01/14/2018: Articles Summaries - Breast & Lung Cancers

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BREAST CANCERS Ribociclib plus letrozole versus letrozole alone in patients with de novo HR+, HER2− advanced breast cancer in the randomized MONALEESA‑2 trial
O' Shaughnessy, J et al. Breast Cancer Res Treat. 2017 Nov 21.
PubMed ID: 29164421


First line hormonal therapy alone or in combination with CDK 4/6 inhibitor is the preferred treatment option for hormone receptor positive advanced breast Ca based on pivotal phase III trials that revealed significant survival advantage with the addition of CDK 4/6 inhibitors.

Interim results from the phase III MONALEESA-2 trial that compared ribociclib with letrozole vs placebo and letrozole demonstrated prolonged PFS and 44% reduction in the risk of disease progression or death with ribociclib compared to placebo in women with hormone positive advanced breast cancer. O' Shaughnessy and colleagues presented results from MONALEESA-2, focusing on the subgroup of patients with de novo advanced disease. Results are summarized below.


  • Patients: locally confirmed HR positive, HER2 negative recurrent or metastatic breast cancer, no previous systemic treatment for advanced disease, postmenopausal, ECOG 0-1; adjuvant/neoadjuvant nonsteroidal AI treatment allowed if DFS > 12 mos.
  • Study design: phase III, double-blind placebo-controlled RCT
  • Intervention
    • Experimental:
      • Ribociclib 600 mg PO daily 3 weeks on, 1 week off
      • Letrozole 2.5 mg PO daily
    • Control: Letrozole 2.5 mg PO daily + Placebo
  • Endpoints
    • Primary: PFS
    • Secondary: OS, ORR, CBR, safety


  • 668 patients randomized: ribociclib + letrozole (RL) n=334, letrozole + placebo (LP) n=334
  • 227 (34%) presented with de novo advanced breast Ca at diagnosis
  • Baseline patient characteristics: median age 63 yrs., Caucasian 80%, 60% ECOG 0, 99% stage IV at study entry, 36% with ≥ 3 metastatic sites, 76% bone mets
  • Baseline patient characteristics were well-balanced except for ECOG status 0: 66% (RL) vs 54% (LP)

Table 1: Efficacy Outcomes

  • Safety
    • Most frequent adverse events with ribociclib + letrozole: neutropenia, nausea, fatigue
    • Most common grade 3-4 adverse events (≥ 15%) with ribociclib + letrozole: neutropenia (55%), leukopenia (21%)
    • Neutropenia was the most common cause of treatment interruption/disruption in the ribociclib + letrozole arm (49%).

Table 2: Adverse events and treatment summary


  • In a pre-planned subgroup analysis of the MONLEESA2 trial, treatment with ribociclib in combination with letrozole significantly improved PFS compared to letrozole with placebo in postmenopausal women with de novo HR positive, HER-2 negative advanced breast cancer. The risk of disease progression was reduced by 55%. OS data was immature at interim analysis.
  • ORR and CBR were significantly better with the addition of ribociclib to letrozole. A similar trend was observed in patients with measurable disease.
  • Neutropenia was the most frequently reported adverse event in the ribociclib arm and the most common cause of treatment interruption/discontinuation in almost half of the patients. This is consistent with results in the ITT population of the original first line study in post-menopausal patients (N Engl J Med 2016; 375:1738-1748).
  • The benefit of adding CDK 4/6 inhibitors with an AI was also demonstrated in the PALOMA-2 trial (N Engl J Med 375:1925–1936). Postmenopausal women with HR positive, HER2 negative advanced breast Ca were randomized to palbociclib with letrozole or placebo with letrozole. Palbociclib significantly prolonged PFS compared to placebo (24.8 mos. v 14.5 mos., HR 0.48; p=<0.001). Neutropenia occurred in 66.4% v 1.4%, respectively.
  • Abemaciclib is the third CDK 4/6 inhibitor that was recently approved for HR positive, HER2 negative advanced breast Ca in combination with fulvestrant. The MONARCH-2 study that showed almost double PFS improvement with abemaciclib v placebo (16.4 mos. v 9.3 mos., HR 0.55; p <0.0001 [J Clin Oncol 2017 35:25, 2875-2884]).
  • The substantial magnitude of benefit in terms of PFS improvement with the combination of CDK 4/6 inhibitor and letrozole as 1st line treatment in de novo HR positive HER negative advanced breast cancer has made a huge impact on delaying disease progression. However, clinical benefit also comes at the cost of more hematologic toxicities.
  • Several questions remain unanswered such as sequencing of CDK4/6 inhibitors, the population of patients who will derive the greatest treatment benefit given its considerable cost and toxicities and markers to predict response or resistance to treatment, among others. Long-term follow-up will at least determine whether combination treatment will extend overall survival as this has not yet been demonstrated with any of the three agents.

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Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial
Kim, D-W et al. J Clin Oncol. 2017 Aug 1;35(22):2490-2498.
PubMed ID: 28475456


Patients with ALK-positive metastatic NSCLC achieve good clinical response with crizotinib in the first line setting. However, most patients eventually develop acquired resistance, even after 2nd line treatment. Brigatinib is a next generation ALK TKI inhibitor that was found to inhibit tumors that we¡¯re had resistant mutations to crizotinib. In a phase 1/II trial of brigatinib in advanced ALK-positive NSCLC after failing crizotinib, 62% achieved ORR, with PFS of 12.9 mos. [Ann Oncol 27(suppl 6):vi419-vi420, 2016 (abstract 1207PD)]. However, the incidence of pulmonary events in that trial prompted dose adjustments in the phase II expansion cohort.

Investigators conducted a phase II trial of brigatinib 90 mg once daily and 180 mg once daily with 90 mg lead-in to determine its efficacy and safety in crizotinib-refractory advanced ALK-positive NSCLC.


  • Patients: Histologically/cytologically confirmed locally advanced or metastatic ALK-positive NSCLC, progressed on crizotinib, ECOG 0-2, asymptomatic, stable CNS metastases, no previous treatment except crizotinib.
  • Study design: Phase II open-label RCT
  • Intervention:
    • Arm A: Brigatinib 90 mg OD
    • Arm B: Brigatinib 180 mg OD with 7-day lead-in at 90 mg OD
    • ** Patients in arm A could receive 180 mg OD upon disease progression at 90 mg dose
  • Endpoints:
    • Primary: ORR (per investigator)
    • Secondary: ORR (per central IRC), CNS response (IRC-assessed intracranial confirmed ORR and PFS in patients with active brain metastases), DOR, PFS, OS, safety, QOL


  • 222 patients randomized to arm A (n=110) and arm B (n=112)
  • Baseline patient characteristics: median age 54 yrs., 68% white, 57% ECOG 1, 39% smokers, 97% adenocarcinoma, 69% brain metastases, 74% prior chemotherapy, 65% with CR/PR to prior crizotinib, 12.6 mos. median duration of crizotinib treatment
  • Median time to response: 1.8 mos. vs. 1.9 mos.
  • One patient in arm B with G1202R mutation achieved PR.

Table 1: Efficacy Outcomes

  • Safety
    • Most common adverse events: nausea (33%/40%), diarrhea (19%/38%), headache (28%/27%), cough (8%/34%)
    • Most common grade ≥ 3 adverse events: hypertension (6% each arm), increased blood CPK (3%/9%), pneumonia (3%/5%), increased lipase (4%/3%).
    • Pulmonary AEs with early onset (median 2 days): 14 patients (6%) of which 7 (3%) were grade ≥ 3 and occurred at 90 mg on both arms.
    • Factors associated with early onset pulmonary AEs: older age and shorter interval (< 7 days) between last crizotinib dose and first brigatinib dose
  • Most common causes of dose reduction: increased blood CPK, pneumonitis, rash
  • QOL
    • QOL scores gradually improved from baseline but slowly declined thereafter, although still higher than baseline.
    • QOL was comparable in both arms at baseline and follow-up.

Table 2: Adverse Event and Treatment Summary


  • In the phase II ALTA trial, treatment with brigatinib resulted in rapid and durable tumor responses in ALK-positive advanced NSCLC after progression on crizotinib. The 180 mg dose with 90 mg lead-in appeared to prolong PFS by 3.7 mos. (6.4 mos. by IRC) and OS and provided better intracranial responses compared to 90 mg dose.
  • Early-onset pulmonary events that included dyspnea, hypoxia, cough, pneumonia, or pneumonitis were observed in 6% overall. This is consistent with previous studies, seemed to be related to the starting dose and were manageable with treatment interruption/dose reduction. These events warrant anticipatory management and early intervention especially among older patients and with short interval between criztonib and brigatinib treatment, as suggested by multivariable analysis.
  • The PFS and intracranial ORR advantage of the 180 mg dose came at the cost of more frequent adverse events, dose reductions and treatment interruptions. QOL seemed to improve initially but gradually declined after 7 mos. of treatment. No difference was observed in QOL in both treatment arms at baseline and during follow-up.

• ALTA trial was limited by small sample size and short follow-up period (median follow-up 7.8 mos. and 8.3 mos.). Moreover, the study was not statistically powered for PFS and OS analysis; therefore survival outcomes are merely descriptive.

• Brigatinb provided response rates that are comparable to studies on 2nd line ceritinib and alectinib in ALK-positive advanced NSCLC after failing crizotinib. Brigatinib is a new addition to treatment options in this cohort. Brigatinib received accelerated FDA approval in April 2017 for ALK-positive metastatic crizotinib-refractory NSCLC based on results from the ALTA trial. An ongoing phase III trial is investigating the efficacy of brigatinib 180 mg (lead-in) dose vs. crizotinib in treatment naive alk positive metastatic nsclc (NCT02737501).

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