05/29/2019: Article Summaries - Lung & GI Cancers

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LUNG CANCERS GI CANCERS

Summary

LUNG CANCERS
 

Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non–Small Cell Lung Cancer. The ALTER 0303 Phase 3 Randomized Clinical Trial

Han, B et al. JAMA Oncol. 2018;4(11):1569-1575.

Introduction:

Anlotinib is a novel TKI that targets VEGF receptor, EGFR, fibroblast growth factor receptor, PDGF receptor and stem cell factor receptor. In the phase II ALTER trial, patients with advanced NSCLC who progressed on third line or further treatment were randomized to to anlotinib or placebo (Br J Cancer.2018;118(5):654-661). Anlotinib significantly improved PFS compared to placebo (4.8 vs. 1.2 mos., HR 0.32; p<0.001). These encouraging findings prompted researchers to conduct the ALTER 0303 trial to confirm its efficacy.

Methods:

  • Patients: histologically or cytologically confirmed NSCLC, failed at least 1 line of treatment (chemotherapy, TKI) if with driver alterations or progressed on at least 2 lines of chemotherapy if without driver alterations, ECOG 0-1, uncontrolled brain metastases or controlled for <2 mos.
  • Study design: phase III, double-blind, placebo-controlled RCT
  • Intervention: 
    Experimental: Anlotinib 12 mg/day 2 wks. on, 1 wk. off
    Control: Placebo
  • Endpoints 
    Primary: OS
    Secondary: PFS, ORR, DCR, QOL, safety

Results:

  • 440 patients randomized 2:1 to anlotinib (n=296) and placebo (n=143)
  • Baseline patient characteristics: 67.8% male, 57% ≤ 60 yrs. old, mean age 56.8
    yrs., 76% adenocarcinoma, 20% squamous, 94% stage IV, 56% ≤ 3 metastatic
    sites, 31.6% EGFR mutation, 1.6% ALK rearrangement, 55% 2 previous lines of
    chemotherapy, 51% previous targeted treatment, 42% previous RT, 81% ECOG
    1, 51% smokers

Table 1. Efficacy outcomes

Outcomes

Anlotinib

Placebo

HR (95% CI)

p value

OS – mos.

9.6

 

6.3

0.68 (0.54-0.97)

0.002

     EGFR mutant

-

-

0.59 (0.37-0.93)

-

     EGFR mutant

-

-

0.73 (0.55-0.97)

-

6-mo. OS - % 

70.6

52.8

-

-

12-mo. OS - %

40

27.8

-

-

18-mo. OS - %

26.2

22.7

-

-

 PFS - mos.

5.4

1.4

0.25 (0.19-0.31)

-

     EGFR mutant

-

-

0.15 (0.09-0.24)

-

     EGFR mutant

-

-

0.29 (0.22-0.39)

-

ORR - %

9.2

0.7

-

< 0.001

ORR - %

81

37.1

-

< 0.001

QOL

  • Patients on anlotinib maintained baseline major health status throughout the study.

Table 2. Treatment summary and adverse events

Result

Anlotinib

Placebo

Median treatment duration - wks.

18

6

Subsequent therapy - %

48.6

65

     Chemotherapy

22.5

41.3

Any grade hypertension - % 

67.7

16.8

Grade >= 3 hypertension - %

13.6

0

Any grade fatigue - %

52

28.7

Grade >= 3 hyponatremia - %

8.2

3.5

Any grade TSH elevation - %

46.6

8.4

Grade >= 3 elevated γ-glutamyltransferase - %

5.4

7

Any grade hand-foot syndrome - %

43.9

9.1

Grade >= 3 hand-foot syndrome - %

3.7

0

Any grade diarrhea - % 35.4 14.7
Any grade hypercholesterolemia - % 41.8 14

 

Discussion:

  • Anlotinib extended OS by 3.3 mos. and was associated with 32% reduction in the
    risk of death compared to placebo as third line or further treatment in Chinese
    patients with advanced NSCLC. Anlotinib was associated with 75% lower risk of
    disease progression or death vs. placebo. Exploratory analysis yielded OS and
    PFS benefit in most patient subgroups. The magnitude of benefit for both OS and
    PFS was greatest in the subgroup with EGFR mutation.
  • Tumor response rates were eight times greater in the anlotinib arm compared to
    the placebo arm. More than twice the proportion of patients on placebo achieved
    durable responses with anlotinib.
  • In the phase II ATLANTIC trial, durvalumab yielded tumor responses in up to
    30.9% and OS between 9.3 to 13.3 mos. as third line treatment in three cohorts of
    heavily pretreated patients classified by EGFR/ALK mutation and PD-L1
    expression with advanced NSCLC. Although the EGFR-/ALK- NSCLC with ≥
    90% tumor PD-L1 expression group (cohort 3) achieved the highest tumor
    response, these patients were less heavily pretreated compared to the other 2
    cohorts (Lancet Oncol. 2018;19(4):521-536. The study population was slightly
    younger and 87% were EGFR positive compared to only a third in the ALTER
    0303 trial.
  • In summary, treatment with anlotinib is effective, well tolerated and does not
    compromise QOL in heavily pretreated Chinese patients with advanced NSCLC.
    A larger study with a more heterogeneous, unselected population is warranted to
    further confirm these encouraging findings.

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GI CANCERS
 

 

Cabozantinib in Patients with Advanced and Progressing Hepatocellular
Carcinoma​

Abou-Alfa, GK et al. N Engl J Med 2018;379:54-63

Introduction:

The prognosis for many patients with hepatocellular carcinoma (HCC) is poor despite
treatment. Although targeted therapy with vascular endothelial growth factor (VEGF)
inhibitors has improved clinical outcomes, disease progression still occurs due to
acquired resistance. Cabozantiib is a multi-targeted inhibitor of tyrosine kinases including
vascular endothelial growth factor (VEGF) receptors 1-3, MET and AXL.

A phase II study of cabozantinib in advanced HCC showed promising clinical activity,
with a median progression-free survival (PFS) of 5.2 mos. and overall survival (OS) of
11.5 mos. Researchers undertook a phase III trial to further investigate the efficacy and
safety of cabozantinib in this setting.

Methods:

  • Patients: cytologically or histologically proven HCC not amenable to curative
    treatment, Child–Pugh class A liver function, previously received sorafenib and
    with disease progression on at least one systemic treatment (up to two previous
    systemic treatments for HCC), ECOG performance status 0-1
  • Study design: phase III, double-blind, placebo-controlled RCT
     
  • Intervention
    Experimental: Cabozantinib 60 mg PO daily
    Control: Placebo
     
  • Endpoints
    Primary: OS
    Secondary: PFS, objective response rate (ORR), disease control rate (DCR),
    safety

Results:

  • 707 patients randomised 2:1 to cabozantinib (n=470) and placebo (n=237)

Table 1. Baseline patient characteristics (selected)

Characteristics

Result

Median age  - yrs.

64

Males - %

83

Canada/US – %

24

Asia - %

25

Europe - %

48

ECOG 0 - %

54

HBV etiology - %

38

HBV etiology - %

28

Alcohol use etiology - %

20

Extrahepatic disease spread - %

78

Macrovascular invasion - %

31

Extrahepatic spread, macrovascular invasion or both - %

84

Table 2. Efficacy Outcomes

Outcomes

Cabozantinib

Placebo

HR (95% CI)

p value

OS - mos.

10.2

8

0.76 (0.63-0.92)

0.005

12 mo. OS - %

46

34

-

-

24 mo. OS - %

18

13

-

-

OS (prev. sorafenib only) - mos.

11.3

7.2

0.70 (0.55-0.99)

-

PFS-mos.

5.2

1.9

0.44 (0.36–0.52)

<0.0001

PFS (prev. sorafenib only) - mos.

5.5

1.9

0.40 (0.32-0.50)

-

ORR (RECIST 1.1) - %

4

<1

-

0.009

DCR - %

64

33

-

-

  • Received subsequent therapy (except RT): 26% vs. 33%
    Safety

Table 3. Adverse event and treatment summary

Event

Cabozantinib

Placebo

Treatment duration - mos.

3.8

2

Dose reduction - %

62

13

Treatment discontinuation - %

16

3

Any grade AE - %

99

92

Grade 3-4 AE - % 68 36
Serious AE - % 50 37
Grade 5 AE - % 12 12

AE - adverse event

  • Cause of treatment discontinuation in &gt;1%: palmar–plantar erythrodysesthesia,
    fatigue, decreased appetite, diarrhea, nausea
  • Most common grade 3-4 AE with cabozantinib: palmar–plantar
    erythrodysesthesia (17% vs. 0%), hypertension (16% vs. 2%), increased aspartate
    aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), diarrhea (10% vs.
    2%)
  • Grade 5 AEs related to cabozantinib: hepatic failure, bronchoesophageal fistula,
    portal-vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism,
    hepatorenal syndrome

Discussion:

  • Among patients with advanced HCC who on previous treatment including
    sorafenib, cabozantinib significantly prolonged OS by 2.2 mos. and PFS by 3.3
    mos. compared to placebo, with 64% lower relative risk of disease progression or
    death and 24% lower relative risk of death. Although PFS duration was longer for
    cabozantinib across pre-planned patient subgroups, in terms of OS, subgroups that
    did not appear to benefit with cabozantinib included Asians, no extrahepatic
    disease spread, macrovascular invasion or both and HCV etiology.
  •  ORR was higher with cabozantinib compared to placebo. DCR almost doubled in
    the cabozantinib group. Most patients achieved stable disease on cabozantinib
    (60% vs. 33%).
  • Palmar–plantar erythrodysesthesia was the most common adverse event with
    cabozantinib. Dose reductions, treatment discontinuation and high grade AEs
    were more frequent in the cabozantinib group compared to placebo. Grade 5
    adverse events related to cabozantinib occurred in six patients. The safety profile
    of cabozantinib in this study is consistent with previous literature.
  • Overall, the CELESTIAL study results support the conclusion that cabozantinib is
    more efficacious than placebo based on significant improvement in PFS and OS
    in advanced HCC previously treated with sorafenib. Dose reductions could
    mitigate adverse events with cabozantinib and improve its safety profile.
    Cabozantinib is another 2 nd line option for advanced HCC together with
    regorafenib. It is important to note that patients would only be eligible for
    regorafenib if they previously tolerated sorafenib, while no such inclusion criteria
    was required in the CELESTIAL study. Ramucirumab is another 2 nd line option,
    but only had a small survival benefit in the select group of patients with AFP
    >=400. Nivolumab is a promising 2 nd line option with impressive response rate
    and survival data but phase III trial evidence is still lacking. Identifying which
    subgroup of patients will benefit most with cabozantinib is important since the
    study included a highly selected population. Further studies could provide
    additional evidence to support the use of and sequencing of PD-L1 inhibitors and
    VEGF inhibitors in HCC.

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