Best of Oncology Weekly - Lung Cancer and Hematology Journal Article Summaries

December 2nd, 2018
 
Please enjoy this edition of our Best of Oncology Weekly newsletter, featuring key journal article summaries in lung cancer and hematology. These articles were selected, prepared, and reviewed by our expert faculty members.
Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC
Antonia SJ et al., N Engl J Med. 2018 Sep 25. 
PubMed ID: 30280658

Impact: Durvalumab after chemo/radiation significantly improved overall survival, with the median OS not reached in the durvalumab with an 11 percent improvement at 2 years. Read more...

More Lung Cancer Updates
Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma
Morschhauser F et al., N Engl J Med. 2018 Sep 6.
PubMed ID: 30184451

Impact: The RELEVANCE trial revealed similar efficacy with rituximab-lenalidomide followed by maintenance rituximab and rituximab-chemotherapy followed by maintenance rituximab as first line treatment in advanced follicular lymphoma. This combination is an alternative treatment regimen in this subgroup of patients. 
Read more...

More Hematology Cancer Updates
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Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC

Antonia, SJ et al. N Engl J Med Sept. 2018 DOI: 10.1056/NEJMoa1809697

 

 

Introduction:

 

Chemoradiotherapy is standard of care treatment in locally advanced, unresectable stage III NSCLC. However, disease progression occurs in most cases despite treatment. The PACIFIC trial investigated the efficacy of adding durvalumab after chemoradiotherapy (CRT) in stage III NSCLC patients without disease progression after induction therapy (N Engl J Med 2017;377:1919-29). Compared with placebo, durvalumab significantly improved PFS by 11.2 mos. and reduced the risk of disease progression or death by 48%. Updated results for this study are summarized below.

 

Methods:

 

  • Patients: cytologically or histologically proven locally advance or unresectable stage III NSCLC, received at least 2 previous cycles of platinum-based chemotherapy or concurrently with RT (mean dose to lung <20Gy, V20 <35% or both), no disease progression after treatment, PS 0-1

 

  • Study design: phase III, double blind RCT

 

  • Intervention

            Experimental: Durvalumab 10 mg/kg IVq2w up to 12 mos.

            Control: Placebo

            * All patients received previous chemo/CRT without disease progression.

 

  • Endpoints

            Primary: PFS, OS

            Secondary: PFS at 12 and 18 mos., ORR, DOR, time to death or distant

                              metastasis (TDDM), 12-mo. OS, safety, HRQOL

 

Results:

 

  • 713 randomised 2:1 to durvalumab (n=476) vs. placebo (n=237)

 

  • Baseline patient characteristics: median age 64 yrs., 70% male, 69% white, 53% stage IIIA, 51% PS 1, 54% nonsquamous, 75% former smokers, 92% previous RT (≥54 to ≤66 Gy), 99.7% concurrent CRT, 48% partial response from CRT, 22% with PD-L1 expression ≥25%, 41% with PD-L1 expression < 25%, 37% unknown PD-L1 status, 6% with EGFR mutation, 67% EGFR negative or wild-type, 55% cisplatin-based chemotherapy (cis-etop 21%)

 

Table 1. Treatment summary

 

 

Durvalumab

Placebo

Median infusions - n

20

14

Median duration of treatment – wks.

40.1

28

Subsequent anticancer therapy - %

41

54

        Chemotherapy

26.9

30   

        Immunotherapy

8

22.4

Subsequent RT - %

17.2

23.6

 

 

Table 2. Efficacy Outcomes

 

Outcomes

Durvalumab

Placebo

HR (95% CI)

P value

OS– mos.

NR

28.7

0.68 (0.47-0.99)

0.0025

12-mo OS– %

83.1

75.3

-

-

24-mo. OS – %

66.3

55.6

-

0.005

PFS – mos.

17.2

5.6

0.51 (0.41-0.63)

-

12-mo OS– %

55.7

34.4

-

-

18-mo. OS – %

49.5

26.7

-

-

TDDM – mos.

28.3

16.2

0.53 (0.41-0.68)

-

Freq. of new lesions - %

22.5

33.8

-

-

     lung

12.6

18.6

-

-

New brain mets - %

6.3

11.8

-

-

Time to 2nd progression/death – mos.

28.3

17.1

0.58 (0.46-0.73)

-

Time to 1st subsequent treatment/death – mos.

21

10.4

0.58 (0.47-0.72)

-

Time to 2nd subsequent treatment/death – mos.

29.3

18.6

0.63 (0.50-0.79)

-

ORR - %

30

17.8

-

<0.001

DOR – mos.

NR

18.4

-

-

NR – not reached

 

 

      Safety

 

  • Most common cause of treatment discontinuation: pneumonitis (4.8% vs. 2.6%), radiation pneumonitis (1.3% each), pneumonia (1.1% vs. 1.3%)

 

Table 3. Adverse events and treatment summary

 

Adverse event

Durvalumab

Placebo

Any grade AE - %

96.8

94.9

Grade 3 or 4 AE - %

30.5

26.1

Discontinuation due to AE - %

15.4

9.8

Serious AE - %

29.1

23.1

Death due to AE - %

4.4

6.4

Any grade AE (special interest) - %

66.7

49.1

Any grade hypothyroidism - %

11.6

1.7

Grade 3-4 pneumonia - %

4.4

3.8

Grade 3-4 anemia - %

2.9

3.4

 

Discussion:

 

  • Durvalumab after chemo/radiation significantly improved overall survival, with the median OS not reached in the durvalumab with an 11 percent improvement at 2 years.

 

  • Updated analysis of the PACIFIC trial at a median follow-up of 25.2 mos. revealed sustained treatment benefit with durvalumab compared to placebo in patients with stage III NSCLC without disease progression after CRT. PFS advantage that was observed at interim analysis translated to OS benefit, corresponding to 32% reduction in the risk of death and was consistent across all  prespecified subgroups.

 

  • Results for PFS, time to death or distant metastases, tumor response, frequency of new lesions and new brain metastases were consistent with previous results, thereby demonstrating durable treatment response with durvalumab consolidation. Durvalumab delayed second disease progression or death by 11.2 mos. and time to first subsequent treatment or death by 10.6 mos.

 

  • The safety profile of durvalumab in PACIFIC trial was similar to previous literature. Although durvalumab was associated with slightly higher rates of high grade and serious adverse events as well as treatment discontinuation, treatment-related deaths were comparable in both groups.

 

  • Posthoc analysis of survival outcomes by PD-L1 tumor expression yielded inconclusive results due to small sample size and wide confidence intervals. Only 63% had PD-L1 evaluable tumor samples in this study.

 

  • Updated results from the PACIFIC trial provide further evidence on the efficacy of durvalumab as consolidation therapy in locally advanced, unresectable stage III NSCLC after CRT, thereby confirming previous FDA approval for this indication.

 

More Lung Cancer Updates

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma

Morschhauser F at al. N Engl J Med 2018;379:934-47.

 

Introduction:

 

In advanced follicular lymphoma, rituximab with chemotherapy followed by maintenance rituximab has improved median progression-free survival (PFS) to around 6-10 yrs., with 90% 3-yr. overall survival (OS) rate. However, chemotherapy is associated with significant myelosuppression, cardiac toxicity and secondary malignancy, among others. Preclinical studies revealed that the combination of lenalidomide, an immunomodulatory agent with rituximab heightens apoptosis and antibody-dependent cell-mediated cytotoxicity of B-cell non-Hodgkin’s lymphoma cells. Based on promising findings from phase II trials, researchers investigated the efficacy and safety of first line rituximab with lenalidomide vs. standard of care treatment both followed by maintenance rituximab in advanced follicular lymphoma.

 

Methods:

 

  • Patients: histologically confirmed, CD20-positive follicular lymphoma (grade 1 to 3a), needed treatment based on Groupe d’Étude des Lymphomes Folliculaires (GELF) criteria, treatment-naive

 

  • Trial design: phase III, open-label trial

 

  • Intervention:

Experimental: [RL] Rituximab + lenalidomide followed by maintenance rituximab

Control: [RC] Rituximab + chemotherapy (R-CHOP, R-CVP or rituximab-bendamustine) followed by maintenance rituximab

 

  • Endpoints:

Primary: PFS, complete response (CR) at 120 wks. (confirmed or unconfirmed)

Secondary: OS, duration of response (DOR), safety

 

Results:

 

  • Interim analysis at a median follow-up of 37.9 mos. revealed comparable results. CR at 120 wks. was 48% for RL vs. 53% for RC (p=0.13), with an overall response rate of 61% vs. 65%, respectively as assessed by an independent review committee (IRC). Best overall response by IRC was 84% vs. 89%, respectively. Similar results were obtained for survival outcomes. 3-yr. PFS was 77% vs. 78% (HR 1.10 [0.85-1.43]; p=0.48) and 94% were alive (OS) at 3 yrs. in both groups [HR 1.16 [0.72-1.86]).

 

  • Subgroup analysis revealed treatment benefit for PFS and CR at 120 wks. in favor of RL regardless of prognostic factors. In the RC group, patients with low risk disease by Follicular Lymphoma International Prognostic Index (FLIPI) score and Anne Arbor stage I and II derived the greatest benefit.

 

  • Histologic transformation (posthoc analysis) occurred soon after randomization. In the RL group, transformation occurred in 5 out 10 patients within 28 wks. after randomization and all 10 patients had transformation at 120 wks. In the RC group, transformation did not occur in any of the 7 patients at 28 wks.; 6 out of 7 patients had transformation at 120 wks.

 

  • Any grade adverse events that were more frequent in the RC group included anemia (89% vs. 66%), fatigue (29% vs. 23%), nausea (42% vs. 20%), vomiting (19% vs. 7%). Any grade cutaneous reactions (43% vs. 24%), diarrhea (37% vs. 19%), rash (29% vs. 8%)and abdominal pain (15% vs. 9%) were more commonly observed in the RL group.

 

  • Grade 3-4 adverse events occurred in 65% (RL) and 68% (RC). Neutropenia was the most grade 3-4 event, occurring more frequently in the RC group (50% vs. 32%). Grade 4 neutropenia was almost 4x more frequently reported in the RC group vs. RL group (31% vs. 8%). Similarly, the rates of infections were higher with RC (any grade: 12% vs. 5%, grade 3-4: 4% vs. 2%) despite more antibiotic use and growth factor support (68% vs. 23%) in the RC group. Treatment-related deaths occurred in 1% in both groups. Secondary malignancies were observed in 7% (RL) vs. 10% (RC).

 

  • In summary, the RELEVANCE trial revealed similar efficacy with rituximab-lenalidomide followed by maintenance rituximab and rituximab-chemotherapy followed by maintenance rituximab as first line treatment in advanced follicular lymphoma. This combination is an alternative treatment regimen in this subgroup of patients. 

More Hematology Updates

 

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