02/03/2019: Articles Summaries - GI & Lung Cancers

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 GI CANCERS LUNG CANCERS

Summary

GI CANCERS
 

 

Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial

Yang, H et al. J Clin Oncol 36:2796-2803

 

Introduction:

 

Esophageal cancer is prevalent in China, accounting for >50% of morbidity and mortality worldwide. Although recent data on neoadjuvant chemoradiotherapy (NCRT) followed by surgery in esophageal cancer demonstrated survival benefit, results from previous clinical trials are inconclusive. To determine the efficacy and safety of this treatment strategy in a large Chinese population with a high prevalence of esophageal squamous cell carcinoma (ESCC), researchers conducted the NEOCRTEC5010 study.

 

Methods:

 

  • Patients: histologically proven ESCC, potentially resectable, stage T1-4N1M0/T4N0M0 (stage IIB or III) before treatment, no previous treatment for advanced disease

 

  • Study design: phase III open-label RCT

 

  • Intervention

            Experimental: NCRT + surgery

            Control: Surgery alone

            NCRT: vinorelbine 25 mg/m2 day 1,8 + cisplatin 75 mg/m2 day 1 or 25 mg/m2

                                     day 1-4 every 21 days for 2 cycles + 40 Gy RT in 20 fractions

            Surgery: McKeown or Ivor Lewis esophagectomy, 2 field lymphadenectomy,

                           total mediastinal lymph node dissection, left and right recurrent

                           laryngeal nerve dissection

 

  • Endpoints

            Primary: overall survival (OS)

            Secondary: disease-free survival (DFS), rate of R0 resection, pathologic

                                response, safety

 

Results:

 

  • 451 patients randomized to NCRT + surgery (n=224) vs. surgery alone (=227)

 

Table 1. Baseline patient characteristics (selected)

 

Characteristic

ITT population

Median age – yrs.

57

Male - %

81

BMI - kg/m2

22

KPS 90 - %

99

Middle third location - %

70

Clinical T stage cT3

60

N1- %

81

Clinical stage III - %

83

 

Table 2. Efficacy Outcomes

 

Outcome

NCRT+ S

Surgery

HR (95% CI)

p value

OS – mos.

100.1

66.5

0.71 (0.53-0.96)

0.025

1 yr. OS - %

90

86.2

-

-

2 yr. OS - %

75.1

72.5

-

-

3 yr. OS - %

69.1

58.9

-

-

DFS (R0 resection) - %

100.1

41.7

0.58 (0.43 -0.78)

<0.001

R0 resection - %

98.4

91.2

-

0.002

Lymph nodes dissected - n

20

26

-

<0.001

Positive lymph nodes - %

33.2

64.8

-

<0.001

Downstage (III) - %

10.8

62.6

-

<0.001

PCR - %

43.2

0

-

 

PCR – pathologic complete response

 

      Safety

 

Table 3. Treatment summary and adverse events during NCRT (selected)

 

 

NCRT

Completed 2 cycles - %

87.1

Completed 40Gy RT - %

99

Completed NCRT + surgery - %

82.6

Grade 3-4 hematologic toxicity - %

54.3

Grade 3-4 nonhematologic toxicity - %

7.2

Any grade leukopenia - %

80.7

Grade 3 leukopenia - %

31.8

Grade 4 leukopenia - %

17

Any grade neutropenia - %

74

Grade 3 neutropenia - %

23.3

Grade 4 neutropenia - %

22.4

Any grade anemia - %

56.5

Any grade thrombocytopenia - %

39.9

Grade 3 thrombocytopenia - %

4.5

Grade 4 thrombocytopenia - %

2.7

Any grade vomiting - %

56.5

Any grade anorexia - %

56.1

Any grade radiation esophagitis - %

37.7

Grade 3 radiation esophagitis - %

2.7

 

  • Postoperative complications did not differ significantly between groups except for arrhythmia (p=0.001).

 

Table 4. Postoperative complications (most common, not significant)

 

Complication (%)

NCRT + S

Surgery

Arrhythmia*

13

4

Pulmonary infection

10.8

14.5

Anastomotic leakage

8.6

12.3

Pneumothorax

4.9

2.6

Recurrent nerve injury

3.2

3.6

Chylothorax

2.7

3.1

Peritreatment mortality

2.2

0.4

90-day mortality

0.5

0.9

* significantly different between groups

 

Discussion:

 

  • Compared with surgery, NCRT followed by surgery significantly improved OS by 29% and DFS by 42% in patients with locally advanced ESCC. The high rate of R0 resection in the NCRT group is reflective of better tumor response with this strategy vs. surgery alone.

 

  • Significant improvement in the number of lymph nodes dissected and tumor downstaging was associated with NCRT followed by surgery, thereby demonstrating clinically significant reduction in tumor burden and lymph node metastases. Furthermore, the number of positive lymph nodes with NCRT was half of that resected after surgery alone. The pathologic CR (pCR) rate was 43% with NCRT, consistent with previous literature.

 

  • Postop complications including 90-day mortality did not significantly differ between groups. Although NCRT was associated with high grade hematologic toxicity in half of the patients, majority (82%) completed NCRT and 99% received the full RT dose. Combination therapy did not appear to significantly increase toxicity.

 

  • In the phase III CROSS trial, patients with locally advanced esophageal or gastroesophageal junction carcinoma were randomized to NCRT with surgery vs. surgery alone (Lancet Oncol 16:1090-1098, 2015). At a median follow-up of 5 yrs., NCRT with surgery significantly doubled OS (48.6 vs. 24 mos., HR 0.68; p=0.003) in the ITT population. In the ESCC subgroup (81.6 v. 21.1 mos., HR 0.48; p=0.008), survival was likewise superior with NCRT followed by surgery. However, the ESCC subgroup was small (n=84, 23%), R0 resection rate (69%) and 5-yr. OS of 28% for surgery alone (ESCC subgroup) were suboptimal compared to results from the NEOCRTEC5010 study.

 

  • Two cisplatin regimens, including a 4-day treatment schedule that did not require aggressive hydration and was suitable for outpatient administration were used in the trial. The study population was highly selected. The study included Chinese patients who have a high prevalence of ESCC, majority had good performance status, N1 disease and clinical stage III. Surgery was also extensive, with total mediastinal lymph node and bilateral recurrent laryngeal nerve dissection that may have contributed to better survival outcomes.

 

  • In summary, NCRT followed by surgery provided clinically meaningful improvement in pCR rate and tumor downstaging that translated into a clinically and statistically significant survival advantage over surgery alone in a Chinese population with locally advanced ESCC. 

More GI Cancer Updates

 

LUNG CANCERS
 

Final Overall Survival Analysis From a Study Comparing First-Line Crizotinib Versus Chemotherapy in ALK-Mutation-Positive Non–Small-Cell Lung Cancer

Solomon, B et al. J Clin Oncol 36. DOI: https://doi.org/10.1200/JCO.2017.77.4794

 

Introduction:

 

In patients with ALK-positive NSCLC, crizotinib showed good clinical efficacy, with significant improvement in PFS (10.9 vs. 7 mos., HR 0.45 [0.35-50]; p < 0.001) and 1-yr. OS (84 vs. 79%) compared to chemotherapy (N Engl J Med 371:2167-2177, 2014).  Preliminary results from the PROFILE 1014 trial that compared crizotinib with platinum/pemetrexed revealed superior response rates and PFS as first line therapy in advanced ALK-positive NSCLC (N Engl J Med 371:2167-2177, 2014). This summary reports final OS and safety analysis of PROFILE 1014 trial.

 

Methods:

 

  • Patients: advanced NSCLC, positive for ALK rearrangement, no prior treatment for advanced disease, treated brain metastases (BM) stable for ≥ 2 wks., prior to enrollment and no ongoing corticosteroid requirement

 

  • Study design: open-label, phase III RCT

 

  • Intervention

Experimental: Crizotinib 250 mg PO BID

Control: Pemetrexed 500 mg/m2 + Cisplatin 75 mg/m2 or Carboplatin AUC 5 q3w 

              x 6 cycles

 

  • Outcomes

Primary: PFS

            Secondary: OS, ORR, safety, patient-reported outcomes

 

Results:

 

  • 343 patients randomized to crizotinib (n=172) vs. chemo (n=171)

 

  • All patients permanently discontinued treatment at the time of final analysis mostly due to study completion (crizotinib – 47.1% vs. chemo = 40.4%)

 

Table 1. Efficacy Outcomes

 

 

Crizotinib

Chemo

HR (95% CI)

P value

OS - mos.

NR

47.5

0.760 (0.548-1.053)

0.0978

1-yr. OS - %

83.5

78.4

-

-

18-mo. OS - %

71.5

66.6

-

-

4-yr. OS - %

56.6

49.1

-

-

Without brain mets at baseline (n=127 vs. 124)

OS - mos.

NR

43.7

0.672 (0.457-0.987)

0.0413

With brain mets at baseline (n=45 vs. 47)

OS –mos.

23.5

49.5

1.285 (0.716-2.306)

0.3991

Adjusted for crossover

OS– mos.

59.8

19.2

0.346 (0.081-0.718)*

-

*RPSFTM - rank-preserving structural failure time model analysis to adjust for crossover

 

Table 2. Poststudy treatment

 

 

Crizotinib

Chemo

Received at least 1 treatment - %

53.5

86.5

Crossed over to crizotinib - %

-

84.2

ALK TKI - %

23.8

0.6

Other than ALK TKI - %

32

1.8

 

     Safety

 

  • Most common AEs with crizotinib: vision disorder (73%), diarrhea (66%), nausea (59%)

 

  • Most common AEs with chemo: nausea (58%), fatigue (39%), vomiting (36%)

 

Table 3. Treatment summary

 

 

Crizotinib

Chemo

At least 1 dose reduction - %

39.8

12.4

Duration of treatment – mos.

14.7

10.9

 

  • Most common grade 3-4 AEs with crizotinib: neutropenia (15%), elevated transaminases (14%), pulmonary embolism (8%)

 

  • Most common grade 3-4 AEs with chemo: neutropenia (15%), anemia (10%), pulmonary embolism (7%), thrombocytopenia (7%).

 

Discussion:

 

  • Final OS analysis of the PROFILE 1014 study at a median follow-up of 45 mos. revealed no OS advantage with the use of first line crizotinib over platinum-based chemotherapy in advanced ALK-positive NSCLC. After adjusting for a high crossover rate from the chemotherapy arm (84.2%), an OS benefit emerged in favor of crizotinib, corresponding to a 66% reduction in the risk of death.

 

  • The PFS advantage that was initially observed with crizotinib at interim analysis (10.9 vs. 7 mos., HR 0.45; p<0.001) did not extend to overall survival (N Engl J Med 371:2167-2177, 2014). This is quite commonly seen with TKIs largely due to crossover of patients in the chemotherapy arm to the TKI group. Even more recent results from the ALEX study that compared alectinib vs. crizotinib demonstrated PFS benefit in the first line setting no OS benefit was reported at interim analysis although that data is still maturing (N Engl J Med 377:829-838, 2017).

 

  •  Long-term follow up revealed no new safety signals. Adverse events were consistent with previous literature. Patients on crizotinib had longer treatment duration than those on chemotherapy. At least 40% of the study population completed treatment per study protocol.

 

  • The median OS of was 4 years in the chemotherapy arm and not yet reported in the crizotinib arm. 

More Lung Cancer Updates