Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial

Abstract

Background: About 25% of pancreatic cancers harbour actionable molecular alterations, defined as molecular alterations for which there is clinical or strong preclinical evidence of a predictive benefit from a specific therapy. The Know Your Tumor (KYT) programme includes US patients with pancreatic cancer and enables patients to undergo commercially available multi-omic profiling to provide molecularly tailored therapy options and clinical trial recommendations. We sought to determine whether patients with pancreatic cancer whose tumours harboured such actionable molecular alterations and who received molecularly matched therapy had a longer median overall survival than similar patients who did not receive molecularly matched therapy.

Methods: In this retrospective analysis, treatment history and longitudinal survival outcomes were analysed in patients aged 18 years or older with biopsy-confirmed pancreatic cancer of any stage, enrolled in the KYT programme and who received molecular testing results. Since the timing of KYT enrolment varied for each patient, the primary outcome measurement of median overall survival was calculated from the initial diagnosis of advanced disease until death. We compared median overall survival in patients with actionable mutations who were treated with a matched therapy versus those who were not treated with a matched therapy.

Findings: Of 1856 patients with pancreatic cancer who were referred to the KYT programme between June 16, 2014, and March 31, 2019, 1082 (58%) patients received personalised reports based on their molecular testing results. Actionable molecular alterations were identified in 282 (26%) of 1082 samples. Among 677 patients for whom outcomes were available, 189 had actionable molecular alterations. With a median follow-up of 383 days (IQR 214-588), those patients with actionable molecular alterations who received a matched therapy (n=46) had significantly longer median overall survival than did those patients who only received unmatched therapies (n=143; 2·58 years [95% CI 2·39 to not reached] vs 1·51 years [1·33-1·87]; hazard ratio 0·42 [95% CI 0·26-0·68], p=0·0004). The 46 patients who received a matched therapy also had significantly longer overall survival than the 488 patients who did not have an actionable molecular alteration (2·58 years [95% CI 2·39 to not reached] vs 1·32 years [1·25-1·47]; HR 0·34 [95% CI 0·22-0·53], p<0·0001). However, median overall survival did not differ between the patients who received unmatched therapy and those without an actionable molecular alteration (HR 0·82 [95% CI 0·64-1·04], p=0·10).

Interpretation: These real-world outcomes suggest that the adoption of precision medicine can have a substantial effect on survival in patients with pancreatic cancer, and that molecularly guided treatments targeting oncogenic drivers and the DNA damage response and repair pathway warrant further prospective evaluation.

Funding: Pancreatic Cancer Action Network and Perthera.

Figure 1.

Operational summary of the Know Your Tumor programme

Figure 2.

Overall survival. HR=hazard ratio.

Figure 3.

Overall survival (A) starting from the initiation of second-line therapy and progression-free survival (B) for the best therapy received in the second-line setting or later Progression-free survival analyses included only one line of therapy per patient, with the best outcome represented. If a patient rapidly progressed on their second line of therapy but had a more durable response while on their third line of therapy, progression-free survival for the third line of therapy is presented for that patient. HR=hazard ratio. *Progression-free survival data for the matched line of therapy are unavailable for one patient who received a molecularly matched therapy in an earlier treatment setting.

Figure 4.

Actionable alterations alongside progression-free survival for molecularly matched and unmatched therapies given as second-line therapy (A) or as later lines of therapy (B) Swimmer plot highlighting examples of specific regimens documented in patients with actionable alterations. Reasons for discontinuing therapy are shown in the key. This figure provides examples of actual therapies that were selected in patients with actionable mutations. All 38 patients who received a matched therapy in the second line or later are represented here. All patients who only received unmatched therapies in second line and later after receipt of the Perthera report are represented here. Patients were represented only once in either part A or B, with the exception of five patients. CAPEOX=capecitabine and oxaliplatin. FOLFIRI=flurouracil and irinotecan. FOLFIRINOX=fluorouracil, irinotecan, and oxaliplatin. FOLFOX=fluorouracil and oxaliplatin. IMRT=intensity-modulated radiotherapy. MSI-H=high microsatellite instability. nab=nanoparticle albumin-bound. *Five patients represented in both parts A and B. †Only one line of therapy per patient is represented, with the best outcome represented. If a patient rapidly progressed on their third line of therapy but had a more durable response while on their fourth line of therapy, progression-free survival for the fourth line of therapy was presented for that patient in the swimmers plot instead (for both the matched and unmatched groups).

Figure 4.

Actionable alterations alongside progression-free survival for molecularly matched and unmatched therapies given as second-line therapy (A) or as later lines of therapy (B) Swimmer plot highlighting examples of specific regimens documented in patients with actionable alterations. Reasons for discontinuing therapy are shown in the key. This figure provides examples of actual therapies that were selected in patients with actionable mutations. All 38 patients who received a matched therapy in the second line or later are represented here. All patients who only received unmatched therapies in second line and later after receipt of the Perthera report are represented here. Patients were represented only once in either part A or B, with the exception of five patients. CAPEOX=capecitabine and oxaliplatin. FOLFIRI=flurouracil and irinotecan. FOLFIRINOX=fluorouracil, irinotecan, and oxaliplatin. FOLFOX=fluorouracil and oxaliplatin. IMRT=intensity-modulated radiotherapy. MSI-H=high microsatellite instability. nab=nanoparticle albumin-bound. *Five patients represented in both parts A and B. †Only one line of therapy per patient is represented, with the best outcome represented. If a patient rapidly progressed on their third line of therapy but had a more durable response while on their fourth line of therapy, progression-free survival for the fourth line of therapy was presented for that patient in the swimmers plot instead (for both the matched and unmatched groups).