Pertuzumab added to chemo-trastuzumab improved pCR in patients with HER2+ gastric cancer
The addition of pertuzumab to standard perioperative chemotherapy (CT) comprising FLOT* and trastuzumab led to a significant improvement in pathologic complete response (pCR) in patients with HER2+ resectable oesophagogastric adenocarcinoma – at the expense however of higher toxicity rates, results of the phase II/III PETRARCA/FLOT 6 trial have shown.
Gastric cancer is the 5th most common cancer diagnosis globally, with >1 million new cases in 2018. It is the 3rd most common reason for cancer-related death. [CA Cancer J Clin 2018;68:394-424]
Since the publication of the ToGA** trial, trastuzumab has been used in combination with CT to treat stage IV HER2-amplified gastric cancer, said discussant Dr Florian Lordick from the University of Leipzig Medical Center, Germany. “Unfortunately, we look back to an unlucky series of negative trials about HER2-targeted therapies in the past decade … We also saw negative data with the addition of pertuzumab to standard CT and trastuzumab.”
A long-term follow-up of the JACOB trial reveals that pertuzumab, when added to CT and trastuzumab, may have some effect. “However, it is not sufficiently effective to improve overall survival (OS) in a significant way,” said Lordick.
The PETRARCA team thus probed further into the potential benefit of adding pertuzumab to CT-trastuzumab in this setting. Eighty-one participants (median age 60 years, 79 percent male, cT3/T4 86 percent) were randomized 1:1 to receive four pre- and postoperative FLOT cycles, either alone (arm A) or in combination with trastuzumab 8/6 mg/kg and pertuzumab 840 mg Q3W, followed by nine cycles of trastuzumab/pertuzumab maintenance treatment (arm B). While most participants completed pre-operative treatment (93 percent and 90 percent in arms A and B, respectively), the trial closed prematurely and did not proceed to phase III. [ESMO 2020, abstract 1421MO]
The pCR rate was significantly improved in arm B vs A (35 percent vs 12 percent; p=0.02). “[This is,] in fact, the highest rate of pathologic response ever seen with systemic treatment,” said study co-author Dr Salah-Eddin Al-Batran from the University Cancer Center Frankfurt, Germany.
This translated to an improvement in disease-free survival (DFS) in arm B vs A (DFS; not reached vs 26 months; hazard ratio, 0.58; p=0.14) at a median follow-up of 22 months. “DFS was not reached yet in arm B, indicating improvement,” said Al-Batran. “[For arm A,] this is in line with the results of the pivotal FLOT 4 trial (DFS 30 months), taking into account the high rate of T4 tumours at the gastro-oesophageal region. [Therefore,] this can be considered a very good result in the control arm.”
Compared with arm A, arm B had higher rates of pathological lymph node negativity (68 percent vs 39 percent) and dose modification (70 percent vs 44 percent).
Postoperatively, arm B had fewer patients with T3/T4 than arm A (29 percent vs 41 percent [T3] and 0 percent vs 7 percent [T4]). “[This] indicates better downstaging [of the disease],” said Al-Batran.
Margin-free resection rates were similar in arms A and B (90 percent and 93 percent, respectively), as were surgical morbidity rates (43 percent and 44 percent, respectively).
Grade ≥3 adverse event rate was greater in arm B vs A (85 percent vs 75 percent), the most common being diarrhoea (41 percent vs 5 percent) and leukopenia (23 percent vs 13 percent). However, toxicities were manageable with dose modifications, noted Al-Batran.
Overall, the findings suggest that preliminary disease-free status with the arm B regimen is very promising, said Al-Batran. However, while the signals look “promising, the results are not yet ready for practice,” Lordick pointed out.
Also, the lack of study arm for CT and trastuzumab without pertuzumab might have been a drawback, added Lordick. “[Therefore,] we really do not know if [the effect] is due to the addition of trastuzumab or pertuzumab.” Nonetheless, this has been somehow counterbalanced by the EORTC – INNOVATION*** study, which has a population and study arms similar to PETRARCA, plus a third study arm comprising CT and trastuzumab only. [BMC Cancer 2019;19:494]