# Presentation: 683941

## Presented by Martin H. Cohen, M.D.at the27 July 2004meeting of the Oncologic Drugs Advisory Committee

## NDA 21-677

- Alimta®
- Pemetrexed
- LY231514

## Proposed Indication

- Alimta as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy

## Study Design

- One randomized trial comparing treatment with  Alimta to treatment with docetaxel 75 mg/2
- Stratification factors:
- P.S.; Disease stage; Number of prior regimens;
- Response to last prior chemo; prior platinum; prior paclitaxel; baseline homocysteine; treatment site

## Docetaxel 2nd line

|  |  |  | Survival |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Pts | RR | Med (mo) | p
OS | 1 yr
(%) | p
1 yr |
| DOC 75 vs BSC | 55
49 | 5.5%
-- | 7.5
4.6 | 0.01 | 37
12 | <0.05
 |
| Doc 75
Vs 
IC (V/I) | 125
123 | 5.7
0.8 | 5.7
5.6 | 0.13
 | 30
20 | 0.025 |

## Alimta Administration 

- Alimta  500 mg/m2 IV infusion over 10 minutes on Day 1 of each 21-day cycle.
- Folic acid 350-1000 mcg daily
- Vitamin B12 1000 mcg every 3rd cycle
- Dexamethasone 4mg po bid days -1, 0, +1 (rash prophylaxis)

## Docetaxel Administration 

- Docetaxel  75 mg/m2 as an intravenous infusion over 60 minutes on Day 1 of each 21-day cycle.
- Dexamethasone 8 mg po bid days -1, 0, +1 (fluid retention & hypersensitivity)

## Study Conduct

- 135 Investigational sites in 23 countries
- Approximately 21% of the study population came from United States Institutions

## Selected Patient Characteristics

|  | Alimta
N=283 | Docetaxel
N=288 |
| --- | --- | --- |
| PS 0-1 | 89% | 88% |
| 1 Prior chemo regimen | 94% | 95% |
| Prior platinum | 91% | 93% |
| Prior paclitaxel | 27% | 26% |
| Homocysteine > 12 | 30% | 29% |

## Efficacy Endpoints

- Primary – Overall Survival
- Secondary
- – Response Rate and Duration
-  Time to Progression
-  Progression Free Survival
-  Symptom Burden (LCSS)

## Response Rate & Duration

|  | Alimta
N=264 | Docetaxel
N=274 |
| --- | --- | --- |
| CR (%) |  1 (0.4) | 0 |
| PR (%) | 23 (8.7) | 24 (8.8) |
| Total RR | 9.1% | 8.8% |
| 95% CI | 5.9, 13.2 | 5.7,12.8 |
| Resp Dur (median) | 4.6 mo | 5.3 mo |

## Time to Progression

|  | ITT |  | RT |  |
| --- | --- | --- | --- | --- |
|  | Alimta
N=283 | Doc
N=288 | Alimta n=265 | Doc
N=276 |
| Median (mo) | 3.4 | 3.1 | 3.1 | 3.5 |
| % censored | 25 | 28 | 20 | 25 |

## Post-study chemotherapy

|  | Alimta
N=265 | Docetaxel
N=276 |
| --- | --- | --- |
| Any drug | 126 (48%) | 107 (39%) |
|    Docetaxel | 85 (32%) | 11 (4%) |
|    Gemcitabine | 17 (6%) | 32 (12%) |
|    Vinorelbine | 6 (2%) | 25 (9%) |
|    Gefitinib | 5 (2%) | 21 (8%) |

## Post-study chemotherapy & Survival 

|  | Alimta
N=265 |  | Docetaxel
N=276 |  |
| --- | --- | --- | --- | --- |
|  | N | MS  | N | MS  |
| No P-S chemotherapy | 139 | 6.2 mo | 169 | 5.0 mo |
| Post-study docetaxel | 85 | 9.6 mo | 11 | 10.1 mo |
| Other chemotherapy | 41 | 10.6 mo | 96 | 11.2 mo |

## No post-study chemo. Last PS

| 
Last PS | Alimta
N=139 | Docetaxel
N=169 |
| --- | --- | --- |
| 0 or 1 | 108 (78%) | 123 (73%) |
| 2 | 28 (20%) | 37 (22%) |
| 3 or 4 | 1   (1%) | 7   (4%) |
| Unknown | 2   (1%) | 2   (1%) |

## Post-study chemotherapy & Survival 

|  | Alimta
N=265 |  | Docetaxel
N=276 |  |
| --- | --- | --- | --- | --- |
|  | N | MS  | N | MS  |
| No P-S chemotherapy | 139 | 6.2 mo | 169 | 5.0 mo |
| Post-study docetaxel | 85 | 9.6 mo | 11 | 10.1 mo |
| Other chemotherapy | 41 | 10.6 mo | 96 | 11.2 mo |

## Patient Exposure

|  | Alimta
N=265 | Docetaxel
N=276 |
| --- | --- | --- |
| Median No. of cycles | 4 | 4 |
| % of planned dose intensity | 96.6 | 94.4 |

## All Toxicities Regardless of Causality Percent of Patients

| Toxicity | Alimta
N=265  | Docetaxel
N=276 | p-value |
| --- | --- | --- | --- |
| Grade 1 | 97.4 | 94.6 | 0.128 |
| Grade 2 | 96.6 | 96.7 | 1.0 |
| Grade 3 | 66.4 | 76.8 | 0.008 |
| Grade 4 | 18.1 | 49.2 | 0.000 |
| Grade 3 or 4 | 69.0 | 84.1 | 0.000 |

## CTC Grade 3 or 4 Neutropenia*

|  | Alimta
N=265 | Docetaxel
N=276 |
| --- | --- | --- |
| Febrile neutropenia* | 5 (2) | 35 (13) |
| Infection with neutropenia | 0 (0) | 16 (5.8) |
| 
* Uncorrected p value <0.001 |  |  |

## All Toxicities Regardless of Causality Excluding WBC Events*

| Toxicity | Alimta
N=265 | Docetaxel
N=276 | p-value |
| --- | --- | --- | --- |
| Grade 1 | 95.5 | 92.0 |   0.112 |
| Grade 2 | 95.1 | 95.3 |        >0.999 |
| Grade 3 | 63.8 | 65.2 | 0.788 |
| Grade 4 | 16.6 | 21.7 | 0.156 |
| Grade 3 or 4 | 67.9 | 69.2 | 0.781 |

- * febrile neutropenia, leukocytes, lymphopenia, neutrophils/ granulocytes, infection with grade 3 or  4 neutropenia, infection/febrile neutropenia,  other

## CTC Grade 3 or 4 AE’s  

|  | Alimta (%) | Docetaxel (%) | p-value |
| --- | --- | --- | --- |
| Alopecia | 0.4 | 3.0 | 0.04 |
| Diarrhea | 0.4 | 4.0 | 0.01 |
| Fatigue | 15.8 | 16.7 | 0.817 |
| Nausea | 3.8 | 2.5 | 0.466 |
| Vomiting | 1.5 | 1.4 | 1.0 |
| Stomatitis | 1.1 | 1.1 | 1.0 |
| Pulmonary | 6.8 | 9.8 | 0.217 |
| Neurosensory* | 7.5 | 9.8 | 0.365 |
| * Grade 2-4 |  |  |  |

## Selected TEAEs – All grades*

|  | Alimta | Docetaxel |
| --- | --- | --- |
| Nausea | 98 (37%) | 59 (21%) |
| Weight loss | 76 (29) | 44 (16) |
| ALT increased | 23 (9) | 6 (2) |
| AST increase | 20 (8) | 3 (1) |
| Ccr decreased | 12 (5) | 1 (0.4) |
| Alopecia | 19 (7) | 108 (39) |
| * Selection based on an uncorrected p value <  0.001
 |  |  |

## Selected TEAEs –All Grades*

|  | Alimta | Docetaxel |
| --- | --- | --- |
| Myalgias | 23 (9) | 42 (15) |
| Arthralgias | 19(7) | 36 (13) |
| Neurotoxicity | 2 (1) | 10 (4) |
| Diarrhea | 60 (23) | 91 (33) |
| Constipation | 58 (22) | 34 (12) |
| Fatigue | 133 (50) | 115 (42) |
| Rash | 37 (14) | 19 (7) |
| * Selection based on an uncorrected p value <0.05
 |  |  |

## Hospitalizations

|  | Alimta
N=265 | Docetaxel
N=276 |
| --- | --- | --- |
| Admissions | 337 | 364 |
| Days | 1722 | 1410 |

## Efficacy Conclusions

- Post-study chemotherapy confounds survival results
- 	- 85 (32%) of Alimta pts received post-study docetaxel
-    - Patients who did not receive post-study chemotherapy had shorter survival
- 	- 30 more docetaxel treated patients received no post-study chemotherapy compared to Alimta treated patients.
-    - Majority of untreated P-S patients had PS 0-1
- Response rates were 9.1% (A) and 8.8% (D)

## Safety Conclusions

- Toxicity spectrum of Docetaxel and Alimta differ.
-   - Docetaxel produces more neutropenia and neutropenic complications (febrile neutropenia, infections, G-CSF use)
-      neurotoxicity, myalgias, alopecia and diarrhea
-   - Alimta produces more thrombocytopenia, skin rash, fatigue, nausea and vomiting, ALT and AST increase, decreased CCr, and weight loss.
- Folic acid and Vitamin B12 supplements are known to decrease Alimta toxicity. Whether they would also decrease docetaxel toxicity is unknown.