Cyramza® (Ramucirumab)

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Ramucirumab: RELAY Part C

In the ongoing RELAY+ trial (RELAY part C), the 1-year PFS rate was 63% for East Asian treatment-naïve patients with EGFR mutation-positive metastatic NSCLC receiving ramucirumab plus gefitinib.

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Summary

  • In the ongoing RELAY+ trial (RELAY part C), the 1-year PFS rate (95% CI) was 63% (50.3-73.1) for East Asian treatment-naïve patients with EGFR mutation-positive metastatic NSCLC receiving ramucirumab plus gefitinib. The PFS rate of 63% was higher than the expected 1-year PFS rate of 55% for ramucirumab plus gefitinib.1
  • The combination of ramucirumab and gefitinib was well-tolerated and no new safety concerns were identified.1
  • Of the 25 patients with an EGFR-activating mutation detected by NGS at the 30-day follow-up, 12 (48%) showed post progression EGFR T790M.1

Study Design

The RELAY+ trial (RELAY part C) is an ongoing, open-label, single arm, 2-period, exploratory portion of the RELAY trial. Part C was designed in 2 periods to evaluate the efficacy and safety of ramucirumab in East Asian patients (Japan, South Korea, or Taiwan) in combination with

  • gefitinib in treatment-naïve patients with EGFR mutation-positive metastatic NSCLC (period 1), and
  • osimertinib in patients with T790M-positive metastatic NSCLC whose disease has progressed on ramucirumab plus gefitinib (period 2).2

In period 1, patients received treatment with gefitinib (250 mg/day) plus ramucirumab (10 mg/kg every 2 weeks) until disease progression or unacceptable toxicity. In period 2, T790M-positive patients received treatment with osimertinib (80 mg/day) plus ramucirumab (10 mg/kg every 2 weeks) until second PFS event or unacceptable toxicity.2

Patients could be enrolled if they had an EGFR mutation of exon 19 deletion or exon 21 L858R and ECOG PS of 0 or 1.2

Patients were excluded from participation if they had

  • prior anticancer therapy for stage IIIB/IV NSCLC
  • known EGFR T790M mutation
  • CNS metastases, or
  • evidence of clinically active interstitial lung disease.2

Outcome Measures

The primary endpoint of part C is 1-year PFS.2

Secondary endpoints include

  • ORR
  • DOR
  • time to second disease progression (PFS2)
  • PK, and
  • safety.2

An exploratory objective was the evaluation of EGFR T790M status at baseline and at post progression 30-day follow-up as assessed in liquid biopsy samples by Guardant360 NGS.2

Patient Demographics

Baseline patient characteristics are summarized in Patient Demographics and Baseline Characteristics.

Patient Demographics and Baseline Characteristics2

Characteristica

ITT Population
(N=82)

Female

54 (65.9)

Median age, years (min–max)

68 (44–85)

Country

Japan

68 (82.9)

South Korea

6 (7.3)

Taiwan

8 (9.8)

Smoking historyb

Ever

26 (31.7)

Never

54 (65.9)

ECOG PS 0

43 (52.4)

EGFR mutation type

Exon 19 deletion

36 (43.9)

Exon 21 (L858R) substitution mutation

46 (56.1)

Disease classification

Primary metastatic

61 (74.4)

Recurrent metastatic

21 (25.6)

EGFR testing methodc

Therascreen® or Cobas®

32 (39.0)

Otherd

50 (61.0)

Abbreviations: ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; ITT = intent-to-treat; max = maximum; min = minimum; PS = performance status.

aData are presented as n (%) unless otherwise indicated.

bSmoking history was unknown or missing for 2 patients (2.4%).

cDetermined by local testing.

dPolymerase chain reaction and sequencing-based methods.

Efficacy Results

Efficacy outcomes are summarized in Efficacy Outcomes of RELAY+ in the ITT Population.

At the primary analysis with data cutoff date of August 23, 2019 (median [IQR] duration of follow-up, 13.8 [12.3-15.9] months), 30 (37%) patients were still receiving ramucirumab plus gefitinib. The 1-year PFS rates (95% CI) were

  • 65% (52.4-75.1) for the ITT population (n=82)
  • 67% (48.6-80.3) for patients with exon 19 deletion (n=36), and
  • 63% (45.0-77.1) for patients with exon 21 L858R (n=46) mutation.2

At the updated analysis with data cutoff date of November 25, 2020, with an additional 15 months of follow-up data, 10 (12.2%) patients were still receiving ramucirumab plus gefitinib. The 1-year PFS rates (95% CI) were

  • 63% (50.3-73.1) for the ITT population (n=82)
  • 67% (48.6-80.3) for patients with exon 19 deletion (n=36), and
  • 59% (41.4-73.3) for patients with exon 21 L858R mutation (n=46).1

The median PFS (95% CI) for the ITT population was 14.1 (12.2-17.9) months.1

Efficacy Outcomes of RELAY+ in the ITT Population1,2

Outcome

ITT Population 
(N=82)

Data Cutoff Date: August 23, 2019

Data Cutoff Date: November 25, 2020

1-year PFS rate, % (95% CI)

65 (52.4-75.1)a

63 (50.3-73.1)

ORR, % (95% CI)

71 (59.6-80.3)

71 (59.7-80.3)

DCR, % (95% CI)

99 (93.4-100.0)

99 (93.4-100.0)

Median DOR, months (95% CI)b

13.6 (11.1-18.2)c

14.0 (11.1-16.7)d

Abbreviations: DCR = disease control rate; DOR = duration of response; ITT = intent-to-treat; ORR = objective response rate; PFS = progression-free survival.

aAs of the data cutoff for the primary analysis, median PFS was immature (59% censored).

bCalculated in the responder population, N=58.

cMedian DOR was immature with a censoring rate of 57%.

dCensoring rate of 27.6%.

As of November 25, 2020, of the 25 patients with an EGFR-activating mutation detected by NGS at the 30-day follow-up, 12 (48%) showed post progression EGFR T790M.1

Safety Results

In RELAY+, with data through November 25, 2020, all patients experienced ≥1 TEAE of any grade. Grade ≥3 TEAEs were reported in 73% of patients and an SAE was reported in 32% of patients. Overview of Adverse Events and Study Discontinuations in RELAY+ (Data as of November 25, 2020 Cutoff) shows additional AE and discontinuation data.1

Overview of Adverse Events and Study Discontinuations in RELAY+ (Data as of November 25, 2020 Cutoff)1

Eventa

Safety Populationb
(N=82)

TEAE

82 (100)

Grade ≥3 TEAE

60 (73.2)

SAE

26 (31.7)

Discontinuations due to AE

16 (19.5)

Discontinuations due to SAE

5 (6.1)

Deaths due to AE on study treatmentc

2 (2.4)

Deaths due to AE within 30 days of treatment discontinuation

0

Abbreviations: AE = adverse event; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

aData are presented as n (%).

bPatients may be counted in more than 1 category.

cDeaths are also counted as SAEs and discontinuations due AEs. One patient died due of acute cardiac failure and one patient died of congestive heart failure.

Most Common Treatment-Emergent Adverse Events Reported in ≥30% of Patients in RELAY+ (Data as of November 25, 2020 Cutoff)1

Preferred Term, n (%)

Safety Population
(N=82)

Any Grade

Grade ≥3a

≥1 TEAE

82 (100)

60 (73)

Dermatitis acneiform

57 (70)

3 (4)

Increased AST

52 (63)

10 (12)

Diarrhea

51 (62)

5 (6)

Increased ALT

50 (61)

19 (23)

Hypertension

42 (51)

21 (26)

Proteinuria

38 (46)

1 (1)

Paronychia

37 (45)

0 (0)

Stomatitis

37 (45)

0 (0)

Dry skin

29 (35)

0 (0)

Epistaxis

25 (31)

0 (0)

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; TEAE = treatment-emergent adverse event.

aOverall, 5 patients (6.1%) had grade 4 TEAEs; these were: aortic valve stenosis, ileus, AST increased, pneumonitis, and laryngeal obstruction (1 patient each, 1.2%). Two patients died (1 each of acute cardiac failure and congestive heart failure).

Adverse Events of Special Interest in RELAY+ (Data as of November 25, 2020 Cutoff)1

System Organ Class
Preferred Term, n (%)

Safety Population
(N=82)

Any Grade

Grade ≥3

Bleeding/hemorrhage events

43 (52)

1 (1)

Epistaxis

25 (31)

0

GI hemorrhage events

7 (9)

0

Pulmonary hemorrhage events

2 (2)

0

Hypertension

42 (51)

21 (26)

Proteinuria

40 (49)

2 (2)

Liver failure/liver injury

62 (76)

22 (27)a

Increased ALT

50 (61)

19 (23)

Increased blood bilirubin

12 (15)

0

Infusion-related reactionsb

1 (1)

0

Other TEAE of interest

ILD eventsc

2 (2)

2 (2)d

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal; ILD = interstitial lung disease; TEAE = treatment-emergent adverse event.

aOne patient had grade 4 TEAE of AST increased.

bEvents that occurred on the day of ramucirumab administration.

cILD events included pneumonitis.

dOne patient had grade 4 TEAE of pneumonitis.

No new safety issues were identified. However, grade ≥3 liver injury events were more common than in the RELAY study, which is consistent with the established safety profile of gefitinib.1

After progression in period 1 of RELAY+, 6 patients tested positive for T790M mutation and received osimertinib plus ramucirumab. One patient subsequently discontinued from the study due to an AE of grade 1 ejection fraction decreased, and the remaining 5 patients discontinued due to PD. No additional deaths were reported. Period 2 of the study is ongoing.1

References

1Nishio M, Nishio K, Reck M, et al. RELAY+: exploratory study of ramucirumab+gefitinib in untreated patients with EGFR-mutated metastatic NSCLC: updates on efficacy, safety, and biomarker outcomes. Poster presented at: Japanese Society of Medical Oncology (JSMO/Virtual): February 18-21, 2021.

2Nishio M, Nishio K, Reck M, et al. RELAY+: exploratory study of ramucirumab plus gefitinib in untreated patients (pts) with epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC). Poster presented at: 56th Annual Meeting of the American Society of Clinical Oncology (ASCO Virtual); May 29-31, 2020. Accessed May 29, 2020. https://meetinglibrary.asco.org/record/184856/poster

Glossary

AE = adverse event

CNS = central nervous system

DOR = duration of response

ECOG = Eastern Cooperative Oncology Group

EGFR = epidermal growth factor receptor

IQR = interquartile range

ITT = intent-to-treat

NGS = next-generation sequencing

NSCLC = non-small cell lung cancer

ORR = objective response rate

PD = progressive disease

PFS = progression-free survival

PFS2 = progression-free survival 2

PK = pharmacokinetic(s)

PS = performance status

SAE = serious adverse event

TEAE = treatment-emergent adverse event

Fecha de la última revisión: 2020 M05 13


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