Point/Counter

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

Click here to read the Cover Story, “Pancreatic cancer — a changing outlook if diagnosed early.”

POINT

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. Disclosure: Chiorean reports no relevant financial disclosures.

Click here to read the Cover Story, “Pancreatic cancer — a changing outlook if diagnosed early.”

POINT

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.

PAGE BREAK

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. Disclosure: Chiorean reports no relevant financial disclosures.

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