06/16/2019: Article Summaries - Breast & Lung Cancers

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BREAST CANCERS LUNG CANCERS

Summary

BREAST CANCERS

 

Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: MONALEESA-3​

Slamon D et al. J Clin Oncol 36. 2018. DOI: https://doi.org/10.1200/JCO.2018.78.9909

Introduction:

Ribociclib is a small molecule CDK4/6 inhibitor that significantly prolonged PFS compared to placebo when given in combination with letrozole as first line treatment in postmenopausal women with advanced HER2 negative breast cancer (Engl J Med 375:1738-1748,2016). Previous studies also demonstrated clinical benefit with ribociclib in combination with fulvestrant after failing first line endocrine therapy. To further assess the benefit of this combination, researchers conducted the MONALEESA-3 trial to determine its efficacy as first line treatment and in patients who received one line of prior endocrine therapy for advanced disease.

Methods:

  • Patients: postmenopausal women or men with histologically or cytologically-proven HR positive, HER2 negative advanced breast cancer not amenable for curative treatment, de novo advanced or relapsed after > 12 mos. after completing (neo)adjuvant endocrine therapy without prior treatment for advanced/metastatic disease (treatment-naïve) or relapse on or within 12 months from completing (neo)adjuvant endocrine therapy with no treatment for advanced/metastatic disease (early relapse), or relapse >12 months from completing (neo)adjuvant therapy with subsequent progression after one line of endocrine therapy for advanced/metastatic disease or advanced/metastatic disease at diagnosis that progressed after one line of endocrine therapy for advanced disease with no prior (neo)adjuvant treatment for early disease, no symptomatic visceral disease
  • Study design: phase III double-blind, placebo-controlled RCT
  • Intervention
    Experimental: Ribociclib 600 mg PO 3wks on, 1 week off + fulvestrant 500 mg IM day 1 every 28 days (additional dose on day 15 on cycle 1)
    Control: Placebo + fulvestrant
     
  • Outcomes
    Primary: PFS
    Secondary: OS, ORR, CBR, safety

Results:

  • 726 patients randomized 2:1 to ribociclib + fulvestrant (n=484) and placebo + fulvestrant (n=242)
  • Baseline patient characteristics: 100% female, median age 63 yrs., 86% white race, 65% ECOG 0, 99% stage IV, 99% ER positive, 71% PR positive, 81% non-de novo disease-free interval, 51% endocrine therapy treatment-naïve, 59% prior (neo) adjuvant endocrine therapy, 32% with 2 metastatic sites, 75% bone metastasis, 60% visceral metastasis (30% lung, 50% lung or liver), 44% lymph node metastasis.

Table 1. Efficacy Outcomes

Outcomes

Ribociclib

Placebo

HR (95% CI)

p value

PFS – mos.

20.5

12.8

0.59 (0.48-0.73)

<0.001

treatment-naive

-

-

0.57 (0.41-0.80)

-

1 prior treatment

-

-

0.56 (0.42-0.74)

-

ORR - %

32.4

21.5

-

<0.001

measurable dse.

40.9

28.7

-

0.003

CBR - %

70.2

62.8

-

0.020

measurable dse.

69.4

59.7

-

0.015

Safety:

  • Most common adverse events in both groups: neutropenia, nausea, and fatigue
  • Most common SAE: pneumonia (1.9% v 0%), dyspnea (1.2% v 2.1%)
  • • Five deaths in the ribociclib group were not attributed to study treatment; one patient died from ARDS suspected to be related to study treatment.

Table 3. Adverse event and treatment summary

Event

Ribociclib

Placebo

Duration of treatment – mos.

15.8

12

Dose reduction - %

37.9

4.1

Dose reduction due to adverse event - %

33.1

3.3

Any grade neutropenia - %

69.6

2.1

Grade 3 neutropenia - % 46.6 0
Grade 3 neutropenia - %/td> 6.8 0
Any grade diarrhea - % 29 20.3
Any grade leukopenia - % 28.4 1.7
Grade 3 leukopenia - % 13.5 0
Any grade prolonged QT interval - % 6.2 0.8
Grade 3-4 elevated ALT - % 6.6 1.9
Grade 3-4 elevated AST - % 4.8 1.2
Serious adverse event - % 28.6 16.6
Deaths – n (%) 13 (2.7) 8 (3.3)

Discussion:

  • MONALEESA-3 trial demonstrated significant improvement in PFS with ribociclib-fulvestrant compared to fulvestrant alone in postmenopausal women with HR positive, HER2 negative advanced breast cancer. The addition of ribociclib to fulvestrant delayed disease progression by 7.7 mos. (absolute difference) compared to fulvestrant alone and reduced the risk of disease progression or death by 41%. Early separation of survival curves was noted and results were consistent across pre-defined subgroups except for Asian subgroup (n=88). OS data was immature at interim analysis.
  • Combination therapy yielded superior tumor responses compared to fulvestrant particularly in patients with measurable disease at baseline. Majority of patients achieved PR and SD in both groups.
  • Ribociclib-fulvestrant was associated with significantly higher rates of adverse events and dose reductions. QT prolongation and elevated transaminases occurred in 6% in the ribociclib-fulvestrant group. One death from ARDS was suspected to be related ribociclib-fulvestrant. Hematologic toxicities were the most frequent adverse events with combination therapy, particularly neutropenia. Although manageable, supportive therapy could further mitigate these events.
  • The PALOMA-3 trial randomized women with advanced HR positive, HER2 negative breast cancer who relapsed or progressed during prior endocrine therapy to palbociclib-fulvestrant or placebo-fulvestrant (N Engl J Med 373:209-219, 2015). Palbociclib-fulvestrant significantly prolonged PFS (9.2 mos. v 3.8 mos.; HR 0.42; p <0.001). Similar rates of neutropenia were reported although the study included both pre and postmenopausal women and had shorter PFS in both groups for 2nd line therapy compared to MONALEESA-3 study.
  • In the MONARCH-2 study, abemaciclib with fulvestrant also provided significant improvement in PFS (16.4 mos. v 9.3 mos.; HR 0.55; p <0.001) compared to placebo with fulvestrant in women who failed prior endocrine therapy for advanced HR positive, HER2 negative breast cancer (J Clin Oncol 35:2875-2884, 2017). ORR in the subgroup with measurable disease was slightly higher at 48.1% compared to 40.9% in MONALEESA-3. Abemaciclib had a different safety profile, with more diarrhea but less frequent neutropenia compared to palbociclib and ribociclib.
  • In summary, ribociclib with fulvestrant is a promising new addition as 1st or 2nd line therapy to the therapeutic landscape of HR positive, HER2 negative advanced breast cancer, based on these findings. The safety profile of combination therapy and cost of treatment are potential limitations in clinical practice. Data collection is ongoing; final OS analysis will determine whether PFS benefit with ribociclib-fulvestrant will translate to OS advantage.

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LUNG CANCERS

Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer and EGFR Activating Mutations

Mok, T et al. J Clin Oncol 36. 2018. DOI: https://doi.org/10.1200/JCO.2018.78.7994

Introduction:

Dacomitinib is a 2nd generation, irreversible TKI with activity against EGFR/HER1, HER2, and HER4 that distinguishes it from 1st generation TKIs gefitinib and erlotinib. In the ARCHER 1050 trial, dacomitinib significantly prolonged PFS by 5.5 mos. (HR 0.59; p<0.001) compared to erlotinib as first line treatment in patients with advanced EGFR-mutation-positive NSCLC (Lancet Oncol 18:1454-1466, 2017). Results of final OS analysis are summarized below.

Methods:

  • Patients: histologically or cytologically confirmed newly diagnosed stage IIIB/IV or recurrent NSCLC (minimum 12 mos. disease-free interval between completion of adjuvant/neoadjuvant therapy and recurrence of NSCLC), at least 1 documented EGFR mutation, no brain or leptomeningeal metastasis
  • Trial design: phase III, open-label RCT
  • Intervention: 
    Experimental: Dacomitinib 45mg PO daily q28 days
    Control: Gefitinib 250mg PO q28 days
  • Endpoints 
    Primary: PFS (IRC)
    Secondary: PFS (investigator), ORR, DOR, OS, OS at 30 mos., time to treatment failure, safety, patient-reported outcomes

Results:

  • N=452 randomized and analyzed by ITT, dacomitinib N=227, gefitinib N=225
  • Baseline patient characteristics: median age 61 yrs., 60% female, 77% Asians (51% Chinese), 70% ECOG 1, 81% stage IV, 64% never smokers, 59% Exon 19 deletion mutation
  • There were slightly more men in the gefitinib arm (44.4%) than in the dacomitinib arm (35.7%).

Table 1. Efficacy Endpoints

Outcome

Dacomitinib

Gefitinib

HR (95% CI)

p value

OS – mos.

34.1

 

26.8

0.760 (0.582-0.993)

0.0438

     Exon 19 del*

34.1

NR

0.880 (0.613-1.262)

0.4862

     Exon 21 L858R**

32.5

23.2

0.707 (0.478-1.045)

0.0805

     Asian¶

34.2

29.1

0.812 (0.595-1.108)

0.1879

     Non-Asian§

29.5

20.6

0.721 (0.433-1.201)

0.2073

30-mo. OS – %

56.2

46.3

-

-

OS† - mos.

-

-

0.739 (.0489-1.115)

0.1417

*55.8% censored ** 44.9% censored ¶ 53.8% censored § 43.4% censored
† OS censored for first subsequent therapy (systemic therapy, RT, surgery)

QOL

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

Table 2. OS in first subsequent therapy subgroups

 

Dacomitinib

Gefitinib

Chemotherapy

%

27.8 35.6

OS – mos.

29.5 24.6
3rd Gen EGFR TKI

%

9.7 11.1

OS – mos.

36.7 NR
Other EGFR TKI

%

8.8 8.4

OS – mos.

34.7 32.1

 

Discussion:

  • Long-term results of ARCHER 1050 trial confirm the efficacy of dacomitinib as first line treatment in patients with advanced EGFR positive NSCLC. Significant improvement in OS by 7.3 mos. (absolute difference) was observed with dacomitinib compared to gefitinib in this study population. This is consistent with previously reported PFS advantage (14.7 vs. 9.2 mos.) with the use of dacomitinib in treatment-naïve advanced EGFR positive NSCLC (Lancet Oncol 18:1454-1466, 2017).
  • Subset analysis of OS revealed at least half of the study population (49.8 vs. 62.2%) went on to receive subsequent therapy, most commonly with chemotherapy. Patients who received 3rd generation and other EGFR TKIs had better survival outcomes compared to those who received chemotherapy. This finding is merely suggestive due to small patient numbers in these subgroups.
  • A head-to-head comparison of afatiniib vs, gefinitib in the LUX-LUNG 7 trial reported PFS improvement in favor of afatinib (Lancet Oncol 17:577-589, 2016). Although afatinib provided marginal improvement in PFS (11 vs. 10.9 mos,, HR 0.73; p=0.17), this did not translate to improvement in OS.
  • Results from the FLAURA trial showed osimertinib to be superior to gefitinib or erlotinib in untretated EGFR-mutated advanced NSCLC (N Engl J Med 378:113-125, 2018). PFS significantly improved with osimertinib (18.9 vs. 10.2 mos., HR 0.46, p<0.001). However, OS results were immature at interim analysis.
  • It should be noted that this study excluded patients with brain metastasis. FLAURA and LUX lung 3 allowed for patients with asymotomatic brain metastasis.
  • In summary, dacomitinib provided significant improvement in OS compared to gefitinib as first line therapy in patients with advanced, EGFR mutated NSCLC. Dacomitinib is a reasonable upfront therapy based on these findings. Whether dacomitinib is better than afatinib or osimertinib and sequencing of TKIs that will yield the best clinical outcomes warrants further investigation.

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