distinguish between responders and nonresponders such that we then classified patients as ‘favorable’ if they had a combination of peak titer greater than 800 and a peak fold change greater than 8.”

Mita added that the marker combination was associated with the highest sensitivity and positive predictive value.

To conduct this analysis, investigators performed anti-adenoviral antibody assessment using a quantitative ELISA 1 to 24 hours prior to treatment at baseline and before each dose at 3, 6, 9, and 12 months or at the study-withdrawal visit. The assay assessed for both raw titers as well as fold change, which was calculated as the ratio of on-treatment antibody levels compared with baseline levels. The final treatment response was assessed at the trial’s primary end point of 12 months following the first dose or at the time of high-grade recurrence.

Patients enrolled to the trial received a single intravesical 75-mL dose of nadofaragene firadenovec (3 × 1011 viral particles/mL) over 1 hour.1 The replication-deficient recombinant adenovirus is designed to deliver interferon–α-2b (INFα-2b) to the bladder epithelium. The therapy mimics viral infection, resulting in IFNα-2b production and subsequent tumor regression offering a novel treatment for patients whose tumors do not respond or recur after BCG.

In the absence of high-grade recurrence, patients received repeat dosing via catheter at 3 months, 6 months, 9 months, and 12 months; additional dosing was permitted at investigator’s discretion. The primary end point was complete response at any time. A total of 157 patients were enrolled and treated in the study and nonresponders were reported at 6 months (n = 21), 9 months (n = 8), and 12 months (n = 15).

The efficacy population included 151 patients and a complete response was observed in 59.6% (95% CI, 51.3%-67.5%) of patients at 3 months. The duration of response or high-grade recurrence-free survival was 7.31 months (range, 5.68-11.93).

The optimal titer threshold was determined based on the assessment of peak titers and peak fold change. For both responders and nonresponders, peak titers were achieved for most patients approximately 6 months after initiation of treatment; peak fold changes were also observed to occur by month 6. Therefore, investigators selected the optimal antibody titer level threshold to be 200 at baseline and 800 post treatment when maximizing the area under the receiver operating characteristic curve.

Mitra noted that baseline level (200) was not associated with a difference between responders and nonresponders; “however, a posttreatment cutoff of 800 was able to significantly distinguish between responders and nonresponders at 3 months and importantly also at peak titer levels.”

Most crossovers between low- and high-titer subgroups occurred in the first 6 months of treatment. After this time point the highest proportion of responders continued to have posttreatment titers greater than 800, further supporting the use of peak titers as a marker to predict durable response.

Finally, Mita presented an exploratory analysis of baseline titers levels as predictive markers for posttreatment titer level. Despite not being associated with durable response, low baseline titers were associated with low posttreatment titers (≤ 800). High posttreatment titers levels (> 800) were significantly associated with patients who had high baseline titer levels.

Specifically, for those with high posttreatment levels, the median baseline antibody level at 3 months was 400 (interquartile range [IQR], 200-1600) compared with 200 (IQR, 125-400) for those with low posttreatment titers (

For those who had high posttreatment titers at peak, the median baseline antibody level was 400 (IQR, 200-800) vs 200 (IQR, 1-400) for those with low posttreatment titers (

1. Mitra AP, Narayan VM, Boorjian SA, et al. Anti-adenoviral antibody levels predict nadofaragene firadenovec response in BCG-unresponsive NMIBC: results from a phase 3 trial. 

. 2021;206(suppl 3):e119-e120. doi:10.1097/JU.0000000000001977.02

2. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd-IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive bladder cancer: a phase II randomized study. 

. 2017;35(30):3410-3416. Published correction in 

3. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. 

. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4

According to secondary analysis results of a phase 3 study, antibody titers and fold changes are possibly predictive of nadofaragene firadenovec efficacy in patients with bacillus Calmette-Guérun unresponsive non-muscle invasive bladder cancer.

Elevated Antibody Titers May Be a Prognostic Marker in BCG-Unresponsive NMIBC

With addition 16-month follow-up, the benefit of fam-trastuzumab deruxtecan-nxki (Enhertu) as treatment of patients with HER2-overexpressing metastatic colorectal cancer (mCRC) showed results that were consistent with the primary analysis of the DESTINY-CRC01 trial (NCT03384940) study, according to a presentation given during the 2021 ASCO Annual Meeting.

Data from a cohort of 53 patients with HER2-positive mCRC (cohort A) showed that treatment with trastuzumab deruxtecan elicited a confirmed objective response rate (ORR) of 45.3% (95% CI, 31.6%-59.6%). All responses were partial response (PR), and stable disease was observed in 37.7% of patients. The disease control rate (DCR) was 83.0% (95% CI, 70.2%-91.9%). The median duration of response (DOR) of 7.0 months (95% CI, 5.8-9.5).

Patients included in cohort A had HER2-overexpressing disease defined by investigators as immunohistochemistry (IHC) score 3+ or IHC 2+/in situ hybridization (ISH)+. The ORR for these patients served as the primary end point of the study.

“In the primary analysis of cohort A, results yielded promising primary antitumor activity and a manageable safety profile,” Takayuki Yoshino, MD, said in a presentation of the data. “These [continued] promising results support continued exploration of [trastuzumab deruxtecan] in patients with HER2-positive mCRC.” Yohshino is the director of gastroenterology and gastrointestinal oncology and the head of the Clinical Research Coordinating Division at the National Cancer Center Hospital Japan in Tokyo.

Trastuzumab deruxtecan has demonstrated efficacy across cancers with HER2 expression, including breast and lung cancers. Approximately 25% of patients with CRC have metastatic disease and 2% to 3% of those patients have HER2-amplified tumors. Median overall survival (OS) with available options does not surpass 8 months, representing an unmet clinical need for approved targeted therapies in this patient population.

The phase 2 DESTINY-CRC01 trial enrolled patients with unresectable and/or mCRC with 

 expression via central confirmation whose disease is also 

 V600E wild type. Patients must have received at least 2 prior therapies and prior treatment with anti-HER2 therapy was allowed. Patients were stratified into one of 3 cohorts based on 

 expression: IHC 3+, IHC 2+/ISH+ (cohort A; n = 53), ICH2+/ISH- (cohort B; n = 15), or IHC 1+ (cohort C; n = 18). All patients received trastuzumab deruxtecan 6.4 mg/kg administered once every 3 weeks.

Median follow up at the time of final analysis was 62.4 weeks for cohort A, 27.0 weeks for cohort B, and 16.9 weeks for cohort C. No patients remained on treatment at data cutoff of December 28, 2020. The secondary end points of the study included ORR for cohorts B and C, progression-free survival (PFS), overall survival (OS), DOR, DCR, and safety.

The baseline patient characteristics were consistent across groups (N = 86) with a median age of 58.5 years (range, 27-79), more than half of patients in each cohort were from Europe (53.5%) and left-sided primary tumors were dominant (90.7%). Further, a majority of patients were microsatellite stable (80.2%).

In cohort A, 75.5% of patients had a HER2 status of IHC 3+, 24.5% had IHC 2+, and 98.1% reported ISH+. Because of the overexpression of HER2 in this cohort, 30.2% of patients had prior anti-HER2 treatment which accounted for the total number of patients in the study with prior HER2-targeted therapy.

The median number of prior regimens for metastatic disease was 4 (range, 2-11) and all patients received prior irinotecan.

Additional efficacy results for all cohorts were presented by Yoshino; no patients in cohort B or cohort C had a confirmed response. Stable disease was reported in 60% and 22.2% of patients, respectively, and corresponded with a 60% (95% CI, 32.3%-83.7%) and a 22.2% (95% CI, 6.4%-47.6%) DCR in each cohort, respectively.

The median treatment duration across cohorts A, B, and C was 5.1 months (95% CI, 3.9-7.6), 2.1 months (95% CI, 1.4-2.6), and 1.4 (95% CI, 1.3-1.5), respectively.

The median PFS for cohort A was 6.9 months (95% CI, 4.1-8.7) and the median OS was 15.5 months (95% CI, 8.8-20.8), which Yoshino noted was “very impressive for heavily pretreated patients.” The median PFS for cohorts B and C was 2.1 months (95% CI, 1.4-4.1) and 1.4 months (95% CI, 1.3-2.1), respectively; median OS was 7.3 months (95% CI, 3.0-not estimable) and 7.7 months (95% CI, 2.2-13.9), respectively.

In a subgroup analysis of ORR in cohort A, Yoshino said that no difference exists stratified by age, gender, region, or prior anti-HER2 treatment. However, he highlighted that “some difference exists when stratified by ECOG performance status and HER2 status, with ECOG [performance status] of 0 and [IHC 3+] as good indicators of response.” Specifically, the ORR in patients with ECOG performance status of 0 (n = 37) was 54.1% (95% CI, 36.9%-70.5%) compared with 25.0% (95% CI, 7.3%-52.4%) in those with ECOG performance status of 1 (n = 16). Patients with IHC 3+ (n = 40) had an ORR of 57.5% (95% CI, 40.9%-73.0%) compared with only 7.7% in patients with ICH 2+/ISH+ disease (n = 13).

Finally, the best change in tumor size was reported for cohort A and Yoshino noted that “most patients had tumor reduction regardless of prior HER2-treatment [and] IHC 3+ seemed to be a good indicator of treatment response compared [with] IHC 2+/ISH+.”

The safety profile of trastuzumab deruxtecan was consistent with low grade gastrointestinal and hematologic treatment-emergent adverse effects (TEAEs) being the most common in the overall population (N = 86). The most common TEAEs included nausea (61.6%), anemia (36.0%), fatigue (36.0%), and decreased appetite (34.9%). The most common grade 3 or higher TEAEs were neutropenia (22.1%), anemia (14.0%), decreased platelet count (9.3%), and nausea (5.8%).

TEAEs associated with death were reported in 10.5% of the overall patient population. Drug-related TEAEs associated with death were reported in 3 patients overall (3.5%); 2 patients in cohort A and 1 in cohort B. TEAEs led to drug discontinuation, dose reduction, drug and drug interruption in 15.1%, 17.4%, 39.5% of the overall population, respectively.

Interstitial lung disease (ILD), an AE of special interest, was observed in 8 patients (9.3%); ILD grade 2 was reported in 4 patients, grade 3 was reported in 1 patient, and grade 5 ILD occurred in 3 patients. In the 3 fatal cases, median onset of ILD was 22 days (range, 9-120) and death occurred a median of 6 days after diagnosis (range, 6-19).

For all instances of adjudicated drug-related ILS, the median time to onset was 61 days (range, 9-165) and all 8 patients were treated with corticosteroids; all 4 patients with grade 2 ILD recovered.

Yoshino noted that updated ILD guidelines should be followed which recommend interruption or discontinuation of trastuzumab deruxtecan as soon as ILD is suspected. “[ILD] is an important risk and required careful monitoring and prompt intervention,” he said.

Yoshino T, Di Bartolomeo M, Singh Raghav KP, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). 

. 2021;39(suppl 15):3505.doi:10.1200/JCO.2021.39.15_suppl.3505

With addition 16-month follow-up, the benefit of fam-trastuzumab deruxtecan-nxki as treatment of patients with HER2-overexpressing metastatic colorectal cancer showed results that were consistent with the primary analysis of the DESTINY-CRC01 trial study.