AACR 2021: Practice-Changing Trials Show Improved Survival in Non-Small Cell Lung Cancer and Non-Hodgkin Lymphoma

By Chase Doyle

A pair of phase 3 clinical trials presented during the AACR virtual annual meeting 2021 could be practice-changing for patients with relapsed/indolent non-Hodgkin lymphoma (NHL) and resectable non-small cell lung cancer (NSCLC) while a small prospective study exceeded historical results in metastatic castration-resistant prostate cancer (mCRPC).

Copanlisib-Rituximab Combo Halves Disease Progression or Death Risk in Indolent NHL

Findings from a phase 3 randomized trial could signal a new treatment option for patients with relapsed indolent NHL, including those unfit for chemotherapy (Abstract CT001)1. Results of the CHRONOS-3 study showed a 48% reduction in the risk of disease progression or death with the combination of copanlisib plus rituximab as compared with rituximab plus placebo. The centrally assessed overall response rate was also significantly higher in the treatment arm versus rituximab plus placebo (81% vs 48%).

“Copanlisib represents the first PI3K inhibitor to be safely combined with rituximab, and the first to demonstrate broad and superior efficacy in combination with rituximab across all indolent histologic subtypes,” said lead study author Matthew Matasar, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, NY.

Rituximab monotherapy is a widely recognized standard of care in the treatment of patients with relapsed indolent B-cell lymphoma who have had either a long remission after rituximab-based therapy or who are either unwilling or unfit to receive chemotherapy. According to Dr. Matasar, however, the clinical benefit of rituximab alone can be short-lived.

Copanlisib is a selective, potent, intravenously administered pan-class I PI3K inhibitor with selective activity against the alpha and delta isoforms and is approved as monotherapy for the treatment of relapsed follicular lymphoma in patients who have received two or more prior lines of therapy.

In the CHRONOS-3 trial, patients with CD20-positive indolent B-cell lymphoma, including low grade follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma and lymphoplasmacytic lymphoma, or Waldenstrom macroglobulinemia, were randomized to copanlisib plus rituximab (n=307) or rituximab plus placebo (n=151).

Patients were eligible if they were progression-free for more than 12 months post-rituximab or progression-free for more than 6 months post-rituximab if they were unwilling or unfit for chemotherapy. The primary endpoint of the study was progression-free survival (PFS) by central review.

Approximately 80% of patients enrolled in the study had gone more than 12 months from their last rituximab regimen, and the majority of patients had follicular lymphoma.

The study was strongly positive for improvements in PFS across histologies, said Dr. Matasar, with a 7.7-month improvement in PFS (hazard ratio [HR] = 0.52; P<0.0001). Response rates were also higher in the treatment arm as compared with rituximab alone (81% vs 48%).

According to Dr. Matasar, the combination regimen also demonstrated a manageable safety profile that is consistent with previous reported toxicities of both agents administered as monotherapies. The most common adverse events with copanlisib plus rituximab were hyperglycemia and hypertension. Pneumonitis occurred in 6.8% of patients, but only 2% of patients experienced grade 3 pneumonitis, and less than 1% of patients had grade 4 pneumonitis.

Session moderator, Charles Swanton, MBBS, PhD, FRCP, Royal Society Napier Professor at the Francis Crick Institute and University College London Hospitals, noted that the combination of copanlisib and rituximab represents a new treatment option for patients with relapsed, indolent NHL who experience a long remission after first-line therapy or who are unfit for chemotherapy, but he also underscored the toxicities associated with the addition of a pan-class I PI3K inhibitor to rituximab.

“Grade 3 and grade 4 toxicities were more common with the combination therapy, with treatment-emergent adverse events in the form of hypertension and hyperglycemia, as would be expected with a pan-class I PI3K inhibitor,” said Dr. Swanton.

Neoadjuvant Immunotherapy Promising Treatment Option for Early-Stage Lung Cancer

For patients with early-stage, resectable NSCLC, the combination of nivolumab plus chemotherapy could represent a promising neoadjuvant treatment option.

Results of the phase 3 CheckMate-816 trial showed that the addition of the immune checkpoint inhibitor nivolumab to chemotherapy significantly improved pathological complete response (pCR) from 2.2% with chemotherapy alone to 24.0% in the nivolumab plus chemotherapy arm (Abstract CT003)2.

This benefit was also consistent across disease stages, histology, tumor mutational burden (TMB), and PD-L1 expression levels, authors of the study reported.

Importantly, the combination regimen maintained a tolerable safety profile and did not impede the feasibility of surgery, said lead study author, Patrick M. Forde, MBBCh, Associate Professor of Oncology at Sidney Kimmel Cancer Center and Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University, Baltimore, MD.

“Exploratory subset analysis also showed that circulating tumor DNA clearance was more frequent with nivolumab plus chemotherapy compared with chemotherapy alone, and this appeared to be associated with pCR,” Dr. Forde added.

Dr. Forde noted that neoadjuvant or adjuvant chemotherapy is recommended for patients with resectable NSCLC, but the 5-year overall survival (OS) gain is only 5%. Although several studies have suggested an association between pCR and survival in NSCLC, with an HR of 0.49, said Dr. Forde, resectable NSCLC treated with neoadjuvant chemotherapy alone shows low rates of pCR historically in published studies, with a median of 4% and a range of 0% to 16%.

Recent single-arm phase two studies with immunotherapy, either as a single agent or in combination, however, have shown encouraging outcomes in the neoadjuvant setting.

In CheckMate-816, adults with stage 1B to 3A resectable NSCLC and no sensitizing EGFR mutations or ALK alterations were randomized to either neoadjuvant chemotherapy plus nivolumab (n=179) or neoadjuvant chemotherapy alone (n=179), followed by surgery. The primary endpoints were pCR (defined as 0% residual viable tumor cells in both the primary and sample lymph nodes) and event-free survival by Blinded Independent Review.

With neoadjuvant chemotherapy alone, the pCR was only 2.2%, Dr. Forde reported. With the addition of nivolumab to chemotherapy, however, pCR improved to 24%, and this was highly statistically significant (P=.0001).

Among patients who underwent resection, pCR increased from 3.2% on chemotherapy alone to 30.5%. Results showed no difference by stage, histology, PD-L1, or tumor mutational burden.

Of note, patients who received nivolumab plus chemotherapy were more likely to clear circulating tumor (ct) DNA between the first and third cycle of neoadjuvant therapy, and patients who had ctDNA clearance were more likely to have a pCR at the time of surgery, said Dr. Forde.

Treatment-related adverse events were consistent with the known effects of the drugs evaluated.

Session moderator, Dr. Swanton, noted that the addition of nivolumab to chemotherapy did not impact the ability of patients to reach definitive surgery, which he called an “important endpoint for patients in neoadjuvant studies.”

In the nivolumab-chemotherapy arm, 83% of patients went on to receive definitive surgery, compared with 75% of patients in the chemotherapy arm.

“The CheckMate 816 clinical trial is the first phase 3 trial to show a benefit of neoadjuvant immunotherapy and chemotherapy for resectable NSCLC,” Dr. Swanton concluded.

Dual Checkpoint Inhibitors Show Anti-Tumor Activity in Prostate Cancer

Dual checkpoint inhibition with nivolumab and ipilimumab has demonstrated anti-tumor activity in patients with mCRPC .

Initial findings of the ongoing phase 2 NEPTUNES trial showed a complete response rate of 28.6% with combination immunotherapy (Abstract LB004).3 Although numerically higher than other checkpoint inhibitor studies in prostate cancer, the activity fell short of the 40% threshold for a positive outcome.

Of note, authors of the study reported that nivolumab plus ipilimumab demonstrated significant activity in biomarker selected, pretreated patients with metastatic castrate-resistant disease, a finding which could lead to improved patient selection in future trials.

“Responders were enriched with patients with defective mismatch repair or BRCA 1 and 2 alterations,” said lead study author Mark Linch, MD, PhD, of University College London. “We believe that further study of nivolumab and ipilimumab in biomarker-selected patients with metastatic castration-resistant prostate cancer is warranted.”

According to Dr. Linch, single-agent checkpoint inhibition has shown limited activity in mCRPC, but the combination of anti-CTLA-4 and anti-PD-1 immunotherapy demonstrated a signal of activity in previous studies.

In the Checkmate-650 study, for example, patients receiving the combination of nivolumab and ipilimumab post-docetaxel had a response rate of 10%, but prior to docetaxel the combination yielded a response rate of 25%4. In addition, approximately 20% of this patient population has been found to have high levels of T-cell infiltration in the primary tumor.

“We hypothesized that men with defective DNA mismatch repair or high inflammatory infiltrates will be more likely to respond to nivolumab and ipilimumab, and we call this the immunogenic signature,” said Dr. Linch.

For the phase 2 NEPTUNES trial, patients who were receiving androgen deprivation therapy, had archival cancer tissue or disease amenable to biopsy, and had received at least one prior line of systemic therapy for metastatic prostate cancer were eligible. The study’s primary endpoint was a composite response rate comprising radiologic response, PSA response (at least 50% reduction), and conversion of circulating tumor cells at 9 weeks. A response rate of at least 40% was considered a favorable outcome, while a response rate of 20% or fewer was considered unfavorable.

“This was a highly pretreated population,” said Dr. Linch, who reported that 50% of the cohort had received at least 3 prior lines of therapy, 50% had received radiotherapy for primary disease control, and only 11% of patients had not received docetaxel.

Initial results of the study showed a composite response rate of 28.6%, with 10 out of 25 patients responding.

“Although this did not achieve the 12 responses that we were hoping for, it’s certainly higher than previously seen for combination checkpoint inhibitors in prostate cancer,” said Dr. Linch, who noted that with a median follow-up of 7.2 months, most responses were ongoing at data censoring.

In addition to the 10 patients who achieved the composite response, 8 patients had a PSA response, and 4 had a radiologic response. Median OS was approximately 18 months and median PFS was nearly 5 months.

Although consistent with previously reported toxicities, Dr. Linch also noted that 57% of patients experienced a serious treatment-related adverse event.

“The rate of incomplete treatment was high, suggesting that alternate dosing schedules may be required,” said Dr. Linch.

A second cohort that began enrollment in September of 2020 is evaluating a lower dose of the combination regimen, and translational biomarker analysis is ongoing.


CHRONOS-3 was sponsored by Bayer AG. Dr. Matasar reported relationships with Bayer AG, Roche/Genentech, GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacyclics, Juno, Merck, Rocket Medical, Seattle Genetics, Takeda, and Teva.

CheckMate 816 was supported by Bristol Myers Squibb (BMS). Dr. Forde disclosed relevant relationships with Amgen, AstraZeneca, BMS, Daiichi Sankyo, Janssen, Novartis, and Kyowa.

The ongoing phase 2 NEPTUNES trial is supported by Bristol Myers Squibb (BMS). Dr. Linch disclosed relevant relationships with Astellas, AstraZeneca, BioNTech, Pfizer, Merck, BMS, Shionogi, and GlaxoSmithKline.


  1. Matasar MJ, et al. CHRONOS-3: Randomized phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma (iNHL). AACR 2021; Abstract CT001.
  2. Forde PM, et al. Nivolumab + platinum-doublet chemotherapy vs chemotherapy as neoadjuvant treatment for resectable (Ib-IIIa) non-small cell lung cancer in the phase III CheckMate 816 trial. AACR 2021; Abstract CT003.
  3. Linch M, et al. Nivolumab and ipilimumab treatment in prostate cancer with an immunogenic signature: Cohort 1 of the NEPTUNES multicenter, two-stage biomarker-selected phase II trial. AACR 2021; Abstract LB004.
  4. Sharma P, Pachynski RK, Narayan V, et al. Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial. Cancer Cell. 2020;38(4):489-499.e3.
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