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. 2020 Feb 12;25(7):562–e1012. doi: 10.1634/theoncologist.2020-0034

Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non‐Small Cell Lung Cancer with ALK Translocation

Sandip Pravin Patel 1,, Suchita Pakkala 2, Nathan A Pennell 3, Karen L Reckamp 4, Silvana Lanzalone 5, Anna Polli 5, Jamal Tarazi 6, Francisco Robert‐Vizcarrondo 7
PMCID: PMC7356710  PMID: 32048771

Abstract

Lessons Learned

  • This study evaluating first‐line crizotinib plus pembrolizumab in patients with anaplastic lymphoma kinase (ALK)–positive advanced non‐small cell lung cancer (NSCLC) was terminated early because increased availability of second‐generation ALK inhibitors resulted in difficulty identifying and accruing eligible patients.

  • In the small number of patients enrolled, elevated transaminases were the most common treatment‐related toxicity. No other relevant toxicities were observed.

  • Although no definitive conclusions could be drawn because of the small number of patients studied, the higher frequency of severe transaminase increases noted in this sample should be of concern if ALK inhibitor and PD‐L1/PD‐1 inhibitor combinations are tested in future studies.

Background

Previous research suggests single‐agent crizotinib is efficacious for the treatment of anaplastic lymphoma kinase (ALK)–rearranged advanced non‐small cell lung cancer (NSCLC).

Methods

This study evaluated the safety and preliminary antitumor activity of crizotinib plus pembrolizumab as first‐line therapy in patients with ALK‐rearranged NSCLC. Patients were initially treated at dose level 0 (DL0) with crizotinib 250 mg twice daily and pembrolizumab 200 mg every 3 weeks (cycle duration was 3 weeks). If a dose‐limiting toxicity occurred, subsequent patients were enrolled at a lower dose level (dose level −1 [DL−1]: 3 weeks of crizotinib monotherapy 250 mg twice daily, followed by crizotinib 250 mg twice daily with the addition of pembrolizumab 200 mg every 3 weeks). The primary endpoint was dose‐limiting toxicity. Antitumor activity was assessed.

Results

Nine patients were enrolled: two at DL0, then seven at DL−1. Dose‐limiting toxicities occurred in four patients (grade 3 increases in alanine aminotransferase [ALT] and aspartate aminotransferase [AST] and grade 3 fatigue at DL0; grade 3 increase in ALT and grade 3 increases in both ALT and AST at DL−1).

Conclusion

The maximum tolerated dose was not determined because slow accrual resulted in early study termination.

Discussion

ALK tyrosine kinase inhibitors (TKIs) have improved response rates and prolonged progression‐free survival compared with first‐line chemotherapy in the 3%–5% of patients with advanced NSCLC harboring ALK rearrangements 1.

Relatively few patients with ALK‐positive NSCLC have been included in programmed death ligand 1 (PD‐L1) inhibitor studies 2, 3. The effect of ALK rearrangement on PD‐L1 checkpoint inhibition remains unclear, although PD‐L1 expression is increased in ALK‐positive NSCLC tumors compared with PD‐L1 expression in ALK‐negative tumors 2, 4. Although ALK TKIs, including crizotinib, are effective in ALK‐positive NSCLC 1, 5, the potential relationship between ALK rearrangements and PD‐L1 expression and resistance to single‐agent ALK TKIs suggests synergistic effects with targeted ALK TKI therapy plus anti–PD‐1 inhibitor immunotherapy, such as pembrolizumab 6, 7.

This study attempted to identify the optimal dose of crizotinib in combination with pembrolizumab as first‐line treatment in patients with ALK‐rearranged advanced NSCLC. The study was terminated early because an increase in the availability of second‐generation ALK inhibitors resulted in difficulty identifying and accruing eligible patients. Thus, the maximum tolerated dose could not be determined because of the early termination.

Although crizotinib plus pembrolizumab had a higher frequency of and more severe transaminase increases than the known safety profile of each drug 7, 8, no new safety issues were identified. The most common toxicity was elevated transaminases, which occurred in eight patients and was treated with corticosteroids in two patients, one each at DL0 and DL−1. In three patients, one of whom also had extensive liver tumor involvement, this was a dose‐limiting toxicity (Table 1).

Table 1.

Dose‐limiting toxicities, serious adverse events, and permanent discontinuations, by patient

Patient Dose levela , b Dose‐limiting toxicity Serious adverse event Permanent discontinuation due to AE
1 0 Grade 3 AST and ALT increases Grade 3 AST and ALT increase attributed to pembrolizumab Pembrolizumab discontinued due to grade 3 pembrolizumab‐related AST increase (day 22); crizotinib continued until disease progression (day 259)
2 0 Grade 3 fatigue Grade 4 pneumonitis attributed to pembrolizumab and disease related grade 4 pneumonia leading to death Crizotinib and pembrolizumab discontinued because of grade 4 pembrolizumab‐related pneumonitis (day 63)
3 −1 0 0 0
4 −1 0 0 0
5 −1 Grade 3 ALT increase 0 Pembrolizumab discontinued due to grade 3 ALT increase (day 15); crizotinib reduced (200 mg b.i.d.) continued until disease progression (day 322)
6 −1 0 0 0
7 −1 0 0 0
8 −1 Grade 3 AST and ALT increases Grade 3 AST and ALT increases attributed to pembrolizumab Pembrolizumab discontinued due to grade 3 AST and ALT increases (day 15); crizotinib discontinued due to grade 3 ALT increase and grade 2 AST increase (day 43)
9 −1 0 0 0
a

Dose level 0: crizotinib 250 mg twice daily plus pembrolizumab 200 mg every 3 weeks.

b

Dose level −1: crizotinib 250 mg twice daily monotherapy lead‐in followed by crizotinib 250 mg twice daily plus pembrolizumab 200 mg every 3 weeks.

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; b.i.d, twice a day.

Reversible elevations in transaminase levels were the most common treatment‐related adverse events (AEs) for both drugs. Severe hepatotoxicity resulting in death and grade ≥ 3 elevated transaminase rates of ∼10%–46% have been reported with other PD‐1 inhibitor/ALK TKI combinations in ALK‐positive or ‐negative NSCLC 6, 9. In our small study, the rate of elevated transaminases was within this range, and all resolved after permanent treatment discontinuation. None was associated with concomitant bilirubin increases, and no crizotinib‐related serious AEs occurred after resuming crizotinib following pembrolizumab discontinuation, in contrast with another NSCLC study wherein sequential checkpoint inhibitor and crizotinib treatment had a higher incidence of hepatotoxicity than crizotinib alone 9.

One partial response (PR) occurred at DL0 in a patient with PD‐L1 tumor proportion score (TPS) ≥1%. At DL−1, one complete response (CR) occurred in a patient with PD‐L1 TPS ≥50%, and three PRs occurred in patients each with PD‐L1 TPS ≥1%, PD‐L1 TPS <1%, and PD‐L1 TPS not evaluable.

Trial Information

Disease Lung cancer – NSCLC
Stage of Disease/Treatment Metastatic/advanced
Prior Therapy None
Type of Study – 1 Phase I
Type of Study – 2 Modified toxicity probability interval
Primary Endpoint Maximum tolerated dose
Secondary Endpoint Recommended phase II dose
Additional Details of Endpoints or Study Design Objective responses assessed by RECIST version 1.1
Investigator's Analysis Active, but patient numbers too low for accurate comparison

Drug Information: Dose Level 0

Drug 1
Generic/Working Name Crizotinib
Trade Name Xalkori
Company Name Pfizer Inc.
Drug Type Small molecule
Drug Class ALK inhibitor
Dose 250 milligrams (mg) per flat dose
Route Oral (p.o.)
Schedule of Administration Dose level 0: 250 mg twice daily in combination with pembrolizumab
Drug 2
Generic/Working Name Pembrolizumab
Trade Name Keytruda
Company Name Merck Sharp & Dohme
Drug Type Monoclonal antibody
Drug Class Programmed death receptor‐1 (PD‐1 blocking antibody)
Dose 200 milligrams (mg) per flat dose
Route IV
Schedule of Administration Dose level 0: 200 mg every 3 weeks in combination with crizotinib

Drug Information: Dose Level −1

Drug 1
Generic/Working Name Crizotinib
Trade Name Xalkori
Company Name Pfizer Inc.
Drug Type Small molecule
Drug Class ALK inhibitor
Dose 250 milligrams (mg) per flat dose
Route Oral (p.o.)
Schedule of Administration Dose level –1: 250 mg b.i.d. as monotherapy for 3 weeks (lead‐in) then in combination with pembrolizumab
Drug 2
Generic/Working Name Pembrolizumab
Trade Name Keytruda
Company Name Merck Sharp & Dohme
Drug Type Monoclonal antibody
Drug Class Programmed death receptor‐1 (PD‐1 blocking antibody)
Dose 200 milligrams (mg) per flat dose
Route IV
Schedule of Administration Dose level –1: 200 mg every 3 weeks after crizotinib monotherapy lead‐in period
Abbreviations: ALK, anaplastic lymphoma kinase; b.i.d., twice a day; p.o., by mouth.

Dose Escalation Table for Dose Level 0

Dose level Dose of drug: crizotinib Dose of drug: pembrolizumab Number enrolled Number evaluable for toxicity
0 250 mg twice daily 200 mg every 3 weeks 2 2

Dose Escalation Table for Dose Level −1

Dose level Dose of drug: crizotinib Dose of drug: pembrolizumab Number enrolled Number evaluable for toxicity
−1 250 mg twice daily as monotherapy for 3 weeks (lead‐in) then in combination with pembrolizumab 200 mg every 3 weeks after crizotinib monotherapy lead‐in period 7 7

Patient Characteristics: Dose Level 0

Number of Patients, Male 1
Number of Patients, Female 1
Stage at Initial Diagnosis, n (%) IVB 0
Ia 1 (50)
IV 1 (50)

Initial diagnosis was in 2009. At time of study entry (2015), patient had metastatic disease.

Age Median (range): 64.5 (56–73)
Performance Status: ECOG

0—0

1—2

2—0

3—0

Unknown—0

Other Not collected
Cancer Types or Histologic Subtypes Adenocarcinoma, 2

Patient Characteristics: Dose Level −1

Number of Patients, Male 4
Number of Patients, Female 3
Stage at Initial Diagnosis, n (%) IVB 1 (14)
I 0
IV 6 (86)
Age Median (range): 51.0 (42–79)
Performance Status: ECOG 0—2
1—5
2—0
3—0
Unknown—0
Cancer Types or Histologic Subtypes Adenocarcinoma, 5
Adenosquamous, 2

Primary Assessment Method: Dose Level 0

Number of Patients Enrolled 2
Number of Patients Evaluable for Toxicity 2
Number of Patients Evaluated for Efficacy 2
Evaluation Method RECIST 1.1
Response Assessment CR n = 0 (0%)
Response Assessment PR n = 1 (50%)
Response Assessment SD n = 1 (50%)
Response Assessment PD n = 0 (0%)
Outcome Notes Dose level 0 Objective response TPSa
Patient 1 PR ≥1%
Patient 2 <1%

Strong positive is ≥50% TPS; positive is ≥1%; negative <1%.

Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; TPS, tumor proportion score.

Primary Assessment Method: Dose Level −1

Number of Patients Enrolled 7
Number of Patients Evaluable for Toxicity 7
Number of Patients Evaluated for Efficacy 7
Evaluation Method RECIST 1.1
Response Assessment CR n = 1 (14.3%)
Response Assessment PR n = 3 (42.9%)
Response Assessment SD n = 2 (28.6%)
Response Assessment PD n = 0 (0%)
Response Assessment OTHER n = 1 (14.3%)
Outcome Notes Dose level −1 Objective response TPSa
Patient 3 CR ≥50%
Patient 4 ≥50%
Patient 5 PR ≥1%
Patient 6 ≥1%
Patient 7 ≥1%
Patient 8 PR <1%
Patient 9 PR Not evaluable
a

Strong positive is ≥50% TPS; positive is ≥1%; negative <1%.

Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; TPS, tumor proportion score.

Serious Adverse Events: Dose Level 0

Name Grade Attribution
ALT increase 3 Possible
AST increase 3 Possible
Pneumonitis 4 Possible
Pneumonia 4 Unlikely

Serious Adverse Events Legend Across the two treatment dose levels, three patients experienced serious AEs; all were attributed to pembrolizumab and not crizotinib: grade 4 pneumonitis in one patient (DL0), grade 3 ALT increased and grade 3 AST increased in the second patient (DL0), and grade 3 ALT increased and AST increased in the third patient (DL−1).

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Dose‐Limiting Toxicities: Dose Level 0

Dose level Number enrolled Number evaluable for toxicity Number with a dose‐limiting toxicity Dose‐limiting toxicity information
0 2 2 2 Grade 3 ALT increase
Grade 3 AST increase
Grade 3 fatigue

Abbreviations: ALT, alanine aminotransferase; AST; aspartate aminotransferase.

Serious Adverse Events: Dose Level −1

Name Grade Attribution
ALT 3 Possible
AST 3 Possible

Serious Adverse Events LegendAcross the two treatment dose levels, three patients experienced serious AEs; all were attributed to pembrolizumab and not crizotinib: grade 4 pneumonitis in one patient (DL0), grade 3 ALT increased and grade 3 AST increased in the second patient (DL0), and grade 3 ALT increased and AST increased in the third patient (DL−1).

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Dose‐Limiting Toxicities for Dose Level −1

Dose level Number enrolled Number evaluable for toxicity Number with a dose‐limiting toxicity Dose‐limiting toxicity information
−1 7 7 2 Grade 3 ALT increase
Grade 3 AST

Abbreviations: ALT, alannine aminotransferase; AST, aspartate aminotransferase.

Assessment, Analysis, and Discussion

Completion Study terminated before completion
Terminated Reason Did not fully accrue
Investigator's Assessment Active, but patient numbers too low for accurate comparison

This study was conducted to identify the dose level of crizotinib in combination with pembrolizumab in the first‐line treatment of patients with anaplastic lymphoma kinase (ALK)–positive advanced nonsquamous non‐small cell lung cancer (NSCLC). This study was to consist of two phases. The dose finding phase was to determine the maximum tolerated dose (MTD) of the combination regimen. The dose expansion phase was to further evaluate the combination regimen at the MTD to determine whether or not the MTD was also the recommended phase II dose.

Dose level 0 (DL0) was crizotinib 250 mg twice daily (b.i.d.) on a continuous schedule in combination with pembrolizumab 200 mg given intravenously every 3 weeks (Q3W) starting on cycle 1 day 1 [DL0]); dose level −1 (DL−1) was crizotinib 250 mg b.i.d. × 3 weeks as monotherapy, then if tolerated, in combination with pembrolizumab 200 mg Q3W thereafter after crizotinib monotherapy.

After two dose‐limiting toxicities (aspartate aminotransferase [AST] increased/alanine aminotransferase [ALT] increased, and fatigue) were observed in the first two patients enrolled at DL0, DL−1 was opened to enrollment as per the protocol modified toxicity probability interval design. Dose‐limiting toxicities, specifically elevation of liver function tests, were observed in two of seven patients enrolled at DL−1. As the slow study enrollment led the sponsor to prematurely terminate the study during the dose finding phase, a total of nine patients were enrolled, and the MTD had not been identified.

One patient died 60 days after permanent discontinuation of crizotinib and 80 days after permanent discontinuation of pembrolizumab because of grade 5 pneumonia that was attributed to disease progression.

Across the two treatment dose levels, three patients experienced serious adverse events (AEs); all were attributed to pembrolizumab and not crizotinib: grade 4 pneumonitis in one patient (DL0), grade 3 ALT increased and grade 3 AST increased in the second patient (DL0), and grade 3 ALT increased and AST increased in the third patient (DL−1).

One or both study drugs were permanently discontinued in four patients associated with dose‐limiting toxicities. In one patient at DL0 and one patient at DL−1, the dose‐limiting toxicities were reported as serious. At DL0, one patient, who had extensive liver tumor involvement, had dose‐limiting toxicities that were elevated transaminases (grade 3 or 4 ALT and AST increases to 499–2095 IU/L and 433–921 IU/L, respectively) reported as serious AEs and attributed to pembrolizumab. This patient permanently discontinued pembrolizumab because of grade 3 AST increase on day 22, which was treated with prednisone and furosemide. ALT and AST values recovered by day 85. After a 19‐day treatment interruption, crizotinib was continued until day 259, when it was discontinued for disease progression. The other patient at DL0 had grade 3 fatigue, which was considered to be a dose‐limiting toxicity. Both study drugs were permanently discontinued on day 63 because of serious pembrolizumab‐related pneumonitis. The patient died 45 days after stopping both drugs because of disease‐related pneumonia.

The dose‐limiting toxicities at DL−1 were grade 3 ALT increase in one patient and grade 3 increases in ALT and AST in another patient. In the first patient, the grade 3 ALT increase occurred on day 15 and was considered to be related to both drugs; pembrolizumab was permanently discontinued, whereas crizotinib dose was reduced to 200 mg twice daily when ALT increase recovered to grade 1 (day 29) until permanent discontinuation on day 322 because of disease progression. The grade 3 ALT increase normalized on day 50 without requiring any treatment. The increases in ALT (up to 923 IU/L) and AST (up to 663 IU/L) in the other patient occurred during cycle 1 and were classified as serious AEs attributed to pembrolizumab. Pembrolizumab was permanently discontinued, and systemic corticosteroids were given, whereas crizotinib was initially temporarily interrupted (day 15), then reduced to 200 mg twice daily and restarted from day 36, when ALT and AST had recovered to normal values. Crizotinib was permanently discontinued after an increase of ALT to grade 3 and AST to grade 2 (310 IU/L and 192 IU/L, respectively) on day 43, both attributed to crizotinib; values normalized on day 64. None of the transaminase increases was associated with concomitant total bilirubin elevations.

All nine patients treated had at least one AE. At DL0, both patients treated experienced AEs of dysgeusia, elevated transaminases, and pyrexia, all of which were considered to be both crizotinib and pembrolizumab related. Among the seven patients at DL−1, the most frequent crizotinib‐related AEs were diarrhea, increased transaminases, and nausea (each in five patients; 71.4%); the most frequent pembrolizumab‐related AE was increased transaminases (four patients; 57.1%); in one of these, elevated transaminases was attributed to both crizotinib and pembrolizumab. No treatment‐related grade 5 events were reported.

Laboratory data showed shifts from grade ≤ 2 at baseline to grades 3 or 4 after baseline: at DL0, one patient each showed shifts in ALT, AST, and hyponatremia; at DL−1, lymphopenia occurred in two patients (28.6%). In chemistry tests, shifts in ALT occurred in three patients (42.9%), and shifts in AST, hyperglycemia, hyponatremia, and hypophosphatemia in one patient each (14.3%). AST/ALT values were elevated in a total of five patients across the two dose levels, but none met the criteria of a potential Hy's law case.

There were no relevant findings for changes in vital signs, electrocardiogram parameters, and Eastern Cooperative Oncology Group performance status.

An overall assessment of antitumor activity of crizotinib in combination with pembrolizumab could not be documented because of the small number of patients tested at each dose level. Although antitumor activity appeared promising with one complete response and four partial responses observed across the two dose levels, these results were potentially in line with the results obtained in first‐line treatment with crizotinib. No relationship between programmed death ligand 1 (PD‐L1) expression and response was apparent in this small sample.

Pharmacokinetic analysis was not performed for this study report because of the small sample size. Pembrolizumab antidrug antibodies assessed by immunogenicity were negative for all patients.

The exploration of pharmacodynamic characteristics of additional tumor and peripheral blood biomarkers potentially relevant to the mechanism of action of, or the development of resistance to, crizotinib in combination with pembrolizumab could not be evaluated because of the small number of patients evaluated at each dose level.

Patient‐reported outcomes were not evaluated because of the small number of patients tested at each dose level.

The MTD and the recommended phase II dose of this study, which evaluated the combination of crizotinib with pembrolizumab in the first‐line treatment of patients with ALK‐positive advanced nonsquamous NSCLC, could not be determined because of the early study termination associated with low enrollment rate. The safety profile of the combination was found to be consistent with the respective known safety profile of each study drug. Although no new major safety issues were identified in this small sample of patients, the higher frequency of severe transaminase increases noted with the use of this ALK TKI plus PD‐L1 inhibitor combination are a cause of concern. Because the safety profile of crizotinib plus pembrolizumab has not been fully established and the combination is not indicated for treatment of NSCLC, this combination, and possibly other ALK TKI and immune checkpoint inhibitor combinations, should only be used in the context of a clinical trial.

Disclosures

Sandip Pravin Patel: AstraZeneca, Bristol‐Myers Squibb, Eli Lilly, Illumina, Nektar, Novartis, Tempus (C/A), Bristol‐Myers Squibb, Eli Lilly, Fate, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery. Fate Therapeutics, Genocea, Iovance (RF); Nathan A. Pennell: Merck, AstraZeneca, Bristol‐Myers Squibb, Eli Lilly, Cota, Inivata (C/A); Karen L. Reckamp: Takeda (C/A), Pfizer, Takeda, Xcovery (RF); Silvana Lanzalone: Pfizer (E, OI); Anna Polli: Pfizer (E, OI); Jamal Tarazi: Pfizer (E, OI, IP). Suchita Pakkala and Francisco Robert‐Vizcarrondo indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

Acknowledgments

Medical writing support was provided by Michelle Daniels (inScience Communications, Springer Healthcare, Philadelphia, PA) and funded by Pfizer.

No part of this article may be reproduced, stored, or transmitted in any form or for any means without the prior permission in writing from the copyright holder. For information on purchasing reprints contact Commercialreprints@wiley.com. For permission information contact permissions@wiley.com.

Footnotes

  • Sponsors: Pfizer Inc. in collaboration with Merck & Co, Inc.
  • Principal Investigator: Sandip Pravin Patel
  • IRB Approved: Yes

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