TACTI-002 Part A first cohort fully recruited
Immutep announced on 13 June that the initial cohort of 17 first-line non-small cell lung cancer (NSCLC) patients in Part A of the TACTI-002 study has been fully recruited, a little over three months after the first patient was dosed. The rapid recruitment suggests to us that clinicians believe there is potential for their patients to benefit from enrolling in the study.
The open-label TACTI-002 is evaluating efti plus Keytruda in up to 109 patients in three different cancer indications at up to 13 sites in Europe, the US and Australia. Treatment with efti (30mg by subcutaneous (SC) injection) starts on the same day as Keytruda, just as in TACTI-mel Part B. Immutep is conducting the study in collaboration with Merck & Co.
Patients will receive 12 months of efti/Keytruda combination therapy, followed by a further 12 months of Keytruda monotherapy (Exhibit 5). The primary endpoint will be ORR (as per irRECIST).
Exhibit 5: TACTI-002 trial design
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Source: Immutep. Note: One cycle: three weeks; q2w: every two weeks; q3w: every three weeks.
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The three patient populations targeted in TACTI-002 are:
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Part A: first-line advanced/metastatic NSCLC patients, who are PD-1/L-1 naive and have not undergone systemic therapy for advanced/metastatic disease.
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Part B: second-line advanced/metastatic NSCLC patients who have experienced treatment failure (disease progression) following treatment with any PD-1/PD-L1 regimen.
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Part C: second-line squamous cell carcinoma of the head and neck (HNSCC) patients who are PD-1/L1 naive.
The TACTI-002 study is using Simon’s two-stage design. For each of the three treatment indications, an initial cohort of 17–23 patients will be treated. For each indication, if the number of patients with tumour responses exceeds a pre-specified threshold, additional patients will be recruited to take the total to ~37 for that indication, as shown in Exhibit 6.
Exhibit 6: TACTI-002 trial design and expansion thresholds
Indication |
Initial number of patients |
Minimum number of responses for cohort expansion# |
Minimum ORR for cohort expansion |
Additional patients |
Total patients |
Keytruda monotherapy ORR |
Part A: NSCLC 1st line |
17 |
5 |
29% |
19 |
36 |
25%* |
Part B: NSCLC PD1/L1 refractory 2nd line |
23 |
2 |
9% |
13 |
36 |
N/A |
Part C: HNSCC PD1/L1 naïve 2nd line |
18 |
3 |
17% |
19 |
37 |
16-18%** |
Source: Immutep, Edison Investment Research. Note: #The TACTI-002 poster at ASCO 2019 listed the response threshold that needs to be exceeded; to aid clarity we have converted this to the minimum number of responses to be achieved; *Keynote-001 study; **Keynote-012 study.
Part A of the study, which has fully recruited the initial cohort of 17 first-line NSCLC patients, will be enlarged by a further 19 patients if at least five of the 17 patients (29%) respond to efti/Keytruda combo treatment, bringing the total Part A cohort to 36.
To put this in context, we note that the response rate to Keytruda monotherapy among 101 previously untreated NSCLC patients in the large Keynote-001 Phase I study was 25%.
Therefore it will be a positive signal if the TACTI-002 Part A cohort is expanded to the full size, because it will mean the response rate among the first 17 subjects was at least 29% and therefore was higher than that observed in a similar patient cohort in the Keynote-001 study.
Next we looked at how long we might expect it to take for the threshold of five responses to be reached in the Part A cohort. A presentation of the Keynote-001 NSCLC data at ASCO in 2014 included a swimmer plot showing the time to first response (by RECIST v1.1 criteria) in the study. The swimmer plot showed that among the 11 subjects with tumour responses, 4/11 (36%) had responded by 10 weeks, 9/11 (82%) had responded by 20 weeks and all 11 (100%) had responded by 30 weeks after the start of treatment (Exhibit 7).
This suggests that a median follow-up of 20 to 30 weeks might be needed to observe the required number of responses required to trigger cohort expansion. With the first patient having been dosed on 6 March and the 17th subject recruited on 13 June, we would anticipate the cohort expansion threshold being reached some time in Q419. We would consider it a very encouraging sign if the threshold was reached before Q419, because it would suggest that the eventual final response rate in the tranche was likely to be higher than 29%.
Exhibit 7: Time to response in a subset of first-line NSCLC patients in Keynote-001
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Source: Rizvi et al, ASCO 2014 Abstract 8007. Note: Green triangles indicate the onset of tumour response as assessed by independent central review according to RECIST 1.1. Responses were assessed every nine weeks.
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In TACTI-002 Part C, in second-line HNSCC patients who are PD-1/L1 naive, the minimum number of responses that needs to be observed to trigger expansion of the cohort is 3/18 (17%). In the Keynote-012 study of Keytruda monotherapy in second-line recurrent or metastatic HNSCC the ORR was reported as 16% (n=174) in the Keytruda prescribing information, and in a subsequent publication as 18% among 192 patients at long-term follow-up (Mehra et al 2018).
Therefore, TACTI-002 Part C needs to at least match the ORR seen with Keytruda monotherapy in second-line HNSCC to progress to recruiting the full cohort.
The swimmer plot of treatment exposure and responses in Keynote-012 showed that among the 26 subjects who achieved a partial response, 50% had responded by three months, 80% after four months and 85% had responded by six months after the start of Keytruda monotherapy treatment. Therefore, we estimate that if there is a modest 20% increase in ORR from ~18% to ~21%, it might need an average six months follow-up per subject to reach the minimum three responses needed to trigger expansion to the second stage of recruitment for this indication. A larger 50% increase in ORR to ~27% might see the threshold reached after a median follow-up of as little as three or four months.
We could not find any studies of PD1/L1 monotherapy in second-line PD1/L1 refractory NSCLC patients. The minimum response rate for cohort expansion in this patient population in Part B is a modest 9%.
The company has said first data from TACTI-002 are expected in mid-2019, but it is not clear what the nature of these data is likely to be.
INSIGHT testing new administration routes and efti combos
Professor Salah-Eddin Al-Batran, the principal investigator of the INSIGHT investigator initiated trial (NCT03252938), provided an update on the study on the key opinion leader call. INSIGHT contains four strata that are investigating efti in patients with advanced solid tumours in four different settings.
As Exhibit 8 shows, the first two strata are investigating the feasibility of administering efti as a single agent via either intratumoural (IT) injection (Stratum A) or intraperitoneal injection (Stratum B). Each patient receives an escalating dose of efti, ie if the patient tolerates injection of the first, low dose of efti, then two weeks later they will be injected with the next highest dose and so on up to 30mg. Up to nine patients were planned to be treated in each stratum.
Eight patients have already competed the core dose-escalation period for stratum A. No dose-limiting toxicities were observed, confirming the tolerability of 30mg of efti delivered by IT injection in a range of solid tumours (the types of cancers treated have not been disclosed, other than one patient with gastric cancer; see below).
Four patients have completed the core dose-escalation period for stratum B. No dose-limiting toxicities have observed to date.
Exhibit 8: Design of INSIGHT strata A and B
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Strata C and D are investigating the feasibility of combining SC efti with other drugs in patients with advanced solid tumours (Exhibit 9).
Stratum C, which will combine SC efti with standard of care chemotherapy or immune therapy, is not recruiting subjects, with completion of the other strata having priority. However, we note that the design would appear to allow efti to be added to chemotherapy/immunotherapy combinations. For example, Keytruda plus chemotherapy is approved for treating first- and second-line NSCLC patients. Adding efti to this regimen to form a triple efti/Keytruda/chemo combo would generate data in a setting where the mechanism of action of efti (antigen-presenting cell activator) suggests it has the potential to significantly increase response rates.
Stratum D, which is combining SC efti with the anti-PD-L1 drug avelumab (Bavencio, Merck KGaA/Pfizer), is being conducted in collaboration with Merck KGaA and Pfizer. Avelumab has been approved by the FDA for treating the skin cancer known as Merkel cell carcinoma, as well as advanced bladder and kidney cancer. Two patients have been enrolled since 1 June and a third is undergoing pre-enrolment screening.
The first data from avelumab combination therapy in stratum D are expected to be reported before the end of 2019.
Exhibit 9: Design of INSIGHT strata C and D
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