Hammel P, et al. ASCO GI 2018:204

Phase II LAPACT trial of nab-paclitaxel plus gemcitabine for patients with locally advanced pancreatic cancer

Background

About 30% of patients with pancreatic cancer have unresectable, locally advanced disease.1 Induction chemotherapy is recommended for these patients.2 Nanoparticle albumin-bound (nab)–paclitaxel plus gemcitabine treatment led to a greater than 3-fold reduction in primary pancreatic tumour burden when compared with gemcitabine alone in a phase III trial in metastatic pancreatic cancer.3 The findings led to the combination being assessed in locally advanced pancreatic cancer as well. At ASCO GI 2018, Hammel and colleagues presented results from the LAPACT trial evaluating the efficacy and safety of nab-paclitaxel plus gemcitabine in newly diagnosed patients with locally advanced pancreatic cancer (LAPC).4

Study design

  • LAPACT is a prospective, international, multicentre, phase II trial in treatment-naïve patients with LAPC.
  • A total of 110 patients were planned to be included in the trial.
  • The primary endpoint was time to treatment failure (TTF).
  • Secondary endpoints included disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), safety, and quality of life.
  • The investigators planned a post hoc analysis evaluating the resection rate and quality (R0 vs. R1).

Study design

Key findings

Baseline characteristics and disposition

  • A total of 107 patients were enrolled in the study, 106 received induction, and 61 completed induction. (Figure 1)
  • Of the 61 patients who completed induction, 45 received investigator’s choice of subsequent therapy:
    • Twelve continued with the same chemotherapy;
    • Seventeen received chemoradiation; and
    • Sixteen had surgical resection (7 had R0 and 9 had R1).
  • In the intent-to-treat (ITT) population, the median age was 65 years (range: 42–85), with 55.1% of patients being female.
  • In the ITT population, 46.7% of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 and 53.3% had an ECOG PS of 1.
  • In the population of patients eligible for investigator’s choice phase, 60.4% had an ECOG PS of 0 and 39.6% had an ECOG PS of 1.
  • The median treatment duration was 20.7 weeks (range: 1.0–26.1) and the median number of treatments was 5 (range: 1–6).
  • Overall, 60.4% of patients received five cycles of treatment, while 47.2% received six cycles.
  • Most patients had at least one dose reduction (63.2% for nab-paclitaxel and 62.3% for gemcitabine).
    • The majority of nab-paclitaxel dose reductions (98.5%) were due to adverse events.
  • About half the patients had at least one dose delay (50.0% for nab-paclitaxel and 50.9% for gemcitabine).

Figure 1. Patient disposition

Efficacy

  • The median TTF was 8.8 months. (Figure 2)
  • While no patients had a complete response, 32.7% of patients had a partial response, 57.9% of patients had stable disease (SD), and 4.7% of patients had progressive disease.
    • Overall, 44.9% of patients had SD for at least 16 weeks, while 32.7% of patients had SD for at least 24 weeks.
  • The DCR for at least 16 weeks and for at least 24 weeks was 77.6% and 65.4%, respectively.
  • Data for best change in diameter of target lesions from baseline are presented in Figure 3.
  • A total of 89 patients had serum CA19-9 assessments.
    • Serum CA19-9 levels decreased by:
      • Fifty percent or more in 75.3% of patients; and
      • Seventy percent or more in 56.2% of patients.
  • The median PFS was 10.8 months (90% CI: 9.26–11.63) and the estimated 12-month OS was 72% (90% CI: 64.5–78.9).

Figure 2. Time to treatment failure

Figure 3. Best change from baseline in sum of longest diameters of target lesions*

Safety and quality of life

  • Overall, 99.1% of patients had at least one adverse event (AE) and 35.8% of patients had at least one serious AE (SAE). (Table 1)
  • Grade ≥3 AEs were seen in 80.2% of patients and grade ≥3 SAEs were seen in 31.1% of patients.
  • The most common grade ≥3 AE was neutropenia (41.5%).
  • Of interest, 3.8% of patients had grade ≥3 peripheral sensory neuropathy and 0.9% had peripheral neuropathy.
  • Overall, patients’ global health status was maintained through Day 1 of Cycle 6.
  • Among patients presenting with symptoms affecting quality of life at baseline, the greatest complete resolution rates were observed for vomiting (88%), nausea (81%), and constipation (70%). (Figure 4)

Table 1. Safety during induction

Figure 4. Summary metrics for stable/improved quality of life*

Key conclusions

  • The median TTF of 8.8 months exceeded the protocol-specified target of at least 6.6 months.
  • The combination of nabpaclitaxel with gemcitabine demonstrated promising antitumour activity with an ORR of 33% and a DCR of 78%.
  • The combination therapy was tolerable and consistent with the known safety profile.
  • Quality of life was maintained in most patients.
  • Induction with the combination therapy allowed conversion to tumour resection in 16 of 107 patients (15%).

References: 1. Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet 2011;378(9791):607–20. 2. Balaban EP, Mangu PB, Khorana AA, et al. Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016;34(22):2654–68. 3. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369(18):1691–703. 4. Hammel P, Lacy J, Portales F, et al. Phase II LAPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC). J Clin Oncol (ASCO GI Annual Meeting) 2018;36(Suppl): abstr 204.