Positive Findings for Nab-Paclitaxel/Gemcitabine Combination

Daniel D. Von Hoff, MD

Three presentations from the American Society of Clinical Oncology (ASCO) 2013 Annual Meeting extended positive findings from the international phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) comparing nanoparticle albumin- bound (nab) paclitaxel (Abraxane) and gemcitabine (nab-P+G) to gemcitabine (G) in 861 untreated patients with advanced pancreatic cancer.

Principal investigator Daniel D. Von Hoff, MD, reported in January at the 2013 Gastrointestinal Cancers Symposium that MPACT patients receivingnab-P+G had significantly better median overall survival (OS) than patients receiving G (median 8.5 vs 6.7 months; hazard ratio [HR] = 0.72; 95% CI, 0.617-0.835;P=.000015). The combination was superior to single-agent gemcitabine across all efficacy endpoints, and offered an acceptable toxicity profile.¹

During the 2013 ASCO annual meeting in Chicago, the same research group further elaborated MPACT data in three separate reports: PET and CA19-9 test results by patient arm (abstract 4005)²; CA19-9 decreases as a predictor of overall survival (abstract 4058)³; and MPACT factors prognostic of survival (abstract 4059).⁴

Abstract 4005 provided PET and CA19- 9 correlates among a group of enrolled MPACT patients (n=257). A total of 63% of patients receivingnab-P+G had metabolic responses by PET scan versus 38% receiving G (P= .000051). CA19-9 responses (defined as &ge;90% decrease) were observed in 31% of patients receivingnab-P+G versus 14% of G-treated patients (P<.0001).²

Table 1. Best CA19-9 Decreases from Baseline

nab-P+Gn=379

Gn=371

Best CA19-9 decrease &ge;20%, n (%)

230 (61%)

162 (44%)

8-week CA19-9 decrease &ge;20%, n (%)

196 (52%)

140 (38%)

Median OS, months

13.2

9.4

1-year OS, %

53%

34%

hazard ratio [HR] = 0.59; P <.001

Best CA19-9 decrease &ge;90%, n (%)

117 (31%)

51 (14%)

8-week CA19-9 decrease &ge;90%, n (%)

59 (16%)

33 (9%)

Median OS, mo

13.4

9.4

1-year OS, %

57%

20%

hazard ratio [HR] = 0.44; P = 0.0022

In another report from a prespecified exploratory analysis, CA19-9 was evaluated at baseline and then every 8 weeks during study treatment. OS comparisons by different CA19-9 criteria were made using a stratified Cox proportional hazards model. Of 750 patients with an evaluable CA19-9 at baseline, more patients in the combinationnab- P+G arm achieved &ldquo;best CA19-9&rdquo; decreases from baseline of &ge;20% and &ge;90% than patients in the G arm (Table 1).³

Patients who achieved a CA19-9 decrease at 8 weeks of &ge;20% and &ge;90% had significantly longer OS withnab-P+G than with single-agent G.

MPACT investigators, in a third ASCO presentation, provided results from a step-wise multivariate analysis to evaluate the treatment effect as a means to identify possible predictors of OS. The most important predictors of OS were Karnofsky Performance Status (KPS), age, the presence of liver metastases, the number of metastatic sites, and geographical region of this international study (Table 2).⁴

Although the side effect profile of thenab-P+G combination was not discussed in relation to these MPACT-related ASCO abstracts, Von Hoff, reporting from the 2013 Gastrointestinal Cancers Symposium, said that the combination arm experienced higher rates of neutropenia (38% vs 27%), fatigue (17% vs 7%), peripheral neuropathy (17% vs 1%), and diarrhea (6% vs 1%). However, the peripheral neuropathy was rapidly reversible, and 44% of patients who experienced grade 3 or higher peripheral neuropathy were able to resume treatment. Speaking at the San Francisco GI meeting, Von Hoff said, &ldquo;Febrile neutropenia, which is what we really worry about, was low. It was 1% with gemcitabine and 3% with the combination. We were able to give the same dose intensity for long periods of time, so the two [agents] combine well&hellip;&rdquo; and could become a &ldquo;scaffold&rdquo; onto which other things could be added.

Table 2. Factors Predictive of Overall Survival

Factor

HR

Pvalue

Treatment (nab-P+G vs G)

0.72

.0001

Region (Eastern Europe vs North America)

1.22

.0765

Age (<65 vs &ge;65 years)

0.81

.0190

KPS (70-80 vs 90-100)

1.60

<.0001

Liver metastases (yes or no)

1.81

<.0001

No. of metastatic sites (1, 2, 3, >3)

1.08

<.0864

The potential advantages thatnab-paclitaxel could offer patients have not gone unrecognized by patients, physicians, and regulatory bodies alike. As Von Hoff framed a formerly bleak therapeutic landscape, &ldquo;The past few decades have brought us very few treatment advances for patients with advanced pancreatic cancer, which is both deadly and difficult to treat with success.&rdquo;

Referring to the results from MAPCT, Von Hoff said, &ldquo;The fact that Abraxane [nab-paclitaxel] plus gemcitabine demonstrated an overall survival benefit and did so at one and two years, is a significant step forward in offering potential new hope for our patients.&rdquo;

As early as September 21, 2013, the FDA is expected to undertake a priority review ofnab-paclitaxel in combination with gemcitabine for first-line treatment of pancreatic cancer, based on the results from MPACT. Priority review shrinks the time of regulatory review from 10 months to 6 months.

The last drug the FDA approved for treatment of locally advanced, unresectable, or metastatic disease was erlotinib, in 2005.

References

1. Von Hoff DD, Ervin TJ, Arena FP, et al. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). Presented at the 10th Annual Gastrointestinal Cancers Symposium; January 24-26, 2013: San Francisco, CA. Abstract LBA 148.
2. Von Hoff DD, Ervin TJ, Arena FP, et al. Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates.J Clin Oncol. 2013;31(suppl; abstr 4005).
3. Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19- 9 decrease at 8 weeks as a predictor of overall survival (OS) in a randomized phase III trial (MPACT) of weekly nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients with metastatic pancreatic cancer (MPC).J Clin Oncol. 2013;31(suppl; abstr 4058).
4. Moore MJ, Von Hoff DD, Ervin TJ, et al. Prognostic factors (PFs) of survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients with metastatic pancreatic cancer (MPC).J Clin Oncol. 2013;31(suppl; abstr 4059).