# Presentation: 790859

## Past FDA Approvals in Colorectal Cancer

- Amna Ibrahim M.D
- DODP, FDA

**Notes:**
In this presentation I will review past FDA approval of new drug applications for the treatment of colorectal cancer. 

## Outline of Presentation

- Drugs approved for colon cancer (adjuvant, first-line and second-line therapy)
- Studies supporting drug approval
- Drugs discussed at ODAC without subsequent drug approval
- Endpoints supporting approval

**Notes:**
The following are the topics I will discuss in this presentation:
Chemotherapy agents approved for adjuvant, first-line and recurrent therapy and the endpoints used for them will be presented. 
I will review briefly the major trials that led to drug approval, first for drugs for adjuvant therapy and then for first-line and second line therapy. 
I will also briefly discuss two applications for first-line treatment of colorectal cancer presented to ODAC,  but which were not approved:  UFT and then the oxaliplatin NDA in 2000.
Finally, I will conclude with the endpoints that have supported approval of drugs for colorectal cancer in these three 3 treatment settings.

## Agents Approved

| Adjuvant | First-Line | Recurrent |
| --- | --- | --- |
| -Levamisole
(with 5FU)
1990 | -Leucovorin
(with 5FU)
1991 | -Irinotecan
1996,1998
 |
|  | -Irinotecan
(with 5FU/LV)
2000 | -Oxaliplatin
(with 5FU/LV)
2002 |
|  | -Capecitabine
2001 |  |

**Notes:**
The approved agents in the table are listed according to the treatment setting- with the drugs for adjuvant use in the left column, for first-line use in the middle column and those for recurrent cancer in the column on the right. I will present them to you in chronological order.. 
5FU was the first drug approved for colon cancer in 1962. We will not discuss this further since 5FU approval predated the era of controlled clinical trials in oncology. After a long gap, levamisole was approved in combination with 5-FU in 1990 for adjuvant use. 
Although reports in literature have been described results supporting the use of FU/LV for adjuvant therapy, the FDA has not received an NDA submission supporting  this indication. Leucovorin was approved in 1991 in combination with 5FU for first-line therapy. 
Irinotecan initially received accelerated approval for recurrent colorectal cancer in 1996 followed by a full approval for the same indication. Subsequently, in 2000, it was approved for first-line use. 
Capecitabine is the only agent approved for first-line setting based on non-inferiority analyses. 
Oxaliplatin in combination with 5FU/LV received an accelerated approval for recurrent colorectal cancer.

## Historical Endpoints for Approved Agents

- OS
- TTP & RR
- Superiority
- Noninferiority

**Notes:**
As you will see, survival was the endpoint supporting all full approvals , and randomized trials demonstrating superiority led to all but one of the “full” approvals. For one drug, xeloda, non-inferiority in overall survival supported  full approval. 

Two drugs received accelerated approval in previously treated populations. One was supported by RR in single arm trials, and one by RR and TTP superiority shown in interim analysis of a randomized trial.

## Agents for Adjuvant Therapy

## Levamisole (Adjuvant Rx)

|  | Arms | N | Follow up (Yrs) | Reduction in Recurrence 
% | Reduction in Death
% |
| --- | --- | --- | --- | --- | --- |
| Study 1
Duke C Subset | 5FU+lev | 262 | 5 | 36 | 27 |
|  | lev |  |  | 28 | 28 |
|  | Observe |  |  |  |  |
| Study 2 | 5FU+lev | 929 | 2 | 41 | 33 |
|  | lev |  |  | 2 | 6 |
|  | Observe |  |  |  |  |

**Notes:**
Levamisole was approved in combination with 5FU in 1990 based on the results of two trials. After surgery, patients were randomized to no further therapy, levamisole alone or 5FU+levamisole. Levamisole plus 5FU demonstrated a reduction in death rate by about 30%. The follow up period was 2-5 years for these studies. Although the contribution of levamisole to this regimen was not demonstrated in clinical trials, this was the first adjuvant regimen to show a survival  benefit, and levamisole was approved based on these results.

## Agents for First-line Therapy

## 5FU+leucovorin (First-line Rx)

| Study | Arms | N | RR
% | TTP
mo | OS
mo | P 
(one-sided) |
| --- | --- | --- | --- | --- | --- | --- |
| 1 | 5FU | 70 | 10 | 2.9 | 7.7 |  |
|  | 5FU+LV(HD) | 69 | 26 | 6.7 | 12.2 | 0.04 |
|  | 5FU+LV(LD) | 73 | 44 | 6.7 | 12 | 0.05 |
| 2
(Study 1 ext) | 5FU+LV(HD) | 149 | 31 |  | 12.7 | 0.04 |
|  | 5FU+LV(LD) | 153 | 42 |  | 12.7 | 0.01 |
|  | 5FU+MTX+LV | 155 | 14 |  | 8.4 |  |

**Notes:**
The combination of 5FU / LV was approved for treatment of advanced disease in 1991. Study 1 is a 5-arm study, but for simplicity, only 3 arms are shown in this table. A randomized study demonstrated improvement in RR, TTP and OS of high or low dose LV combined with 5FU. 
These two arms of the study were extended along with sequential MTX/5-FU/LV arm from the same study. This is the Study 2 seen in the table. The results remained consistent with the initial study. OS was about 12.5 months in the initial as well as the extension of the study.

## Irinotecan (First-line Rx)

| Study | Arms | N | RR | TTP | OS | P 
(one-sided) |
| --- | --- | --- | --- | --- | --- | --- |
| 1 | CPT 11 
wkly x 4 (q 6 wks) | 226 | 18 | 4.2 | 12 |  |
|  | CPT11 + 5FU/LV 
wkly x 4 (q 6 wks) | 231 | 39 | 7 | 14.8 | <0.05 |
|  | 5FU/LV
qd x 5 (q 6 wks) | 226 | 21 | 4.3 | 12.6 |  |
| 2 | CPT11 + 
inf 5FU/LV | 198 | 35 | 6.7 | 17.4 | <0.05 |
|  | 5FU/LV | 187 | 22 | 4.4 | 14.1 |  |

**Notes:**
In 2000, Irinotecan was approved for first-line therapy following its initial accelerated approval for refractory colon cancer. Two randomized, multicenter trials compared infusional 5-FU/leucovorin (+) or (-) irinotecan in untreated  patients. Each trial had over 300 patients  and demonstrated an improvement in RR, TTP and overall survival. These differences in survival were observed in spite of second-line therapy in a large number of patients on both arms, including crossover to irinotecan-containing regimens in the control arm. 

## Capecitabine (First-line Rx)

| Study | Arms | N | RR 
(%) | TTP
(mo.) | OS
(mo.) | Hazard ratio |
| --- | --- | --- | --- | --- | --- | --- |
| 1 | Cap | 302 | 21 | 4.3 | 12.7 | 1.00
0.84 – 1.18 |
|  | 5FU/LV | 303 | 11 | 4.4 | 13.6 |  |
| 2 | Cap | 301 | 21 | 4.6 | 13.5 | 0.92
0.78 – 1.09 |
|  | 5FU/LV | 301 | 14 | 4.4 | 12.3 |  |

**Notes:**
Capecitabine is the only colon cancer drug approved based on a noninferiority analysis. The combined survival data from two open-label, randomized trials of capecitabine vs. 5FU/LV formed the basis of approval. Sufficient historical data existed to allow a reasonably precise estimate of the effect of 5FU/LV on survival. The non-inferiority analysis showed that at least 50% of the 5FU/LV effect was retained by capecitabine. This drug was approved for a restricted first-line indication:  quote: “for patients when treatment with flouropyrimidines therapy alone is preferred.”

## Agents for Recurrent Cancer

## Irinotecan (Recurrent)(accelerated approval)

| Study | Arms | N | RR 
(%) | TTP
(mo.) | OS
(mo.) | Med Resp Duration |
| --- | --- | --- | --- | --- | --- | --- |
| 1 | Wkly CPT 11 | 48 | 21 | 6.4 | 10.4 | 5.8 mo.
(2.6-15.2) |
| 2 | Wkly CPT 11 | 90 | 13 | 5.9 | 8.1 |  |
| 3 | Wkly CPT 11 125 mg/m2 | 64 | 14 | 5.6 | 10.7 |  |
|  | Wkly CPT 11 100 mg/m2 | 102 | 9 | 6.4 | 9.3 |  |

**Notes:**
In 1996, irinotecan was the first chemotherapy agent since 5FU to receive approval for treatment of pretreated, advanced colorectal cancer. Three single arm studies with RR ranging from 14 to 21% and response duration of 5.8 months led to its accelerated approval for second-line therapy. A survival benefit was subsequently demonstrated in two randomized trials shown in the next slide.

## Irinotecan (Recurrent)(full reg. approval)

| Study | Arms | N | OS
(mo.) | p |
| --- | --- | --- | --- | --- |
| 1 | CPT 11 | 189 | 9.2 | 0.0001 |
|  | Best Supportive Care | 90 | 6.5 |  |
| 2 | CPT 11 | 127 | 10.8 | 0.035 |
|  | 5FU-based
regimens | 129 | 8.5 |  |

**Notes:**
These randomized trials demonstrated superiority in survival by 2 - 2.5 months against Best Supportive Care and 5-FU based regimens and led to full approval in the second-line setting.  
Interestingly, these trials were not part of the original regulatory plan to convert the accelerated approval to full approval.  While the single arm trials were being reviewed by FDA, these confirmatory trials were being conducted in Europe. The initial agreement between the sponsor and FDA was that trials in the first-line setting were to provide initial proof of clinical benefit. 

## Oxaliplatin (Recurrent)(accelerated approval)

| Study | Arms | N | RR 
(%) | TTP 
(mo. 
with 95% CI) | P for RR |
| --- | --- | --- | --- | --- | --- |
| 1 | Oxaliplatin + 5FU/LV
(FOLFOX4) | 152 | 9 | 4.6 
(4.2 – 6.1) | 0.0002 |
|  | 5FU + LV | 151 | 0 | 2.7 
(1.8-3.0)  |  |
|  | Oxaliplatin | 156 | 1 | 1.6 
(1.4-2.7)  |  |

**Notes:**
Oxaliplatin in combination with 5FU/LV received accelerated approval based on improved RR and TTP shown at an interim analysis of a 3 arm, randomized trial. Patients in this trial had disease which progressed on or recurred within 6 months of treatment with the Saltz regimen. The oxaliplatin combination arm had RR of 9% vs 0-1% in the single agent oxaliplatin arm and 5FU/LV control. The TTP was increased by 2-3 months compared to the other two arms.
There were three important observations. Because this trial was randomized, TTP analysis and the small increase in the RR could be evaluated reliably. Because of the inclusion of the single agent oxaliplatin arm, the contribution of 5FU/LV to the combination regimen was shown definitively. It also demonstrated that oxaliplatin should not be used alone in the pretreated population. 
Follow up of this study did not demonstrate a survival advantage for the oxaliplatin regimen. However, as we have read in the literature and heard at ASCO, oxaliplatin is reported to provide benefits in first-line and adjuvant trials settings (although these data have not yet been reviewed by FDA)

## NDAs Discussed at ODAC but not Approved

- Issues at ODAC
- _UFT_-contribution of uracil to UFT-analysis and interpretation of non-inferiority
- _Oxaliplatin (2000)_-trials designed for RR & PFS did not demonstrate OS improvement

**Notes:**
Two NDAs were discussed at ODAC meetings, but were not approved. Some details of these applications remain confidential and cannot be presented.
As FDA discussed with ODAC, there were two main problems with the UFT application. One was that the contribution of Uracil to UFT had not been demonstrated at the time of the ODAC meeting. Regulations require that for fixed-combination drug products the contribution of each active component be shown. The other issue was that FDA had reservations about whether the non-inferiority analysis comparing UFT to 5FU/LV was adequate to demonstrate the efficacy of UFT.  The committee voted in favor of approval if the sponsor could demonstrate the contribution of uracil to UFT.
Two trials were presented to ODAC in 2000 for first-line use of oxaliplatin. Comparing oxaliplatin plus 5FU/LV to 5FU/LV alone, the studies demonstrated an increased response rate and PFS.  Neither study showed an oxaliplatin survival advantage using the protocol-specified primary analysis. FDA noted that one study seemed to demonstrate a trend towards poorer survival for the oxaliplatin 5FU/LV arm.  The committee voted no (12-0) when asked whether the analyses persuasively demonstrated a survival advantage. 

## Basis of Approval

| Adjuvant Therapy
(1 full approval) | Superiority in Survival (1) |
| --- | --- |
| First-line Therapy

(3 full approvals) | Superiority in Survival (2)

Non-inferiority in Survival (1) |
| Therapy for Recurrent Disease
(2 AA; 1 full approval) | Survival (1 full for CPT-11)
RR and/or TTP (1 AA for oxal, 1 for CPT-11) |

**Notes:**
We conclude with this slide which gives an overview of the basis of approval in colorectal cancer,
Levamisole with 5FU is the only drug approved for adjuvant therapy after demonstration of superiority in survival.
3 drugs are approved for first-line therapy and they are 5FU, Irinotecan, and capecitabine. Superiority analyses for the first two, and noninferiority for capecitabine, for survival led to their approval.
Irinotecan and oxaliplatin are the 2 drugs that have received accelerated approval  for recurrent disease based on RR and/or TTP.  For irinotecan, clinical benefit (survival) was demonstrated later in two randomized studies leading to full approval in the recurrent disease setting.   

## Slide 17

## Oxaliplatin for first-line therapy (2000)