03/10/2019: Articles Summaries - Lung & GU Cancers

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Summary

LUNG CANCERS
 

Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden

Hellmann MD et al. N Engl J Med 2018. DOI: 10.1056/NEJMoa1801946

Introduction:

Combination therapy with nivolumab and ipilimumab has shown promising antitumor activity in advanced NSCLC. The phase 1 CHECKMATE 012 study of nivolumab with ipilimumab revealed good clinical activity and no new safety signals in treatment-naïve NSCLC (Lancet Oncol 2017; 18: 31-41). In the CheckMate 568 study, patients on nivolumb with ipilimumab who had tumor mutational burden  (TMB) of at least 10 mutations per megabase were more likely to respond to immunotherapy, regardless of tumor PD-L1 expression level (AACR presentation, 2018). Investigators conducted the CheckMate 227 trial to determine the efficacy and safety of nivolumab with ipilimumab in advanced NSCLC with a focus on TMB as a predictor of survival. Results from part 1 are presented below.

Methods:

  • Patients: histologically confirmed squamous or nonsquamous recurrent or advanced NSCLC, no previous treatment for metastatic disease, EGFR-/ALK-, ECOG 0-1, provided tumor sample for PD-L1 status determination, asymptomatic or adequately treated CNS metastases with neurologic findings returned to baseline prior to study entry
  • Study design: phase III, multi-part RCT
  • Intervention

Experimental a. Nivolumab 3 mg/kg q2w + ipilimumab 1 mg/kg q6w  

            Control: b. Platinum doublet chemotherapy q3w x 4 cycles

                           c. Nivolumab 240 mg q2w (PD-L1 expression ≥1%)

                           c. Nivolumab 360 mg q2w + platinum doublet chemotherapy q3w x 4   

                               cycles  (PD-L1 expression <1%)

             Maintenance pemetrexed +/- nivolumab was given if with stable disease or 

             response after 4 cycles of chemotherapy (nonsquamous only)

  • Endpoints:

Primary: PFS, OS

Secondary: PFS (nivo vs. chemo) in TMB at least 10 mutations per megabase and PD-L1 expression ≥1%, OS (NI vs. chemo) in TMB at least 13 mutations per megabase, ORR, DOR, safety

Results:

  • 1189 with PD-L1 expression ≥1% randomized to NI (n=396), chemo (n=397), nivo (n=396)
  • 550 patients with PD-L1 expression <1% randomized to NI (n=187), chemo (n=186), nivo (n=177)
  • 57.7% had valid data for TMB analysis
  • Baseline patient characteristics: median age 64 yrs., 52% <65 yrs. old, 68% male, 54% Europe, 64% ECOG 1, 92% current or former smoker, 66.6% nonsquamous, 71% tumor PD-L1 expression ≥1%
  • Median duration of therapy: 4.2 mos. (NI) vs. 2.6 mos. (chemo)
  • 30% in the chemo arm received subsequent therapy

Table 1. Efficacy outcomes

Outcomes

Nivo-Ipi

Chemo

HR (95% CI)

ITT

PFS – mos.

4.9

5.5

0.83 (0.72-0.96)

1-yr. PFS- %

30.9

17

-

Evaluable TMB

PFS – mos.

4.9

5.5

0.82 (0.68-0.99)

1-yr. PFS- %

32.1

15.2

 

High TMB

PFS – mos.

42.6

13.2

0.58 (0.41-0.81)*

1-yr. PFS- %

7.2

5.5

-

     PD-L1 ≥1%

42

16

0.62 (0.44-0.88)

     PD-L1 <1%

45

8

0.48 (0.27-0.85)

     Squamous

36

7

0.63 (0.39-1.04)

     Nonquamous

46

17

0.55 (0.38-0.80)

ORR - %

45.3

26.9

-

TTR – mos.

2.7

1.5

-

DOR – mos.

NR

5.4

-

Low TMB

PFS – mos.

3.2

5.5

1.07 (0.84-1.35)

* p <0.001         High TMB – tumor mutational burden  ≥10 mutations per megabase

Low TMB - tumor mutational burden  <10 mutations per megabase

Table 2. Efficacy outcomes for secondary endpoints

Outcomes

Nivo

Chemo

HR (95% CI)

PFS – mos.

 

 

 

     TMB ≥13*, PD-L1 ≥1%

4.2

5.6

0.95 (0.61-1.48) †

     TMB ≤10*, PD-L1 ≥1%

7.1

4.2

0.75 (0.53-1.07)

* mutations per megabase       † p=0.78   

Safety

  • Most common any grade adverse events with nivolumab-ipilimumab and nivolumab: rash (16.7% vs. 11%), diarrhea (16.3% vs. 11.3%), pruritus (14.1% vs. 7.7%)
  • Most common grade 3-4 adverse event with nivolumab-ipilimumab and nivolumab: hepatic (8 vs. 3.3%)
  • Most common grade 3-4 adverse events with chemotherapy: anemia (11.2%), neutropenia (9.5%), neutrophil count decreased (6.3%)

Table 3. Adverse events and treatment summary

 

Nivo-Ipi

Nivo

Chemo

Any grade AE - %

75.2

64.2

80.7

Grade 3-4 AE - %

31.2

18.9

36.1

Grade 3-4 serious AE - %

17.7

7.7

10.7

Treatment-related death – n (%)

7 (1.2)

2 (0.5)

6 (1.1)

Treatment discontinuation d/t grade AE - %

17.4

11.5

8.9

Grade 3-4 rash - %

1.6

0.8

0

Grade 3-4 diarrhea - %

1.6

0.8

0.7

Any grade hypothyroidism - %

11.6

6.4

0

  • Patients with high TMB who received nivolumab-ipilimumab had a slightly higher rate of adverse events.

Discussion:

  • First line treatment with nivolumab-ipilimumab resulted in a 42% reduction in disease progression or death compared to chemotherapy in advanced EGFR-/ALK- NSCLC with high TMB, regardless of tumor PD-L1 expression. Immunotherapy delayed metastases by 29.4 mos. in this group. This advantage was most evident in the high TMB group with PD-L1 tumor expression <1% and nonsquamous histology. OS was immature at interim analysis.
  • Niolumab-ipilimumab yielded higher and durable response rates compared to chemotherapy. DOR curves diverged as early as 3 mos. TTR was slightly delayed with nivolumab-ipilimumab, although this is typically seen with immunotherapy and is consistent with previous literature.
  • When nivolumab alone was compared with chemotherapy, PFS was longer with immunotherapy in patients with high TMB and PD-L1 expression > 1%. However, superiority over chemotherapy was not clearly established. The study was not powered to compare nivolumab-ipilimumab with nivolumab alone.
  • At least 44% of tumors tested had high TMB at baseline. TMB was used as a biomarker in the trial, with high TMB defined as ≥10 mutations per megabase, based on a previous study. However, its current application is limited in a clinical trial setting, given the complexity of the assay, issues with reliability, cut-off point, turnaround time, adequacy of tissues for testing, among others.
  • Immunotherapy and chemotherapy had comparable toxicity profiles, although different for the two arms. Hematologic toxicities occurred more commonly with chemotherapy while cutaneous, hepatic adverse events and diarrhea, as well as hypothyroidism were more prevalent in the immunotherapy group.
  • The findings in this trial are quite provocative, although much work still needs to be done in terms of determining which patient population will best benefit with nivolumab-ipilimumab, utility of TMB and it generalizability as a biomarker. Furthermore, OS analysis demonstrating survival benefit is needed to further solidify these results. 

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GU CANCERS
 

 

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial

Parker, C et al. Lancet 2018. http://dx.doi.org/10.1016/S0140-6736(18)32486-3

Introduction:

Systemic therapy is the standard of care in metastatic prostate cancer. In some cases, local therapy to the primary tumor may be offered as well, for palliative purposes. However, prostate-directed therapy in therapy in the metastatic setting may offer additional benefit beyond just symptom palliation. Retrospective studies suggest survival benefit with local radiotherapy (RT) to the primary tumor in metastatic prostate cancer. However, in the HORRAD trial, patients with metastatic prostate cancer who received local RT with androgen deprivation therapy (ADT) did not fare better than those on ADT alone in terms of overall survival (OS) [Eur Urol 2018; published online Sept 25.DOI:10.1016/j.eururo.2018.09.008]. To further investigate the efficacy of prostate-directed RT in men with metastatic prostate cancer in a large trial, researchers initiated the STAMPEDE study.

Methods:

  • Patients: newly diagnosed advanced prostate cancer without previous radical  

               treatment, no contraindications to RT

  • Pre-planned subgroup analysis included low-burden vs high-burden metastatic disease, though this was not a stratification factor. Burden of disease was based on CHAARTED trial definition (high-burden = 4 or more bone metastases with one or more outside the vertebral bodies or pelvis, and/or presence of visceral metastases).
  • Study design: phase III, open-label RCT
  • Intervention

            Experimental: RT (36Gy at 6 weekly fractions or 55Gy in 20 fractions over 4   

                                    weeks) + standard of care (SOC)

            Control: Standard of care

            All patients received ADT: GNRH agonists/antagonists or orchidectomy.

            Docetaxel 75 mg/m2 every 3 weeks ± prednisone 10mg/day was allowed after

            UK approval in December 2015.

  • Endpoints

            Primary: overall survival (OS),

            Secondary: failure-free survival (FFS), progression-free survival (PFS), metastatic progression-free survival, prostate cancer-specific survival, symptomatic local event-free survival, safety

Results:

  • 2061 patients randomised to RT (n=1032) vs. SOC (n=1029)

Table 1. Baseline patient characteristics (selected)

Characteristic

ITT

Median age  - yrs.

68

Prostate cancer pain-free - %

82

Median PSA – ng/mL

97

Gleason 8-10 - %

79

Bone metastases - %

89

WHO performance score 0 - %

71

Previous hypertension - %

42

T3 - %

62

N+ - %

64

High metastatic burden - %

57

Planned docetaxel - %

18

Daily RT - %

52

LHRH analogues - %

99

Median time to RT - days

35

Table 2. Efficacy Outcomes

3-yr. outcomes (%)

RT

Control

HR (95% CI)

p value

OS

65

62

0·92 (0·80–1·06)

0.451

Median – mos.

46

48

-

-

Low metastatic burden

81

73

0·68 (0·52–0·90)

0.007

High metastatic burden

53

54

1·07 (0·90–1·28)

0.420

FFS

32

23

0·76 (0·68–0·84)

<0.0001

Median – mos.

13

17

-

-

Low metastatic burden

50

33

0·59 (0·49–0·72)

<0.0001

High metastatic burden

18

17

0·88 (0·77–1·01)

0.059

Daily RT

 

 

0·69 (0·59–0·80

<0.0001

PFS

44

44

0·96 (0·85–1·08)

0.468

Low metastatic burden

63

58

0·78 (0·63–0·98)

0.033

High metastatic burden

30

35

1·09 (0·94–1·26)

0.252

Metastatic PFS

47

47

0·97 (0·86–1·10)

-

Low metastatic burden

67

62

0·80 (0·63–1·01)

-

High metastatic burden

33

37

1·10 (0·95–1·28)

-

Prostate Ca-specific survival

69

66

0·93 (0·80–1·09)

0.431

Low metastatic burden

86

79

0·65 (0·47–0·90)

0.010

High metastatic burden

56

58

1·10 (0·92–1·32)

0.279

Symptomatic local EFS

55

57

1·07 (0·93–1·22)

-

Low metastatic burden

72

65

0·82 (0·64–1·05)

-

High metastatic burden

43

50

1·23 (1·05–1·46)

-

  • Time to first new treatment after failure-free survival event was similar in both treatment groups.
  • In terms of time to first life-prolonging therapy, patients on RT appeared to receive subsequent treatment earlier upon disease progression but later after randomization compared to controls.

Table 3. Restricted mean survival time in low metastatic burden subgroup

3-yr. outcomes (mos.)

Low metastatic burden

RT

Control

OS

49.1

45.4

FFS

36.1

27.4

PFS

42.9

39.4

Prostate Ca-specific survival

51.8

48.6

Restricted mean – mean restricted to the first 59 months

on trial, p<0.0001

Safety

  • No grade 5 late RT adverse events were reported.
  • Most severe adverse events were related to hormonal therapy in both groups (endocrine-14%).
  • Symptomatic local events occurred in 3% or less in both groups within the treatment period (12 wks. after randomization in patients who did not receive docetaxel).

Table 4. Treatment summary and adverse events

Events

RT

Control

Postprogression treatment - %

    Enzalutamide 

36

32

    Docetaxel

33

33

    Abiraterone

20

21

    Anti-androgen

58

63

Severe adverse event

39

38

Grade ≥ 3 adverse event at 6 mos.

22

21

Grade ≥ 3 adverse event at1 yr.

13

12

Grade ≥ 3 adverse event at 2 yrs.

13

15

Acute RT toxicity (%)*

Daily

Weekly

 

    Grade 1-2 bladder toxicity

66

60

-

-    Grade 3-4 bladder toxicity

5

5

-

    Grade 1-2 bowel toxicity

60

47

-

    Grade 3-4 bowel toxicity

1

<1

-

Late grade 3-4 adverse event*

4

1

-

* Radiation Therapy Oncology Group. (RTOG) scale

  • Urinary tract infection (3% vs. 1%) was the most common symptomatic local event within the treatment period in the RT vs. control group. This incidence rose to 7% vs. 5%, respectively after the treatment window.
  • The most common symptomatic local events in the RT group after the treatment window were urinary tract infection, urinary catheter (3% vs. 2%) and acute kidney injury (3% vs. 1%).

Discussion:

  • This large, multi-stage trial revealed that RT in combination with SOC did not improve overall survival in the unselected ITT patient population.
  • However, pre-planned subgroup analysis demonstrated significantly improved OS in the subgroup of patients with low metastatic tumor burden (40% of the study population) compared to control (SOC alone), with 8% absolute difference corresponding to 32% lower risk of death.
  • No difference was observed in terms of FFS in the ITT population. However, in the low metastatic burden subgroup, at least half of the patients who received RT with SOC were free from biochemical failure, lymph node or distant metastases or death vs. 33% in the SOC group. RT was associated with 41% risk reduction in FFS.
  • A similar trend occurred in the low metastatic burden subgroup in terms of PFS and prostate cancer-specific survival. RT with SOC significantly reduced the risk of disease progression or death by 22% and the risk of death from prostate cancer by 35%.
  • The provocative findings of benefit being restricted only to those with low-metastatic burden are consistent with the results of the aforementioned HORRAD trial, in which patients with fewer than five bone metastases had a non-significant trend towards benefit (HR 0.68, 95% CI 0.42-1.10).
  • The incidence of symptomatic local events was comparable in both groups; urinary tract infection was the most common adverse event. Weekly RT was better tolerated. Acute bowel and bladder toxicity was lower in the weekly vs. daily RT group. Overall, RT did not appear to significantly compound toxicity from SOC. Most of the severe adverse events were attributed to anti-androgen therapy. No treatment-related deaths were reported.
  • Study authors suggest that the benefit of RT in combination with SOC can be extended to pelvic node-positive nonmetastatic disease (TanyN1M0) as an extrapolation of these results and based on previous studies that demonstrate survival benefit with RT in locally advanced (T3-4 N0 M0) prostate cancer.
  • Strengths/Limitations: The study provided a robust sample size, with pre-planned subgroup analyses. However, only 18% received upfront docetaxel with prednisone which is now standard of care treatment (though its role in low-volume metastatic disease remains controversial). Metastatic burden of disease was determined retrospectively. Median follow-up was 37 mos. and shorter than median OS. The convenient RT doses and schedules were determined by consensus and is unique to the study.
  • In summary, the clinically meaningful improvement in OS, FFS, PFS and prostate cancer-specific survival provided by local RT to the prostate in combination with SOC was observed only in the subgroup of men with de novo metastatic prostate cancer and low metastatic burden. The convenient RT schedules in the trial are appealing, given the relatively modest toxicity rates. This study provides supporting evidence on the clinical benefit of local RT in this population.  Local RT with SOC represents a new standard of care to consider with patients with metastatic prostate cancer and low disease burden. Data on long-term adverse events will emerge with longer follow-up and will be much anticipated. Future STAMPEDE studies will aim to assess the efficacy of local ablative therapy to sites of oligometastatic disease in addition to the prostate in patients with low-burden metastatic prostate cancer.

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