gemcitabine; pancreatic cancer; CMV promoter; NK4

Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer

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Patients with advanced biliary tract cancer have a poor prognosis, and first-line standard of care (gemcitabine plus cisplatin) has remained unchanged for more than 10 years. The TOPAZ-1 trial evaluated durvalumab plus chemotherapy for patients with advanced biliary tract cancer.

Methods

In this double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease 1:1 to receive durvalumab or placebo in combination with gemcitabine plus cisplatin for up to eight cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity. The primary objective was to assess overall survival. Secondary end points included progression-free survival, objective response rate, and safety.

Results

Overall, 685 patients were randomly assigned to durvalumab (n=341) or placebo (n=344) with chemotherapy. As of data cutoff, 198 patients (58.1%) in the durvalumab group and 226 patients (65.7%) in the placebo group had died. The hazard ratio for overall survival was 0.80 (95% confidence interval [CI], 0.66 to 0.97; P=0.021). The estimated 24-month overall survival rate was 24.9% (95% CI, 17.9 to 32.5) for durvalumab and 10.4% (95% CI, 4.7 to 18.8) for placebo. The hazard ratio for progression-free survival was 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates were 26.7% with durvalumab and 18.7% with placebo. The incidences of grade 3 or 4 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively.

Conclusions

Durvalumab plus chemotherapy significantly improved overall survival versus placebo plus chemotherapy and showed improvements versus placebo plus chemotherapy in prespecified secondary end points including progression-free survival and objective response rate. The safety profiles of the two treatment groups were similar.

Discussion

TOPAZ-1 was a phase 3 study that evaluated immunotherapy plus chemotherapy as first-line treatment for advanced biliary tract cancer. In previously untreated advanced biliary tract cancer, durvalumab plus gemcitabine and cisplatin demonstrated statistically significant prolonged overall survival versus placebo plus gemcitabine and cisplatin. The overall survival rates at 18 and 24 months, and the increasingly divergent overall survival Kaplan–Meier curves, characterized by the extended tail of the durvalumab arm in the TOPAZ-1 trial, are consistent with the delayed separation of the overall survival Kaplan–Meier curve that is expected with immunotherapy and chemotherapy combinations in solid tumors.19-21

The large, international patient population in the TOPAZ-1 trial was representative of the general population of patients with advanced biliary tract cancer, and characteristics were generally well balanced between treatment groups. A trend toward overall and progression-free survival benefit with durvalumab and chemotherapy was observed across all subgroups analyzed. Although the Asia subgroup appeared to have a relatively larger improvement in survival compared with the rest-of-the-world subgroup, the study was not sized for any individual subgroup evaluations, and no adjustments were made for multiplicity. In addition, the median duration of follow-up in censored patients was approximately 2 months longer in the Asia subgroup compared with the rest-of-the-world subgroup. Because the difference in overall survival rates between treatments continued to increase over time, additional follow-up time may show an improved survival benefit for the rest-of-the-world subgroup. In addition, imbalance in baseline characteristics between the region subgroups, such as the higher proportion of patients with recurrent disease and an ECOG performance score of 1 in Asia compared with the rest of the world, may have contributed to differences in point estimates of the hazard ratios in the subgroups. The addition of durvalumab to chemotherapy benefited patients with tumors characterized by a PD-L1 TAP of 1% or greater and a TAP of less than 1%, indicating that PD-L1 status may have limited value in predicting clinical benefit with durvalumab plus chemotherapy in this patient population. Compared with placebo plus chemotherapy, durvalumab plus chemotherapy was associated with a similar rate of discontinuations due to adverse events; in addition, observed toxicities with durvalumab plus chemotherapy were similar to those commonly seen with either chemotherapy or immunotherapy alone. Importantly, durvalumab did not add additional toxicity to that observed with chemotherapy in this double-blinded trial, and the rates of grade 3 or 4 adverse events were very similar between treatment groups.

First-line standard of care for advanced biliary tract cancer was established more than 10 years ago from the ABC-02 trial, which demonstrated a median overall survival of 11.7 months with gemcitabine and cisplatin versus 8.1 months with gemcitabine monotherapy.7 Outcomes in the gemcitabine and cisplatin group of TOPAZ-1 were comparable to historical controls of gemcitabine and cisplatin,7,22 with a median overall survival of 11.5 months and estimated 18- and 24-month survival rates of 25.6% and 10.4%, respectively.7,22 Our data show that the addition of durvalumab to chemotherapy as first-line treatment was associated with an overall survival hazard ratio of 0.80 (95% CI, 0.66 to 0.97; P=0.021). Although 24.9% and 10.4% of patients were alive at 24 months in the durvalumab and placebo groups, respectively, it is not known whether long-term survival rates exceeding 24 months can be achieved for patients with advanced biliary tract cancer with the addition of durvalumab to chemotherapy.

Although patient characteristics were generally well balanced between treatment groups, it should be noted that microsatellite instability (MSI) status was missing for approximately 50% of patients in each treatment group due to either an insufficient tissue sample or a test result of MSI status unknown. Of the 333 patients with evaluable MSI status, 5 (1.5%) had MSI-high tumors, which is consistent with previous reports of MSI-high prevalence in patients with biliary tract cancer.1,23 Therefore, the statistically significant improvement in overall survival observed in this study is unlikely to be solely attributed to efficacy with durvalumab in the small subset of patients with MSI-high tumors. Exploratory analyses using tumor tissue samples are needed to assess potential survival and response correlations to biomarkers, including driver mutations and tumor mutational burden.

In conclusion, the global, phase 3 TOPAZ-1 trial, at a preplanned interim analysis, met the primary objective of a statistically significant improvement in overall survival in patients with advanced biliary tract cancer; this occurred with similar percentages of Grade 3 and 4 adverse events in both groups. The trial is ongoing toward completion.

Should gemcitabine plus nab-paclitaxel be used in the adjuvant pancreatic cancer setting?

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Yes.

The randomized phase 3 APACT trial was a well-designed adjuvant trial that evaluated the addition of nab-paclitaxel (Abraxane, Celgene) to gemcitabine — the combination was planned based upon the positive results of the MPACT trial in the metastatic setting. Interestingly, around the same time as the MPACT trial, FOLFIRINOX also showed improved OS in the metastatic setting compared with single-agent gemcitabine. Although median survival with FOLFIRINOX appeared to be numerically superior than with gemcitabine and nab-paclitaxel, subsequent real-world analyses indicated no significant differences in OS or time to treatment failure between the two regimens. It is therefore surprising that although the adjuvant FOLFIRINOX study was positive, the adjuvant gemcitabine and nab-paclitaxel trial was not.

Milind Javle, MD
Milind Javle

It is instructive to examine the differences between these two adjuvant trials. The adjuvant FOLFIRINOX trial enrolled 493 patients, mainly from large tertiary centers in France. The APACT study enrolled 866 patients from a large heterogeneous population in the U.S., European Union and Asia. Although DFS served as the primary endpoint of both trials, only the APACT study required an independent review. This difference may appear subtle, but progression after surgery is often diagnosed on clinical grounds alone, such as by a rising CA 19-9 level with increasing abdominal and back pain. Local recurrence within a scar of resected pancreas seldom meets RECIST criteria for progressive disease. Independent reviewer-estimated DFS had not been used as the primary endpoint for an adjuvant pancreatic cancer trial until APACT.

This study was deemed negative because DFS based upon the independent review was not superior with the combination vs. gemcitabine alone (19.4 months vs. 18.8 months). However, this result must be interpreted with caution because the investigator assessment showed a significant DFS difference (16.6 months vs. 13.7 months; HR = 0.82; 95% CI, 0.69-0.96) and a trend toward OS improvement (40.5 months vs. 36.2 months; HR = 0.82; 95% CI, 0.68-0.99) with the combination.

The adjuvant FOLFIRINOX trial was positive and should be considered the standard of care at this time. However, this regimen is associated with considerable toxicity and is often not appropriate for the frail pancreatic cancer population. An estimated 40% of patients with pancreatic cancer do not receive any adjuvant therapy after surgery due to performance status and surgical and medical complications. The FOLFIRINOX regimen is appropriate for patients with a good postoperative recovery and an ECOG performance status of 1.

In summary, DFS guided by independent review may not be an appropriate endpoint for adjuvant pancreatic cancer trials and possibly affected the results of APACT. Those trial results suggest that adjuvant gemcitabine and nab-paclitaxel is worth considering for those patients who are not appropriate candidates for FOLFIRINOX.

References:

Tempero MA, et al. Abstract 4000. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Von Hoff DD, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1304369.

Milind Javle, MD, is professor in the department of GI oncology at The University of Texas MD Anderson Cancer Center. He can be reached at mjavle@mdanderson.org. Disclosure: Javle reports no relevant financial disclosures.

COUNTER

No.

Gemcitabine plus nab-paclitaxel represents one of the gold-standard regimens used in the first-line treatment setting for metastatic pancreatic ductal adenocarcinoma.

E. Gabriela Chiorean, MD
E. Gabriela Chiorean

This led to the development of the APACT study, which evaluated the addition of nab-paclitaxel to gemcitabine after surgical resection of pancreatic cancer. In this trial, the primary endpoint was improvement in DFS assessed by central review, rather than by investigator evaluations, a difference from many previous adjuvant clinical trials. The APACT trial missed the primary endpoint, with median DFS of 19.4 months with the combination vs. 18.8 months with gemcitabine alone (HR = 0.88).

Indeed, DFS was 6 months longer for gemcitabine in APACT than what had been observed in previous clinical trials (13.1 months in ESPAC-4 and 12.8 months in PRODIGE 24). Based on investigators’ review — which included many more events and uncensored patients — the difference in DFS became statistically significant, at 16.6 months with gemcitabine plus nab-paclitaxel vs. 13.7 months with gemcitabine alone (HR = 0.82; P = .0168). Nevertheless, this difference represents a modest improvement, observed mostly at the median, with DFS curves overlapping beyond 15 months and no clear improvement in DFS after 2 years. This means we are not curing more patients with gemcitabine plus nab-paclitaxel. These results are clearly disappointing, especially when compared with modified FOLFIRINOX vs. gemcitabine in PRODIGE 24 (median DFS, 21.6 months vs. 12.8 months; HR = 0.58; P < .0001). In APACT, interim results for OS were just slightly better than for gemcitabine alone (40.5 months vs. 36.2 months; P = .045).

So far, the survival benefit from the addition of nab-paclitaxel to gemcitabine alone seems similar to that from the addition of capecitabine to gemcitabine in ESPAC-4 (HR = 0.82; absolute median OS benefit, 3.5 months).

We need to cure more patients, and we need to significantly prolong survival to justify increased toxicity and cost and possible reduction in quality of life. Gemcitabine plus nab-paclitaxel was simply not good enough in the adjuvant setting. Unless mature OS results show a clear and significant benefit, gemcitabine plus nab-paclitaxel should not be used after pancreatic cancer surgery.

References:

Conroy T, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809775.

Goldstein D, et al. J Natl Cancer Inst. 2015;doi:10.1093/jnci/dju413.

Neoptolemos JP, et al. Lancet. 2017;doi:10.1016/S0140-6736(16)32409-6.

Tempero MA, et al. Abstract 4000. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Von Hoff DD, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1304369.

E. Gabriela Chiorean, MD, is professor of medicine at University of Washington and clinical director of the GI Medical Oncology Program at Seattle Cancer Care Alliance. She can be reached at gchiorea@uw.edu. 

Gemcitabine synergistically enhances the effect of adenovirus gene therapy through activation of the CMV promoter in pancreatic cancer cells

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Adenovirus-mediated gene therapy shows remarkable promise as a new strategy for advanced pancreatic cancer, but satisfactory clinical results have not yet been obtained. To improve this gene therapy, we investigated the effects of gemcitabine (GEM) on transgene expression by adenoviral vectors and their biological effects. We used Ad-lacZ and adenoviral vector-expressing NK4 (Ad-NK4) as representative adenoviral vectors. These vectors express β-galactosidase (β-gal) and NK4 (which inhibits the invasion of cancer cells), respectively, under the control of the CMV promoter. Cells were infected with the individual adenoviruses and then treated with GEM. GEM increased β-gal mRNA expression and β-gal activity, and increased NK4 expression in both culture media and within infected cells, in dose-dependent manners. The increased expression of NK4 delivered by Ad-NK4 had biological effects by inhibiting the invasion of cancer cells. GEM also enhanced NK4 expression in SUIT-2 cells transfected with an NK4-expressing plasmid, suggesting that GEM enhanced CMV promoter activity. In in vivo experiments, NK4 expression within subcutaneously implanted tumors was increased in GEM-treated mice compared with control mice. These results suggest that adenovirus-mediated gene therapy with GEM may be a promising approach for treating pancreatic cancer, and that this combination therapy may decrease the risks of side effects.