Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with Carboplatin, Paclitaxel, and Bevacizumab for First-Line Nonsquamous Non-Small Cell Lung Cancer.

LESSONS LEARNED: The lack of efficacy associated with anti-EGFL7 combined with standard bevacizumab and chemotherapy in this phase II trial in non-small cell lung carcinoma is consistent with the lack of benefit observed in colorectal carcinoma, highlighting the challenge of enhancing the efficacy of VEGF inhibition in unselected populations.Future efforts with agents like anti-EGFL7 should be guided by advances in pharmacodynamic and predictive biomarker development for antiangiogenic agents.
BACKGROUND: Epidermal growth factor-like domain 7 (EGFL7) is an extracellular matrix-associated protein that is upregulated during angiogenesis and supports endothelial cell survival. This phase II trial evaluated the efficacy of the anti-EGFL7 antibody, parsatuzumab, in combination with bevacizumab plus platinum-based therapy for advanced or recurrent nonsquamous non-small cell lung cancer (NS-NSCLC).
METHODS: Patients (n = 104) were randomized to either placebo or parsatuzumab (600 mg) in combination with bevacizumab (15 mg/kg) and carboplatin/paclitaxel, administered on day 1 of each 21-day cycle. Carboplatin and paclitaxel were administered for up to six cycles. Bevacizumab and parsatuzumab/placebo were administered for a maximum of 24 months.
RESULTS: The progression-free survival (PFS) hazard ratio (HR) was 1.7 (95% confidence interval [CI], 1.0-2.8; p = .047). The median PFS was 6.7 months for the parsatuzumab arm versus 8.1 months for the placebo arm. The hazard ratio for overall survival (OS) was 1.1 (95% CI, 0.5-2.2; p = .847). The objective response rate (ORR) was 29% in the parsatuzumab arm and 56% in the placebo arm. Overall safety and tolerability were consistent with the established toxicity profile of bevacizumab.
CONCLUSION: There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line NS-NSCLC. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

RCT Entities:   Population Interventions Outcomes

Discussion

EGFL7 is a tumor‐enriched, vascular‐restricted extracellular matrix protein that promotes endothelial cell adhesion and survival [1]. In murine tumor models, the combination of an anti‐EGFL7 antibody and anti‐VEGF enhanced the antiangiogenesis and survival prolongation associated with anti‐VEGF monotherapy [2]. Parsatuzumab (MEGF0444A) is a humanized anti‐EGFL7 IgG1 monoclonal antibody that selectively blocks the interaction between EGFL7 and endothelial cells. Based on the safety profile and evidence of pharmacodynamic modulation observed in a phase Ib trial of parsatuzumab in combination with bevacizumab with or without paclitaxel [2], [3], parsatuzumab was advanced to two phase II trials, one in colorectal cancer (CRC) [4] and another the current study in NS‐NSCLC, respectively.

The primary objective of this study was to evaluate the efficacy of parsatuzumab in combination with standard carboplatin, paclitaxel, and bevacizumab in patients with advanced or recurrent NS‐NSCLC, as measured by PFS. At the primary analysis, the PFS HR was 1.7 (95% CI, 1.0–2.8; p = .047), with median PFS of 6.7 months for the parsatuzumab arm versus 8.1 months for the control arm. Likewise, secondary outcome measures showed no evidence of benefit: the ORR was 29% in the parsatuzumab arm and 56% in the placebo arm, and the immature HR for OS was 1.1 (95% CI, 0.5–2.2; p = .847). These results reinforce the overall lack of efficacy observed with parsatuzumab in a phase II trial in combination with chemotherapy consisting of folinic acid, 5‐FU, and oxaliplatin, known as modified FOLFOX6 or mFOLFOX6, plus bevacizumab in CRC (HR for PFS and OS, 1.17 and 0.97, respectively) [4].

Although the overall rate of adverse events (AEs) and serious adverse events (SAEs) was similar in the two study arms, a numerical imbalance in grade ≥3 bleeding AEs was observed (four events, including two fatal events, in the parsatuzumab arm versus no events in the placebo arm). Nevertheless, fatal hemorrhage is an established safety signal for bevacizumab in this population, and there was no apparent exacerbation of any other bevacizumab‐related AEs in patients receiving parsatuzumab. Thus, given that the CRC trial [4] did not demonstrate an increased risk of bleeding associated with parsatuzumab, it appears unlikely that the numerical imbalance observed in this trial is reflective of a significant difference in toxicity.

The experience with parsatuzumab illustrates the challenge of improving outcomes with standard bevacizumab and chemotherapy regimens through enhanced antiangiogenesis in unselected populations. Unfortunately, robust predictive biomarkers for bevacizumab in NSCLC patients remain elusive despite intensive efforts. Because archival tissue submission was optional for this small trial, retrospective interrogation of biomarker‐based subgroups was of limited utility. New mechanistic insights and biomarker hypotheses are likely required to guide future development of antiangiogenic combinations.

Trial Information

Lung cancer—NSCLC

Metastatic/advanced

None

Phase II

Randomized

Progression‐free survival

Safety

Inactive because results did not meet primary endpoint

Drug Information for Phase II Control

Placebo

Other

Other

600 mg per flat dose

IV

Bevacizumab

Genentech/Roche

Antibody

Angiogenesis—antivascular

15 mg/kg

IV

Every 21 days until disease progression or unacceptable toxicity for a maximum of 24 months (34 cycles)

Paclitaxel

Small molecule

Microtubule‐targeting agent

200 mg/m2

IV

Every 21 days until disease progression or unacceptable toxicity for a maximum of six cycles.

Carboplatin

Small molecule

Platinum compound

AUC of 6 mg • min/ml (Calvert formula)

IV

Dose: AUC of 6 mg • min/ml (Calvert formula); schedule of administration: every 21 days until disease progression or unacceptable toxicity for a maximum of six cycles

Drug Information for Phase II Experimental

Parsatuzumab (MEGF0444A)

Genentech/Roche

Antibody

Angiogenesis—antivascular

600 mg per flat dose

IV

Every 21 days until disease progression or unacceptable toxicity for a maximum of 24 months (34 cycles)

Bevacizumab

Genentech/Roche

Antibody

Angiogenesis—antivascular

15 mg/kg

IV

Every 21 days until disease progression or unacceptable toxicity for a maximum of 24 months (34 cycles)

Paclitaxel

EBEWE Pharma

Small molecule

Microtubule‐targeting agent

200 mg/m2

IV

Every 21 days until disease progression or unacceptable toxicity for a maximum of six cycles

Carboplatin

EBEWE Pharma

Small molecule

Platinum compound

6 mg per

IV

Every 21 days until disease progression or unacceptable toxicity for a maximum of six cycles

Patient Characteristics for Phase II Both Arms

67

37

Locally advanced or inoperable: 5

Metastatic: 98

Median (range): 63.5 (37–82)

Median (range): No prior therapies: n = 100 (96.2%); Patients with prior therapies: n = 4 (3.8%)

0 — 51 (49.0%)

1 — 53 (51.0%)

2 —

3 —

Unknown —

Primary Assessment Method for Phase II Control

Total patient population

52

51

52

RECIST 1.1

n = 0 (0%)

n = 29 (56%)

8.1 months, CI: 5.88–11.14

5.3 months

Primary Assessment Method for Phase II Experimental

Total patient population

52

52

52

RECIST 1.1

n = 1 (1.9%)

n = 14 (26.9%)

6.7 months, CI: 5.68–7.43

5.4 months

Phase II Control Adverse Events

Phase II Experimental Adverse Events

Adverse Events

Serious Adverse Events Regardless of Relationship to Study Drug in >2 Safety‐Evaluable Patients Overall

Adverse Events Comments

Serious adverse events, regardless of attribution to study drug, were reported for 29 patients (55.8%) in the experimental arm and 30 patients (58.8%) in the placebo arm. All deaths that occurred during the protocol‐specified adverse event reporting period (90 days following last administration of study treatment), regardless of attribution, were to be reported as serious adverse events, including death due to disease progression.

As of March 12, 2014, 42 deaths (24 patients in the parsatuzumab arm and 18 patients in the placebo arm) were reported. In the parsatuzumab arm, 15 deaths occurred during the adverse event reporting period (90 days following last administration of study treatment), of which 7 were attributed to disease progression and 8 were attributed to other adverse events. Of these adverse events, fatal events of gastric ulcer hemorrhage and pulmonary hemorrhage were assessed as related to parsatuzumab and bevacizumab. In addition, an autopsy was performed in association with an event of fatal pneumonia that was assessed as unrelated to study treatment. The immediate cause of death was identified as aspiration of blood caused by intratumoral bleeding. The investigator made no change to the AE term of pneumonia or to the attribution following the autopsy. In the placebo arm, eight deaths occurred during the adverse event reporting period, of which four were attributed to disease progression and four were attributed to other adverse events. None of these events were attributed to study treatment.

Overall, 41 patients (78.8%) in the parsatuzumab arm and 46 patients (90.2%) in the placebo arm experienced a grade 3/4/5 adverse event. Four grade ≥3 bleeding adverse events were reported: grade 5 gastric ulcer hemorrhage (as above), grade 5 pulmonary hemorrhage (as above), grade 4 hemoptysis, and grade 3 hematuria. All four events occurred in the parsatuzumab arm. The hemoptysis event occurred approximately 4 months after discontinuation of parsatuzumab and was attributed to bevacizumab and concomitant warfarin. The other three bleeding events were considered related to parsatuzumab/placebo.

With the exception of the numerical imbalance in grade ≥3 hemorrhage events described above, there was no apparent exacerbation of AEs of special interest in the parsatuzumab arm.

Assessment, Analysis, and Discussion

Study terminated before completion

Company stopped development

Inactive because results did not meet primary endpoint

VEGF‐mediated tumor angiogenesis is a validated anticancer target. Bevacizumab, a monoclonal antibody against VEGF‐A, has demonstrated clinical benefit in several cancers, including non‐small cell lung cancer (NSCLC) [6]. In the phase III Eastern Cooperative Oncology Group (ECOG) 4599 study, the addition of bevacizumab (15 mg/kg) to carboplatin and paclitaxel was associated with a prolongation of progression‐free survival (PFS; hazard ratio [HR] = 0.66) and overall survival (OS; HR = 0.79) [7]. These results were supported by AVAil, another phase III study in first‐line NSCLC, which demonstrated improvement of PFS with the addition of bevacizumab to cisplatin and gemcitabine (HR for 7.5 mg/kg dose = 0.75, HR for 15 mg/kg dose = 0.82) [8]. Strategies to enhance the clinical utility of antiangiogenic therapy include preventing vascular recovery after treatment with a VEGF inhibitor [9], [10].

Epidermal growth factor‐like domain 7 (EGFL7) is a vascular‐restricted extracellular matrix protein that is upregulated during angiogenesis and promotes endothelial cell adhesion and survival under stress [1], [11], [12], [13], [14], [15], [16]. EGFL7 is deposited in perivascular tracks that persist after vessel regression; vessel regrowth after antiangiogenic therapy may occur along these EGFL7‐containing extracellular matrix tracks [11], [17], [18], [19], [20], [21].

Parsatuzumab (MEGF0444A) is a humanized IgG1 monoclonal anti‐EGFL7 antibody therapy that selectively blocks the interaction between EGFL7 and endothelial cells (Genentech unpublished data, [17]). Blocking EGFL7 function in tumors could inhibit vascular growth and regrowth after vessel damage induced by antiangiogenic therapy, thereby further reducing tumor perfusion. In murine tumor models, anti‐EGFL7 given in combination with anti‐VEGF further decreased tumor vascular density ([17] and unpublished data) and resulted in significantly prolonged OS compared with anti‐VEGF alone [2]. Safety, tolerability, and evidence of pharmacodynamic modulation in a phase Ib trial of parsatuzumab in combination with bevacizumab with or without paclitaxel [3] led to the conduct of two concurrent phase II trials of parsatuzumab in combination with bevacizumab and chemotherapy in patients with NSCLC (this study) and colorectal cancer (CRC) [4].

In this study, 104 patients (Table 1) with previously untreated stage IV or recurrent NSCLC were randomized to receive parsatuzumab or placebo in combination with bevacizumab, carboplatin, and paclitaxel until disease progression or unacceptable toxicity (Fig. 2). The protocol‐specified primary analysis was performed after 62 PFS events, with all patients followed for a minimum of 6.5 months. The PFS hazard ratio was 1.7 (95% confidence interval, 1.0–2.8; p = .047), with median PFS of 6.7 months for the parsatuzumab arm versus 8.1 months for the placebo arm (Fig. 1). Objective responses also favored the placebo arm (objective response rate [ORR] 29% in the parsatuzumab arm vs. 56% in the placebo arm).

Table 1.

Baseline patient and disease characteristics

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

Figure 2.

Study scheme.

Abbreviations: AUC 6, area under curve of 6 mg • min/ml (Calvert formula); NSCLC, non‐small cell lung cancer; PD, progressive disease; PS, performance status; q21d, every 21 days.

Figure 1.

Kaplan‐Meier estimates of progression‐free survival. Note: + = censored value.

Abbreviations: CI, confidence interval; parsatuzumab, paclitaxel + carboplatin + bevacizumab + MEGF0444A; placebo, paclitaxel + carboplatin + bevacizumab.

Of note, the performance of the placebo arm compares favorably with the phase III historical benchmarks provided by ECOG 4599 (carboplatin/paclitaxel/bevacizumab, median PFS 6.2 months, ORR 35%) [7] and POINTBREAK (carboplatin/pemetrexed/bevacizumab, median PFS 5.6 months, ORR 33%) [22]. In contrast, the parsatuzumab arm outcomes were consistent with these benchmarks. Whether these efficacy data reflect (a) imbalanced randomization with respect to unrecognized prognostic or predictive factors, or (b) detriment associated with parsatuzumab, cannot be definitively determined based on the small sample size. However, sensitivity analyses that utilize a broader definition of PFS events (e.g., including all death events, clinical progression events, and/or early censoring events) consistently attenuate the PFS difference between the arms (data on file). Moreover, an updated median OS, after an additional 3.5 months of follow‐up and nine more events, showed a median OS of 12.6 months in both arms (hazard ratio 1.23, data on file). Finally, the phase II study of parsatuzumab added to chemotherapy consisting of folinic acid, 5‐FU, and oxaliplatin, known as modified FOLFOX6 or mFOLFOX6, and bevacizumab in first‐line CRC showed a PFS hazard ratio of 1.17 and an OS hazard ratio of 0.97 [4], reinforcing the apparent lack of efficacy rather than harm associated with the addition of parsatuzumab.

Limited exploration of predictive biomarkers suggested a trend toward PFS benefit associated with parsatuzumab in patients with low tumor EGFL7 expression (defined as less than or equal to the median, HR 0.72), consistent with findings in the phase Ib study of parsatuzumab/bevacizumab (data on file). However, caveats include the limited sampling of archival tumor (provided by 49 of 104 patients) and the lack of corroboration of tumor EGFL7 as a predictive marker in the phase II trial of parsatuzumab in CRC [4]. No PFS benefit associated with parsatuzumab was observed in subgroups defined by the stratification factors (ECOG, prior adjuvant therapy, sex) or by plasma VEGF levels.

The overall safety and tolerability profile was similar in the two arms, as reflected by similar proportions of patients experiencing adverse events (AEs; 98% in the parsatuzumab arm, 100% in the placebo arm; Adverse Events table), grade ≥3 AEs (83% in the parsatuzumab arm, 90% in the placebo arm), serious adverse events (56% in the parsatuzumab arm, 59% in the placebo arm; Serious Adverse Events table), and AEs leading to parsatuzumab/placebo discontinuation (35% in the parsatuzumab arm, 33% in the placebo arm). However, a numerical imbalance in grade ≥3 bleeding AEs was observed, with four events in the parsatuzumab arm (grade 5 gastric ulcer hemorrhage, grade 5 pulmonary hemorrhage, grade 4 hemoptysis, and grade 3 hematuria) and no events in the placebo arm. The hemotypsis event occurred approximately 4 months after discontinuation of parsatuzumab and was attributed to bevacizumab and concurrent warfarin. The other three bleeding events were considered related to parsatuzumab. There was no apparent exacerbation of any other bevacizumab‐related adverse events in patients receiving parsatuzumab. Given that fatal hemorrhage is an established risk of bevacizumab‐based therapy in NSCLC patients [23], and given that the phase II trial in CRC did not suggest any trend toward increased risk of bleeding associated with parsatuzumab [4], it seems less likely that the numerical imbalance between the arms reflects a true safety signal. Nevertheless, based on this limited data set, the possibility of an increased risk of bleeding associated with parsatuzumab cannot be excluded.

In conclusion, despite promising preclinical biology supporting the evaluation of anti‐EGFL7 to enhance the antiangiogenic effect of VEGF inhibition, the addition of parsatuzumab to bevacizumab plus standard chemotherapy regimens demonstrated no evidence of efficacy in an unselected population of patients with advanced NSCLC. Unfortunately, robust predictive biomarkers for bevacizumab in NSCLC patients remain elusive despite intensive efforts [24]. As therapy for NSCLC becomes increasingly stratified, with evolving diagnostic strategies to guide the optimal use of immunotherapy as well as targeted agents, it is likely that such predictive biomarkers will be more important than ever for the successful development of antiangiogenic therapies.

Adverse events regardless of relationship to study drug in >10 safety‐evaluable patients, placebo arm (n = 51).

Abbreviation: NC/NA, no change from baseline/no adverse event.

Adverse events regardless of relationship to study drug in >10 safety‐evaluable patients, experimental arm (n = 52).

Abbreviation: NC/NA, no change from baseline/no adverse event.

Abbreviations: AEs, adverse events; d/c, discontinuation; MEGF0444A, parsatuzumab; SAEs, serious adverse events.