Best of Oncology Weekly - Renal and Hematologic Cancer Key Journal Article Summaries

July 29th, 2018
 
Please enjoy this edition of our Best of Oncology Weekly newsletter, featuring key journal article summaries in renal cell carcinoma and multiple myeloma. These articles were selected, prepared, and reviewed by our expert faculty members.
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma
Motzer RJ et al., N Engl J Med. 2018 Apr 5;378(14):1277-1290.
PubMed ID: 29562145

Impact: Checkmate 214 is the first phase III study to demonstrate a significant OS benefit with checkpoint inhibitors over sunitinib for first line advanced RCC. It also is the first study to demonstrate that IMDC criteria can be used as a predictive marker which has led the FDA to approve this combination for intermediate and poor risk patients. Read more...


More GU Cancer Updates
Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study
Raje N et al., Lancet Oncol. 2018 Mar;19(3):370-381.
PubMed ID: 29429912

Impact: This large head-to-head study revealed denosumab to be at least noninferior to zolendronic acid in delaying time to first SRE as first line treatment with standard therapy in symptomatic MM. As a new treatment option with a favorable renal toxicity profile, it did not however provide an OS advantage over zolendronic acid. Read more...

More Hematologic Cancer Updates
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Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

Motzer, RJ et al. N Engl J Med 2018;378:1277-90.

PubMed ID: 29562145

 

Introduction:

 

Sunitinib is standard of care treatment in renal-cell carcinoma (RCC), based on results from a phase III trial that showed 25% objective response rate (ORR), median progression-free survival (PFS) of 9.3 mos. and median overall survival (OS) of 29.3 mos. (N Engl J Med 2013;369: 722-31). However, Sunitinib is associated with a high rate of hematologic toxicity and patients who fail first line Sunitinib have limited treatment options. 

 

Nivolumab is a PD-1 immune checkpoint inhibitor that has been approved in RCC for patients who fail antiangiogenic therapy. Ipilimumab is an anti–cytotoxic T-lymphocyte–

associated antigen 4 (anti-CTLA-4) antibody approved in melanoma. Studies on the  combination of nivolumab with ipilimumab revealed antitumor activity in treatment-naïve and previously treated RCC. The CheckMate 214 study further examined the efficacy and safety of this combination in advanced RCC, with a focus on International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk. 

 

Methods:

 

  • Patients: histologically confirmed previously untreated advanced RCC with clear cell component, Karnofsky performance-status score of at least 70, no central nervous system (CNS) metastases

 

  • IMDC criteria: KPS<80, Dx-Tx Interval<1 year, anemia, thrombocytosis, neutrophilia, hypercalcemia.  0 factors=favorable, 1-2 factors=intermediate, 3+ factors = poor.

 

  • Study design: phase III, open-label RCT

 

  • Intervention

Experimental: Nivolumab 3mg/kg + Ipilimumab 1 mg/kg q3w x 4 cycles 

                        (induction) then nivolumab 3mg/kg q2w (maintenance)

            Control: Sunitinib 50mg daily 4/6w cycle

 

  • Endpoints:  

            Primary: PFS, ORR, OS (intermediate and poor risk patients)

            Secondary: PFS, ORR, OS, outcomes according to PD-L1 expression, health-

                               related quality of life (HRQOL), safety

 

Results:

 

  • 1096 patients randomized and analyzed by intention-to-treat (ITT)

 

Table 1. Baseline patient characteristics*

 

 

IMDC intermediate 

and poor risk

Intention-to-treat

 

NI

 N=425

S

N=422

NI

N=550

S

N=546

Median age – yrs. 

62

61

62

62

Male - %

74

71

75

72

IMDC prognostic risk - %

      Favorable 

      Intermediate

      Poor

 

0

79

21

 

0

79

21

 

23

61

17

 

23

61

16

Canada and Europe - %

35

35

37

36

Tumor PD-L1 expression %

      <1%

      ≥1%

 

74

26

 

71

29

 

77

23

 

75

25

Previous radiotherapy - %

12

12

11

13

Previous nephrectomy - %

80

76

82

80

 ≥2 target/nontarget lesions - %

79

80

78

78

Most common metastases site - %

      Lungs

      Lymph node

 

69

45

 

70

51

 

69

45

 

68

49

*selected

 

 

Table 2. Efficacy outcomes in intermediate and poor-risk patients 

 

 

Nivolumab

Ipilimumab

Sunitinib

HR (95% CI)

P value

OS – mos. 

NR

26

0.63 (0.44-0.89)

<0.001

12-mo. OS – %

80

72

-

-

18-mo. OS - %

75

60

-

-

ORR - %

42

27

-

<0.001

       CR

9

1

-

-

DOR at least 1 yr. - % 

81

70

-

-

DOR – mos. 

NR

18.2

-

-

PFS – mos. 

11.6

8.4

0.82 (0.64-1.05)

0.03*

NR – not reached   * not significant per prespecified 0.009 threshold

 

 

Table 3. Efficacy outcomes in favorable-risk patients (N=249)

 

 

Nivolumab

Ipilimumab

Sunitinib

HR (95% CI)

P value

OS – mos. 

NR

32.9

1.45 (0.51-4.12)

0.27

12-mo. OS – %

94

96

-

-

18-mo. OS - %

88

93

-

-

ORR - %

29

52

-

<0.001

      CR

11

6

-

-

PFS – mos. 

15.3

25.1

2.18 (1.29-3.68)

<0.001

 

 

Table 5. Efficacy outcomes in intermediate and poor-risk patients by PD-L1 expression (N=776)

 

 

Nivolumab

Ipilimumab

Sunitinib

HR (95% CI)

P value

PD-L1 expression ≥1%

100/384

114/392

 

 

OS – mos. 

NR

19.6

0.45 (0.29-0.71)

-

ORR - %

58

22

-

<0.001

PFS – mos. 

22.8

5.9

0.46 (0.31-0.67)

-

PD-L1 expression <1%

284

278

 

 

OS – mos. 

NR

NR

0.73 (0.56-0.96)

-

ORR - %

37

28

-

0.03

PFS – mos. 

11

10.4

1.00 (0.80-1.26)

-

 

  • 79% received all four doses of nivolumab-ipilimumab (induction)

      

Safety

 

  • Most common any grade adverse events with nivolumab-ipilimumab: fatigue (37%), pruritus (28%), diarrhea (27%)

 

  • Most common any grade adverse event with sunitinib: diarrhea (52%), fatigue (49%), hypertension (40%)

 

 

Table 5. Adverse events and treatment summary

 

 

Nivolumab

Ipilimumab

Sunitinib

Dose delays - %

58, 27

59

Treated beyond investigator-accessed progression - %

29

24

Any grade adverse event - %

93

97

Grade 3-4 adverse event - %

46

63

Treatment discontinuation due to adverse event - %

22

12

Treatment-related death - n

8

4

Subsequent therapy - %

39

54

 

 

  • Most common grade 3-4 adverse events with nivolumab-ipilimumab: increased lipase level (10%), diarrhea (4%), fatigue (4%)

 

  • Most common grade 3-4 adverse events with sunitinib: hypertension (16%), palmar-plantar erythrodysesthesia (9%), fatigue (9%)

 

  • 152 (35%) received high-dose glucocorticoids (≥40 mg of prednisone per day or equivalent) for immune-mediated adverse events in the nivolumab-ipilimumab group.

  

 

Discussion:

 

  • Immunotherapy with nivolumab-ipilimumab provided significant OS advantage over standard of care sunitinib as upfront therapy in advanced RCC. This benefit was greatest in the intermediate and poor risk subgroup were the risk of death was reduced by 37%. 

 

  • Early separation of survival curves occurred at around 3 mos., with the curves continuing to diverge beyond 18 mos. Consistent findings were observed in the ITT population in favor of nivolumab-ipilimumab. PFS survival however did reach statistical significance, although this is not unusual with immunotherapy. 

 

  • Nivolumab-ipilimumab yielded durable tumor responses in at least 42% of patients with intermediate of poor risk, as early as 2.8 mos. compared to sunitinib. The study was stopped early when patients on nivolumab-ipilimumab responded very well to immunotherapy. 

 

  • Patients on nivolumab-ipilimumab had longer OS and better tumor responses compared to sunitinib among intermediate and poor risk patients, regardless of tumor PD-L1 expression, although patients with >1% tumor PD-L1 expression fared better compared to those with <1% PD-L1 tumor expression. Although PD-L1 expression may enrich the population for responders, its negative predictive value is not good enough to be a selector of patient treatment.

 

  • Treatment tolerance was consistent with similar trials and study population. The proportion of patients with high-grade toxicity was greater in the sunitinib group, although rates of treatment discontinuation due to adverse events and number of deaths were higher with immunotherapy.  Most of the deaths in the immunotherapy group were related to pulmonary events (pneumonia, bronchitis, immune-mediated bronchitis, lung infection). 

 

  • The use of glucocorticoids in 35% of patients with immune-mediated adverse events and supportive care contributed to a manageable safety profile in the immunotherapy group. Moreover, QOL scores improved with nivolumab-ipilimumab from baseline in the first 6 mos. of treatment. Education in the early management of immune related adverse events is important.

 

  • Checkmate 214 is the first phase III study to demonstrate a significant OS benefit with checkpoint inhibitors over sunitinib for first line advanced RCC.  It also is the first study to demonstrate that IMDC criteria can be used as a predictive marker which has led the FDA to approve this combination for intermediate and poor risk patients.  Favourable risk patients and patients not eligible to receive ipi/nivo should be treated with TKIs like sunitinib or pazopanib.

More GU Cancer Updates

Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study

Raje, N et al. Lancet Oncol 2018; 19: 370–81

PubMed ID: 29429912

 

Introduction:

 

Up to 90% of patients with multiple myeloma (MM) present with painful bony osteolytic lesions. Denosumab inhibits osteoclast activity by binding to and neutralizing RANKL and has been shown to reduce the risk of skeletal-related events (SREs) in solid tumors. To date, only bisphosphonates are approved for MM. In the Myeloma IX trial, zolendronic acid (ZA) prolonged progression-free survival (PFS) and reduced mortality compared to clodronic acid (Lancet 2010; 376: 1989–99). Renal impairment is quite often seen in MM, due to myeloma cast formation, amyloidosis or hypercalcemia and is a contraindication for bisphosphonates. 

 

Based on an unmet need for more treatment options, researchers conducted a head to head comparison of denosumab vs. zolendronic acid as first line treatment in symptomatic MM. 

 

Methods:

 

  • Patients: newly diagnosed MM (≥ 10% monoclonal plasma cells in the bone marrow or the presence of a biopsy proven plasmacytoma, or both, in addition to monoclonal paraprotein being present in the serum or urine, or both, at least 1 documented lytic bone lesion by x-ray or CT/MRI), Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, creatinine clearance at least 30 mL/min

 

  • Study design: phase III double-blind, double-dummy RCT

 

  • Intervention:

Control: Zolendronic acid 4 mg IV + placebo q4 weeks

Experimental: Denosumab 120 mg SC + placebo q4 weeks

* Both groups received first-line antimyeloma treatment (physician’s choice)

               

  • Endpoints:  

            Primary: time to first on-study SRE (denosumab noninferior to ZA)

            Secondary: time to first on-study SRE (denosumab superior to ZA), time to first   

                               and subsequent on-study SRE, PFS, overall survival (OS), safety

 

Results: 

 

  • Denosumab was noninferior to zolendronic acid in delaying time to first SRE (HR 0.98; p non-inferiority=0∙010) in symptomatic MM. First SREs occurred in 60% within the first 3 mos. and 81% within the first 6 mos. Median time to first on-study SRE was 22.8 mos. for denosumab and 24 mos. with zolendronic acid. 

 

  • Denosumab was superior to zolendronic acid for time to first SRE in a post hoc landmark analysis at 15 mos. Median times to first SRE were not estimable (NE) in both treatment arms. 

 

  • No significant difference was observed for OS (49.5 mos. vs. NE, HR 0.90; p=0.41). Median PFS was 46.1 mos. for denosumab vs. 35.4 mos. for zolendronic acid (HR 0.82; descriptive p=0.036). Patients were exposed to treatment for 17 mos., received at least 16 doses, with median cumulative drug exposure of 15 mos.

 

  • Most common grade ≥ 3 adverse events for denosumab and zolendronic acid were neutropenia (15% vs. 15%), thrombocytopenia (14% vs. 12%), anemia (12% vs. 10%), febrile neutropenia (11% vs. 10%) and pneumonia (8% vs. 8%). 

 

  • At least 47% experienced a serious adverse event; fatal events occurred in 10% vs. 11%, respectively. Most of the deaths were deemed to be related to the patients’ comorbidities at baseline. One treatment-related death occurred in the zolendronic acid group. 

 

  • Renal toxicity was reported in 10% on denosumab vs. 17% on zolendronic acid. Hypocalcemia and osteonecrosis of the jaw (ONJ) was seen in 17% vs. 12% and 4% vs. 3%, respectively. Most ONJ events were low grade, resolved in 35% and 25%, respectively; at least 54% of patients had underlying risk factors for ONJ. Treatment was discontinued due to intolerable side effects in 12%, most commonly due to musculoskeletal, connective tissue disorders, ONJ and infections. 

 

  • Anti-denosumab antibody was detected in one patient at baseline and one patient during treatment; both were negative for neutralizing antibodies. 

 

  • Study authors conducted a landmark superiority analysis of time to first SRE at 15 mos. to determine treatment differences because patients with SREs within the first 3 mos. wouldn’t have sufficient exposure to study drugs. 

 

  • In summary, this large head-to-head study revealed denosumab to be at least noninferior to zolendronic acid in delaying time to first SRE as first line treatment with standard therapy in symptomatic MM, 67% of whom had a SRE prior to study enrolment and 52% on first line proteasome inhibitor. As a new treatment option with a favorable renal toxicity profile, it did not however provide an OS advantage over zolendronic acid.  

More Hematologic Cancer Updates

 

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