High pathological responses in borderline resectable NSCLC patients after induction with dual immunotherapy and concurrent chemoradiotherapy

In a selected population comprising borderline operable high T- and low N-stage non-small cell lung cancer (NSCLC), neoadjuvant nivolumab/ipilimumab plus chemoradiotherapy (CRT) resulted in high pathological responses in the phase 2 INCREASE trial. Patients with high pathological responses showed increased tumour-specific cytotoxic T cells in the blood and tumour-draining lymph nodes.

A subgroup of non-metastatic high T- and low N-stage NSCLC patients are borderline resectable and may become resectable after induction with CRT. CRT using platinum-doublet is recommended [1]. Neoadjuvant chemotherapy combined with immunotherapy in resectable NSCLC has demonstrated an improved pathological complete response rate (pCR) [2]. The current INCREASE trial (EudraCT 2019–003454-83) evaluated the efficacy of pre-operative CRT combined with dual immunotherapy (nivolumab/ipilimumab) on the pCR and immunological responses in patients with borderline resectable non-metastatic NSCLC. Dr Idris Bahce (Amsterdam UMC, the Netherlands) presented the first results [3].

The single-arm, prospective, phase 2 INCREASE trial enrolled 30 patients with resectable and borderline resectable, T3–4/N0–2 NSCLC. At the time of data cut-off, 26 participants had completed neoadjuvant treatment and 24 had undergone surgery. On day 1, platinum-doublet concurrent CRT, ipilimumab (1 mg/kg) and nivolumab (360 mg flat dose) were administered, followed by nivolumab (360 mg flat dose) after 3 weeks. Radiotherapy consisted of 50-60 Gy in once-daily doses of 2 Gy, followed by a resection 6 weeks after the last dose of radiation. The primary endpoint was the pCR (a pre-specified pCR threshold of 60% was tested against the historical rate of 30% with CRT alone). Co-primary endpoints were safety and major pathological response (MPR), i.e. ≤10% residual viable tumour cells.

Of all operated participants, 15 (63%) reached a pCR (P<0.001 against historical rate) and 19 (79%) reached an MPR (see Figure). The radiological objective response rate in the resected patients was 12.3%, indicating that the radiological response rate underestimates the pathological response. In patients with a pCR, the number of tumour-specific cytotoxic T cells (CD39⁺/CD8⁺) in peripheral blood and tumour-draining lymph nodes were more increased after neoadjuvant therapy than in non- and partial responders. The toxicity rates were acceptable.

Based on these results, Dr Bahce concluded that “in a selected population comprising borderline operable high T- and low N-stage NSCLC, neoadjuvant nivolumab/ipilimumab plus CRTis safe, provides deep pathological responses and enhances T cell activation. This data supports the use of such strategies in patients presenting with an inoperable NSCLC.”

1. Eberhardt WEE, et al. Ann Oncol. 2015;26(8):1573–1588.
2. Forde PM, et al. N Engl J Med. 2022;386(21):1973–1985.
3. Bahce I, et al. Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable lung cancer: The INCREASE trial. Abstract 950O. ESMO Congress 2022, 09–13 September, Paris, France.

Figure: Tumour regression per participant, including their identified key genomic alterations, histology, smoking-, and PD-L1 status [3].



Black bars represent full tumour regression (pCR, n=15 participants), blue illustrates partial regression (MPR, n=4 additional participants)

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Posted on 16 November 202227 March 2024