Perioperative and Neoadjuvant Immunotherapy in Early Stage Lung Cancer

Clinical studies have demonstrated that the administration of chemotherapy combined with immunotherapy prior to surgery as the initial treatment of early-stage non-small cell lung cancer (NSCLC) may be the most effective treatment for most patients without a cancer causing targetable mutation. Neoadjuvant therapy is treatment that is delivered before surgery with the goal of providing immediate treatment and reducing the size of the cancer for more complete resection. Most recently additional clinical studies suggest that “perioperative” chemoimmunotherapy which combines post surgery immunotherapy with neoadjuvant chemoimmuntherapy produces even better results. 

For the past decade the standard treatment of early stage NSCLC consisted of surgical removal of the cancer followed by adjuvant chemotherapy to reduce the risk of cancer recurrence² based on the results of a Canadian clinical study that demonstrated adjuvant chemotherapy increased the number of patients who lived 5 years or more from 54% to 69% and a US study showing adjuvant chemotherapy increased the number of patients who survived 3 years or more from 69% to 82%. 

More recently researchers have learned that immunotherapy with or without chemotherapy is superior to treatment with chemotherapy alone in NSCLC, and chemo-immunotherapy administered before surgery improves outcomes for patients with early stage disease.

Checkpoint inhibitors are a type of precision cancer immunotherapy and they have changed the treatment of NSCLC – they help to restore the body’s immune system to fight the cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain immune responses, allowing cancer cells to evade detection and destruction by immune effector cells in the body. Checkpoint inhibitors block the PD-1 and PD-L1 pathway and therefore restore and enhance the ability of the bodies immune system to fight the cancer. Results from clinical studies evaluating the checkpoint inhibitors Imfinzi, Opdivo, Keytrua, and Tecentriq have demonstrated they are superior to chemotherapy alone and have become a standard treatment of early stage NSCLC’s that do not have cancer growth driving mutations.^2-5  A diagnostic test to measure the level of PD-L1 is available. 

Neoadjuvant Therapy

Administering systemic treatment before surgery may be beneficial because it can reach the cancer before surgery has disrupted its blood supply and potentially shrink the cancer for easier surgical removal. Systemic treatment before surgery is referred to as neoadjuvant therapy.

The United States Food and Drug Administration has approved neoadjuvant Opdivo immunotherapy combined with platinum-doublet chemotherapy for the treatment of early-stage NSCLC in patients with resectable, stage IB, II, or IIIA NSCLC. Patients were enrolled regardless of the tumors PD-L1 status.

In the pivotal trial leading to FDA approval a total of 358 patients were treated with either Opdivo plus platinum-doublet chemotherapy administered every 3 weeks for up to 3 cycles, or platinum-chemotherapy alone administered on the same schedule. Opdivo neoadjuvant treated patients survived 33 months without cancer recurrence on average compared to 21 months for those receiving chemotherapy alone. 

Imfinzi immunotherapy administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by single-agent Imfinzi as adjuvant treatment after surgery for adults with surgically resectable NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements is also approved. The AEGEAN clinical trial in 802 patients with previously untreated and resectable squamous or non-squamous Stage IIA to IIIB NSCLC demonstrated that patients treated with Imfinizi before surgery also experienced delayed cancer progression and were significantly more likely to have no evidence of cancer at the time of surgery. 

Neoadjuvant treatment with another checkpoint inhibitor, Tecentriq was evaluated in the phase II Lung Cancer Mutation Consortium 3 (LCMC3) clinical study and resulted in a 20% major pathological response rate in patients with previously untreated, resectable, stage IB–III NSCLC. In the study, 181 patients without EGFR or ALK alterations received two doses of neoadjuvant Tecentriq. Overall 20% of patients experience near total eradication of their cancer and 6% experience complete eradication when evaluated at surgery. With a minimum duration of follow-up of 3 years, the 3-year survival rate is 80%.

Taken together the studies suggest that the use of neoadjuvant immunotherapy can be safely administered prior to surgery for early stage NSCLC and that significant eradication of cancer is possible.

Is Perioperative Neoadjuvant  – Adjuvant therapy better?

Although adjuvant and neoadjuvant chemo-immunotherapy are acceptable treatment options for early-stage NSCLC the most recent clinical trial results suggest that combing adjuvant and neoadjuvant therapy may be even better.^8-11

Perioperative treatment with the checkpoint inhibitor Imfinzi (durvalomab) improves pathological complete response (pCR) rates and prolongs cancer free survival in patients with stage IB to III NSCLC, according to findings from the phase 3 AEGEAN clinical trial.

The AEGEAN clinical trial directly compared a treatment strategy of neoadjuvant Imfinzi + platinum-based chemotherapy and post-surgical Imfinzi maintenance to treatment with neoadjuvant chemotherapy alone in 802 patients. The initial trial results were released at the September 2023 World Lung Meetings.⁹

• Imfiniz improved the pCR rate from 4.3% to 17.2% leading to a modest improvement in R0 resection rates.
• The 12 and 24-month cancer free survival rates were both in favor of the perioperative approach.

Neoadjuvant treatment with Opdivo plus chemotherapy followed by surgery and adjuvant Opdivo also improves the duration of cancer free survival when used as initial treatment for early-stage stage II to IIIB NSCLC according to data from the phase 3 CheckMate 77T clinical trial released at the October 2023, ESMO Congress.^10,11

In the trial 461 patients with stage IIA to IIIB previously untreated NSCLC, and no EGFR or known ALK alterations were treated with

• Odivo plus chemotherapy followed by surgery within 6 weeks followed by Opdivo administered 4 weeks for OR
• Chemotherapy alone followed by surgery within 6 weeks and no additional post surgery treatment.

Neoadjuvant Opdivo produced a complete disappearance of cancer (pathologic complete remission pCR) assessed at the time of surgery in 25% of patients compared to only 5% of chemotherapy treated patients. After a median follow-up of 25 months patients treated with perioperative Opdivo demonstrated a clinically meaningful improvement in their survival duration without cancer recurrence. Stage III patients treated with Opdivo survived 30.2 months on average without cancer recurrence compared to only 13.4 months if treated with chemotherapy alone. Similar results were reported for stage II disease but longer follow up is required. For all patients the 18-month cancer free survival rates were improved from 50% to 70% with the addition of perioperative Opdivo. 

In October 2023 the US FDA also approved neoadjuvant keytruda combined with platinum-containing chemotherapy with continuation of adjuvant keytruda after surgery based on clinical trial results demonstrating that combined therapy appears to further reduce the risk of cancer progression. The overall survival benefit from this approach is still premature but perioperative neoadjuvant chemo-immunotherapy followed by surgery and adjuvant immunotherapy may be the new standard treatment option for patients with resectable NSCLC.

It’s never been more important for individuals suspected of having lung cancer to undergo molecular testing before surgical treatment of their cancer. Molecular testing identifies which patients can avoid chemotherapy and its side effects altogether, who will benefit from treatment with a precision cancer medicine and allows the collection of ctDNA that can be used for long term surveillance to detect early recurrences and avoid unnecessary treatment. Despite guidelines recommending testing, many patients with NSCLC who are treated in the community setting are still not undergoing NGS-biomarker testing before treatment. 

• Keep Current with Advances in Lung Cancer Treatment Here.
• The Importance of NGS-Biomarker Testing in NSCLC

Connect With Others for Support and information

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References:

1. Kwiatkowski DJ, Rusch VW, Chaft JE, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3). Presented at: the 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 8503.
2. The International Adjuvant Lung Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected Non-Small Cell Lung Cancer. New England Journal of Medicine. 2004;350:351-360.
3. N Engl J Med. 2018;378:1976
4. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3).
5. Gadgeel SM, Stevenson J, Langer C, et al. Pembrolizumab (pembro) plus chemotherapy as front-line therapy for advanced NSCLC: KEYNOTE-021 cohorts A-C. J Clin Oncol 34, 2016 (suppl; abstr 9016).
6. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/nejmoa2202170.
7. Chaft JE, Oezkan F, Kris MG, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial. Nature Medicine; Published online 12 September 2022. DOI: https://doi.org/10.1038/s41591-022-01962-5
8. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer#:~:text=On%20October%2016%2C%202023%2C%20the,non%2Dsmall%20cell%20lung%20cancer
9. Mitsudomi T, Heymach JV, Reck et al. Surgical outcomes with neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in resectable NSCLC (AEGEAN). Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract OA12.05.

10. Cascone T, Awad MM, Spicer J, et al. CheckMate 77T: Phase 3 study comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab or placebo for previously untreated, resectable stage II–IIIB NSCLC. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA1.

11. ESMO Press Release. Lung Cancer Treatment Research Enters a New Era. Published: October 17, 2023. Accessed: October 21, 2023. https://bit.ly/45VY14Z.